Combination Therapy for the Treatment of Lung Cancer

Abstract

The present invention relates to a method for treating small cell lung cancer (SCLC), particularly in a subject in need thereof, comprising administering to a subject a SSTR binding moiety, particularly 177 A therapeutically effective amount of a radiopharmaceutical compound comprising]Lu-DOTATE is administered to the subject in combination with one or more chemotherapeutic agents, such as carboplatin and etoposide, and optionally an immuno-oncology (I / O) agent, such as tislelizumab.

Description

[Technical field]

[0001] The present invention relates to a method for treating small cell lung cancer (SCLC) in a subject in need thereof, wherein a therapeutically effective amount of a radiopharmaceutical compound comprising an SSTR binding moiety is administered to said subject in combination with a chemotherapeutic agent and, optionally, an immuno-oncology (I / O) agent.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format, the entire contents of which are incorporated herein by reference. The XML copy created on November 7, 2022 is named PAT059204_SL.xml. [Background technology]

[0003] Lung cancer is the most common cause of cancer deaths worldwide, killing 1.8 million people in 2020 (WHO Cancer fact sheet 2021), while lung cancer diagnoses and deaths continue to increase year by year (Bade BC, Dela Cruz CS Lung Cancer 2020: Clin Chest Med; 41: 1-24). Small cell lung cancer (SCLC) is the most lethal and aggressive subtype of lung cancer, accounting for approximately 10-15% of all lung cancers. Patients with limited-stage SCLC (LS-SCLC) have an estimated median survival of 18-23 months, whereas patients with extensive-stage SCLC (ES-SCLC) have an estimated median survival of 8-10 months (Dela Cruz CS, Tanoue LT, Matthay RA (2011) Clin Chest Med; 32: 605-44, Dayen C, Debieuvre D, Molinier O, et al (2017) New insights into stage and prognosis in small cell lung cancer: an analysis of 968 cases. J Thorac Dis; 9 (12): 5101-11).

[0004] Somatostatin receptors (SSTRs) were identified by immunohistochemistry and 68It is expressed in 30-50% of patients with SCLC as evidenced by [Ga]Ga-DOTA-TATE PET / CT scans (Lapa C, Haenscheid H, Wild V, et al (2016) Oncotarget; 7(15): 20033-40, Lehman JM, Hoeksema MD, Staub J, et al (2019) Int J Cancer; 144: 1104-14). It has been shown that somatostatin receptor 2 signaling promotes SCLC proliferation and survival, and high expression of SSTR-2 correlates with worse patient survival (Lehman JM, Hoeksema MD, Staub J, et al (2019) Int J Cancer; 144: 1104-14).

[0005] SCLC is known to be a radiosensitive tumor suitable for external thoracic radiotherapy, which is primarily used as concurrent chemoradiotherapy in patients with LS-SCLC. In ES-SCLC, radiotherapy may be used for symptom control.

[0006] The current standard first-line treatment for patients with ES-SCLC is platinum-based systemic chemotherapy (cisplatin or carboplatin with the topoisomerase II inhibitor etoposide) combined with an immune checkpoint inhibitor (atezolizumab or durvalumab) (NCCN Guidelines Small Cell Lung Cancer Version 3.2021; Dingemans AMC, Fruh M, Ardizzoni A, et al (2021) 32 (7): 839-53).

[0007] In clinical practice, immune checkpoint inhibitors have been shown to 177The hypothesis that it would act synergistically in combination with [Lu]Lu-DOTA-TATE was evaluated in a phase I study in nine patients with either progressive refractory ES-SCLC, or non-progressive ES-SCLC after first-line platinum-based chemotherapy, or progressive grade I-II pulmonary NETs (Kim C, Liu SV, Subramaniam DS, et al (2020) J Immunother Cancer; 8: e000980).

[0008] Similar to the synergistic effect of PRRT and I / O combinations for certain cancers (also reported in WO 2016 / 207732 and WO 2020021465), the combination of PRRT and carboplatin / etoposide has been evaluated and demonstrated significant survival benefits versus PRRT or chemotherapy alone in the preclinical setting (Lewin J, Cullinane C, Akhurst T, et al (2015) Eur J Nucl Med Mol Imaging; 42: 25-32). These preclinical findings were translated to clinical use in patients with metastatic recurrent small cell carcinoma of extrapulmonary origin with high SSTR2 expression who received etoposide (carboplatin was avoided due to renal function) in combination with PRRT. The patient experienced a complete metabolic response and clinical improvement over a period of 4 months. The treatment was well tolerated, except for mild fatigue, nausea, grade 2 anemia, and grade 3 thrombocytopenia. The patient experienced disease progression 4.5 months after starting treatment (Lewin J, Cullinane C, Akhurst T, et al (2015) Eur J Nucl Med Mol Imaging; 42: 25-32). Summary of the Invention

[0009] Thus, despite some advances, there are still limited therapeutic options for the treatment of SCLC, especially ES-SCLC, and the overall prognosis of patients with ES-SCLC remains very poor.

[0010] The present disclosure relates in particular to the use of SSTR peptide targeted nuclide therapy (e.g., 177 The present invention provides a novel therapeutic option for treating SCLC, particularly ES-SCLC, based on the combination of Lu-DOTA-TATE with chemotheray (e.g., carboplatin and etoposide) and immune checkpoint inhibitors (e.g., tislelizumab). [Brief description of the drawings]

[0011] [Figure 1] Clinical trial design. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Specific embodiments 1. A radiopharmaceutical compound for use in treating small cell lung cancer (SCLC), in particular expanded stage small cell lung cancer (ES-SCLC), in a human subject in need thereof, wherein a therapeutically effective amount of a radiopharmaceutical compound comprising a somatostatin receptor binding molecule is administered to said subject in combination, preferably simultaneously, with a therapeutically effective amount of one or more chemotherapeutic agents.

[0013] 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 attached to C, either directly or indirectly via S. The radiopharmaceutical compound for use according to embodiment 1, which is a compound of

[0014] 3. In the formula, M is 90 Y, 131 I, 121 Sn, 186 Re, 188Re, 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 a radiopharmaceutical compound as described in embodiment 2, wherein the compound is Lu.

[0015] 4. A radiopharmaceutical compound for use according to embodiment 2 or 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.

[0016] 5. A radiopharmaceutical compound for use according to any one of embodiments 1 to 4, wherein P is selected from octreotide, octreotate, satreotide, lanreotide, vapreotide, and pasireotide, preferably selected from octreotide and octreotate.

[0017] 6. A radiopharmaceutical compound for use according to any one of embodiments 1 to 5, 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.

[0018] 7. Radiopharmaceutical compounds are 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 according to any one of embodiments 1 to 6, wherein the radiopharmaceutical compound is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,

[0019] 8. A radiopharmaceutical compound for use according to any one of embodiments 1 to 7, wherein said subject has not previously received a systematic treatment for SCLC, in particular ES-SCLC, in particular wherein said subject has not previously received chemotherapy for treating SCLC, in particular ES-SCLC.

[0020] 9. The radiopharmaceutical compound for use according to any one of embodiments 1 to 8, wherein said subject is newly diagnosed with SCLC, in particular ES-SCLC.

[0021] 10. The subject is the same organic compound used in radiopharmaceutical treatment, but with a radioactive metal suitable for imaging, preferably68 Ga, 67 Ga or 64 Cu, more preferably 68 A radiopharmaceutical compound according to any one of embodiments 1 to 9, which is selected for treatment with SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging with Ga.

[0022] 11. The subject is preferably diagnosed with a positron emission tomography (PET) scan of at least one target or non-target lesion. 68 The radiopharmaceutical compound for use according to any one of embodiments 1 to 10, wherein the patient has been diagnosed as SSTR positive by a Ga]Ga-DOTA-TATE imaging PET scan.

[0023] 12. The one or more chemotherapeutic agents are carboplatin (preferably carboplatin AUC5 on day 1 of every 3-week cycle) and etoposide (preferably 100 mg / m on days 1, 2, and 3 of every 3-week cycle). 2 12. The radiopharmaceutical compound for use according to any one of embodiments 1 to 11, comprising administering in a daily dose of

[0024] 13. A radiopharmaceutical compound for use according to any one of embodiments 1 to 12, wherein the radiopharmaceutical compound is administered 1 to 8 times, preferably 2 to 7 times, for example 4 to 6 times, with a treatment interval every two administrations of the radiopharmaceutical compound.

[0025] 14. A radiopharmaceutical compound for use according to any one of embodiments 1 to 13, wherein each administration of said radiopharmaceutical compound comprises a treatment interval of 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks, or even up to 6 weeks, preferably 3 weeks and / or 6 weeks.

[0026] 15. The radiopharmaceutical compound for use according to any one of embodiments 1-14, wherein said one or more chemotherapeutic agents are administered in combination, preferably simultaneously, with two administrations of said radiopharmaceutical compound during the run-in period, preferably a first administration of said radiopharmaceutical compound in the first week of a first administration of chemotherapeutic agent, for example on any of days 3, 4 or 5 of week 1, and a second administration of said radiopharmaceutical compound between weeks 6 and 8, preferably in week 7.

[0027] 16. A radiopharmaceutical compound for use according to embodiment 15, further comprising a maintenance period following the induction period, comprising 1 to 4 administrations of said radiopharmaceutical compound, preferably every 3 weeks.

[0028] 17. A radiopharmaceutical compound for use according to any one of embodiments 1 to 16, comprising the step of administering in combination, preferably simultaneously, one or two therapeutically effective amounts of immuno-oncology (IO) therapeutic agents, preferably selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, or CTLA4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, TIGIT inhibitors, GITR antagonists, TGF-b inhibitors, IL15 / IL15RA complex, CD40 / CD40L complex, OX40 inhibitors, 4-1BB / CD137 complex, ICOS inhibitors, CD47 inhibitors, VISTA inhibitors, GD-2 inhibitors, and B7 / H3 inhibitors, cytokines (e.g., interferons, interlukins), cellular immunotherapy, and cancer vaccines, more preferably PD-1 inhibitors, PD-L1 inhibitors, or CTLA4 inhibitors or combinations thereof. In some embodiments, the inhibitor used herein is an antibody.

[0029] 18. (i) said one or more chemotherapeutic agents are administered during the run-in period, preferably in combination with, and preferably simultaneously with, two administrations of said radiopharmaceutical compound, a first administration of said radiopharmaceutical compound in the first week of the first administration of chemotherapeutic agent, e.g. on any of days 3, 4 or 5 of week 1, and a second administration of said radiopharmaceutical compound between weeks 6 and 8, preferably in week 7; (ii) the tumor immunotherapy agent is administered, preferably in combination with the chemotherapy agent, preferably simultaneously, in the first week, preferably on the day of the first administration of the chemotherapy agent, and every three weeks during the induction period; A radiopharmaceutical compound for use according to embodiment 17.

[0030] 19. Following the implementation period, (i) 1 to 4 administrations of said radiopharmaceutical compound every 3 weeks; and (ii) 1 to 4 administrations of the tumor immunosuppressant every 3 weeks. The radiopharmaceutical compound for use according to embodiment 18, further comprising a maintenance period comprising:

[0031] 20. The PD-1, PD-L1 or CTLA-4 inhibitor is, for example, nivolumab (Bristol-Myers Squibb), ipilimumab, PDR001 / spartalizumab (Novartis), Keytruda / pembrolizumab / MK-3475 / lambrolizumab (Merk & Co), pidilizumab, durvalumab / MEDI4736, atezolizumab / MPDL3280A / Tecentriq / RG7446 (Roche), avelumab, MEDI0680 (AMP-514, Medimmune), REGN2810 / cemiplimab (Regeneron), TSR-042 / dostarlimab / dostarlimab-gxly (Tesaro), PF-06801591 / A radiopharmaceutical compound for use according to any one of embodiments 17-19, selected from the group consisting of an anti-PD1, anti-PD-L1 or anti-CTLA-4 antibody selected from the group consisting of sananlimab (Pfizer), BGB-A317 / tislelizumab (Beigene), BGB-108, INCSHR1210 / camrelizumab (Incyte), and AMP-224 (Amplimmune).

[0032] 21. A radiopharmaceutical compound for use according to embodiment 20, wherein said PD-1, PD-L1 or CTLA-4 inhibitor is tislelizumab and is administered at a dose of preferably about 200 mg to about 500 mg, more preferably about 200 mg to about 400 mg, even more preferably either about 200 mg to about 300 mg, even more preferably either about 200 mg or about 300 mg, even more preferably 200 mg.

[0033] 22. The subject has not previously received systematic treatment for SCLC, particularly ES-SCLC, and in particular the subject has not previously received chemotherapy for treating SCLC, particularly ES-SCLC, and the radiopharmaceutical compound is 177 Lu]Lu-DOTA-TATE, said one or more chemotherapeutic agents being carboplatin and etoposide, said use further comprising administering a therapeutically effective amount of tislelizumab to 17722. A radiopharmaceutical compound for use according to any one of embodiments 1 to 21, further comprising the step of administering in combination, preferably simultaneously, with administration of]Lu-DOTA-TATE.

[0034] 23. (i) The carboplatin and etoposide are administered during the induction period, preferably in the first week after the first administration of carboplatin and / or etoposide, for example on any of the 3rd, 4th or 5th days of the first week. 177 The first administration of [LU]Lu-DOTA-TATE and the second administration of [LU]Lu-DOTA-TATE between weeks 6 and 8, preferably week 7. 177 LU] of the second dose of Lu-DOTA-TATE [ 177 in combination with two doses of LU]Lu-DOTA-TATE, preferably administered simultaneously; (ii) A radiopharmaceutical compound for use according to embodiment 22, wherein tislelizumab is administered in combination with carboplatin and etoposide, preferably simultaneously, in week 1, preferably on the day of the first administration of carboplatin, and every 3 weeks during the run-in period.

[0035] 24. The use follows a lead-in period, (i) Every 3 weeks 177 1 to 4 doses of]Lu-DOTA-TATE, and (ii) 1 to 4 doses of tislelizumab every 3 weeks 24. The radiopharmaceutical compound for use according to embodiment 23, further comprising a maintenance period comprising:

[0036] 25. A radiopharmaceutical compound for use according to any one of the preceding embodiments, wherein said radiopharmaceutical compound is administered in a dose (i.e. daily dose, dose for each administration, non-cumulative dose) ranging between 0.925 GBq (25 mCi) and 29.6 GBq (800 mCi), preferably between 1.48 GBq (40 mCi) and 18.5 GBq (500 mCi), preferably between 1.85 GBq (50 mCi) and 14.8 GBq (400 mCi), more preferably between 3.7 GBq (100 mCi) and 11.1 GBq (300 mCi), and 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).

[0037] 26. A method for treating small cell lung cancer (SCLC), in particular expanded stage small cell lung cancer (ES-SCLC), in a human subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of a radiopharmaceutical compound comprising a somatostatin receptor binding molecule in combination, preferably simultaneously, with a therapeutically effective amount of one or more chemotherapeutic agents.

[0038] 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 attached to C, either directly or indirectly via S. 27. The method of embodiment 26, wherein the compound is

[0039] 28. In the formula, M is 90 Y, 131 I, 121 Sn, 186 Re, 188 Re, 64 Cu, 67 Cu, 59 Fe, 89 Sr, 198 Au, 203Hg, 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 27, wherein Lu is

[0040] 29. The method of embodiment 27 or 28, 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.

[0041] 30. The method of any one of embodiments 26-29, wherein P is selected from octreotide, octreotate, satreotide, lanreotide, vapreotide, and pasireotide, preferably selected from octreotide and octreotate.

[0042] 31. The method of any one of embodiments 26 to 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 selected from DOTA-TOC and DOTA-TATE, more preferably DOTA-TATE.

[0043] 32. 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 method of any one of embodiments 26-31, wherein the agonist is acetylcholinesterase (Ala-Tyr ...

[0044] 33. The method of any one of embodiments 26 to 32, wherein the subject has not previously received systematic treatment for SCLC, particularly ES-SCLC, and in particular the subject has not previously received chemotherapy for treating SCLC, particularly ES-SCLC.

[0045] 34. The method of any one of embodiments 26-33, wherein the subject has been newly diagnosed with SCLC, in particular ES-SCLC.

[0046] 35. The subject is an organic compound similar to that used in radiopharmaceutical treatment, but containing a radioactive metal suitable for imaging, preferably 68 Ga, 67 Ga or 64 Cu, more preferably 68 The method of any one of embodiments 26 to 34, wherein the patient is selected for treatment by SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging with Ga.

[0047] 36. The subject is preferably diagnosed with a positron emission tomography (PET) scan of at least one target or non-target lesion. 68 The method of any one of embodiments 26-35, wherein the patient has been diagnosed as SSTR positive by a Ga]Ga-DOTA-TATE imaging PET scan.

[0048] 37. The method of any one of embodiments 26-36, wherein said one or more chemotherapeutic agents comprises carboplatin and etoposide.

[0049] 38. The method of any one of embodiments 26-37, wherein the radiopharmaceutical compound is administered 1 to 8 times, preferably 2 to 7 times, for example 4 to 6 times, and there is a treatment interval between every two administrations of the radiopharmaceutical compound.

[0050] 39. The method of any one of embodiments 26-38, wherein each 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 weeks and / or 6 weeks.

[0051] 40. The method of any one of embodiments 26-39, wherein said one or more chemotherapeutic agents are administered during the induction period, preferably in combination with, and preferably simultaneously with, two administrations of said radiopharmaceutical compound, with a first administration of said radiopharmaceutical compound in week 1 of the first administration of chemotherapeutic agent, e.g., on any of days 3, 4 or 5 of week 1, and a second administration of said radiopharmaceutical compound between weeks 6 and 8, preferably in week 7.

[0052] 41. The method of embodiment 40, further comprising a maintenance period following the induction period, comprising 1 to 4 administrations of said radiopharmaceutical compound, preferably every 3 weeks.

[0053] 42. The method of any one of embodiments 26-41, comprising administering in combination, preferably simultaneously, one or more therapeutically effective amounts of immuno-oncology (IO) therapeutic agents, preferably selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, TIGIT inhibitors, GITR antagonists, TGF-b inhibitors, IL15 / IL15RA complex, CD40 / CD40L complex, OX40 inhibitors, 4-1BB / CD137 complex, ICOS inhibitors, CD47 inhibitors, VISTA inhibitors, GD-2 inhibitors, B7 / H3 inhibitors, cytokines (e.g., interferons, interlukins), cellular immunotherapy, and cancer vaccines, more preferably PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, or combinations thereof. In some embodiments, the inhibitors used herein are antibodies.

[0054] 43. (i) said one or more chemotherapeutic agents are administered during the run-in period, preferably in combination with, and preferably simultaneously with, two administrations of said radiopharmaceutical compound, with a first administration of said radiopharmaceutical compound in the first week of the first administration of chemotherapeutic agent, e.g. on any of days 3, 4 or 5 of week 1, and a second administration of said radiopharmaceutical compound between weeks 6 and 8, preferably in week 7; (ii) the tumor immunotherapy agent is administered, preferably in combination with the chemotherapy agent, preferably simultaneously, in the first week, preferably on the day of the first administration of the chemotherapy agent, and every three weeks during the induction period; The method of embodiment 42.

[0055] 44. Following the implementation period, (iii) 1 to 4 administrations of said radiopharmaceutical compound every 3 weeks; and (iv) 1 to 4 administrations of the tumor immunosuppressant every 3 weeks. The method of embodiment 43, further comprising a maintenance period comprising:

[0056] 45. The PD-1, PD-L1 or CTLA-4 inhibitor is, for example, nivolumab (Bristol-Myers Squibb), ipilimumab, PDR001 / spartalizumab (Novartis), Keytruda / pembrolizumab / MK-3475 / lambrolizumab (Merk & 45. The method of any one of embodiments 42-44, wherein the anti-PD1, anti-PD-L1 or anti-CTLA-4 antibody is selected from the group consisting of: anti-PD1, anti-PD-L1 or anti-CTLA-4 antibody ...

[0057] 46. ​​The method of embodiment 45, wherein the PD-1, PD-L1 or CTLA-4 inhibitor is tislelizumab and is administered at a dose of preferably about 200 mg to about 500 mg, more preferably about 200 mg to about 400 mg, even more preferably about 200 mg to about 300 mg, even more preferably about 200 mg or about 300 mg, and even more preferably 200 mg.

[0058] 47. The subject has not previously received systematic treatment for SCLC, particularly ES-SCLC, and in particular the subject has not previously received chemotherapy for treating SCLC, particularly ES-SCLC, and the radiopharmaceutical compound is 177

[0036] Lu]Lu-DOTA-TATE, and the one or more chemotherapeutic agents are carboplatin (preferably carboplatin AUC5 on day 1 of a 3-week cycle) and etoposide (preferably 100 mg / m on days 1, 2, and 3 of a 3-week cycle). 2and the use further comprises administering a therapeutically effective amount of tislelizumab to 177 The method of any one of embodiments 26-46, further comprising administering in combination, preferably simultaneously, with administration of [LU]Lu-DOTA-TATE.

[0059] 48. (i) The carboplatin and etoposide are administered during the induction period, preferably in the first week after the first administration of carboplatin and / or etoposide, for example on any of the 3rd, 4th or 5th days of the first week. 177 The first administration of [LU]Lu-DOTA-TATE and the second administration of [LU]Lu-DOTA-TATE between weeks 6 and 8, preferably week 7. 177 LU] of the second dose of Lu-DOTA-TATE [ 177 in combination with two doses of LU]Lu-DOTA-TATE, preferably administered simultaneously; (ii) tislelizumab is administered in combination with carboplatin and etoposide, preferably simultaneously, starting in week 1, preferably on the day of the first dose of carboplatin, and every 3 weeks during the run-in period The method of embodiment 47.

[0060] 49. Following the implementation period, (iii) Every 3 weeks 177 1 to 4 doses of]Lu-DOTA-TATE, and (iv) 1 to 4 doses of tislelizumab every 3 weeks The method of embodiment 48, further comprising a maintenance period comprising:

[0061] 50. The method of any one of embodiments 26-49, wherein said radiopharmaceutical compound is administered in a dose (i.e., daily dose, dose for each administration, non-cumulative dose) ranging between 0.925 GBq (25 mCi) and 29.6 GBq (800 mCi), preferably between 1.48 GBq (40 mCi) and 18.5 GBq (500 mCi), preferably between 1.85 GBq (50 mCi) and 14.8 GBq (400 mCi), more preferably between 3.7 GBq (100 mCi) and 11.1 GBq (300 mCi), and 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).

[0062] 51. Use of a radiopharmaceutical compound in the manufacture of a medicament for treating small cell lung cancer (SCLC), in particular expanded stage small cell lung cancer (ES-SCLC), in a human subject in need thereof, comprising administering to said subject a therapeutically effective amount of a radiopharmaceutical compound comprising a somatostatin receptor binding molecule in combination, preferably simultaneously, with a therapeutically effective amount of one or more chemotherapeutic agents.

[0063] 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 attached to C, either directly or indirectly via S. The use of embodiment 51, wherein the compound is

[0064] 53. In the formula, M is 90 Y, 131 I, 121 Sn, 186 Re, 188 Re, 64 Cu, 67 Cu, 59 Fe, 89 Sr, 198 Au,203 Hg, 212 Pb, 165 Dy, 103 Ru, 149 Tb, 161 Tb, 213 Bi, 166 Ho, 165 Er, 169 Er, 153 Sm, 177 Lu, 213 Bi, 223 Ra, 225 Ac, 227 Ac, 227 Th, 211 At, 67 Cu, 186 Re, 188 Re, 161 Tb, 175 Yb, 105 Rh, 166 Dy, 199 Au, 44 Sc, 149 Pm, 151 Pm, 142 Pr, 143 Pr, 76 As, 111 Ag, and 47 Sc, preferably 177 The use of embodiment 52, wherein Lu is

[0065] 54. The use according to embodiment 52 or 53, 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.

[0066] 55. The use according to any one of embodiments 51 to 54, wherein P is selected from octreotide, octreotate, satreotide, lanreotide, vapreotide, and pasireotide, preferably selected from octreotide and octreotate.

[0067] 56. Use according to any one 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.

[0068] 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 57. The use according to any one of embodiments 51 to 56, wherein the agonist is thiazolidinium phosphate phosphate phosphate (Tap phosphate), thiazolidinium ...

[0069] 58. The use according to any one of embodiments 51 to 57, wherein the subject has not previously received a systematic treatment for SCLC, in particular ES-SCLC, in particular wherein the subject has not previously received chemotherapy for treating SCLC, in particular ES-SCLC.

[0070] 59. The use according to any one of embodiments 51 to 58, wherein the subject has been newly diagnosed with SCLC, in particular ES-SCLC.

[0071] 60. The subject is an organic compound similar to that used in radiopharmaceutical treatment, but containing a radioactive metal suitable for imaging, preferably 68 Ga, 67 Ga or 64 Cu, more preferably 68 A radiopharmaceutical compound according to any one of embodiments 51 to 59, which is selected for treatment with SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging with Ga.

[0072] 61. The subject is preferably diagnosed with a positron emission tomography (PET) scan of at least one target or non-target lesion. 68 The use according to any one of embodiments 51 to 60, wherein the patient has been diagnosed as SSTR positive by Ga]Ga-DOTA-TATE imaging PET scan.

[0073] 62. The one or more chemotherapeutic agents are carboplatin (preferably carboplatin AUC5 on day 1 of every 3-week cycle) and etoposide (preferably 100 mg / m on days 1, 2, and 3 of every 3-week cycle). 2 The use according to any one of embodiments 51 to 61, comprising administering in a daily dose of

[0074] 63. The method according to any one of embodiments 51-62, wherein the radiopharmaceutical compound is administered 1 to 8 times, preferably 2 to 7 times, for example 4 to 6 times, and there is a treatment interval between every two administrations of the radiopharmaceutical compound.

[0075] 64. The method according to any one of embodiments 51-63, wherein each 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 weeks and / or 6 weeks.

[0076] 65. The use according to any one of embodiments 51-64, wherein said one or more chemotherapeutic agents are administered during the induction period, preferably in combination with, and preferably simultaneously with, two administrations of said radiopharmaceutical compound, with a first administration of said radiopharmaceutical compound in the first week of administration of a chemotherapeutic agent, e.g. on any of days 3, 4 or 5 of week 1, and a second administration of said radiopharmaceutical compound between weeks 6 and 8, preferably in week 7.

[0077] 66. The use according to embodiment 65, further comprising a maintenance period following an induction period, comprising 1 to 4 administrations of said radiopharmaceutical compound, preferably every 3 weeks.

[0078] 67. The use according to any one of embodiments 51 to 66, comprising a step of administering in combination, preferably simultaneously, one or two therapeutically effective amounts of immuno-oncology (IO) therapeutic agents, preferably selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, or CTLA4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, TIGIT inhibitors, GITR antagonists, TGF-b inhibitors, IL15 / IL15RA complexes, CD40 / CD40L complexes, OX40 inhibitors, 4-1BB / CD137 complexes, ICOS inhibitors, CD47 inhibitors, VISTA inhibitors, GD-2 inhibitors, and B7 / H3 inhibitors, cytokines (e.g., interferons, interlukins), cellular immunotherapy, and cancer vaccines, more preferably PD-1 inhibitors, PD-L1 inhibitors, or CTLA4 inhibitors or combinations thereof. In some embodiments, the inhibitors used herein are antibodies.

[0079] 68. (iii) said one or more chemotherapeutic agents are administered during the run-in period, preferably in combination with, and preferably simultaneously with, two administrations of said radiopharmaceutical compound, with a first administration of said radiopharmaceutical compound in the first week of the first administration of chemotherapeutic agent, e.g. on any of days 3, 4 or 5 of week 1, and a second administration of said radiopharmaceutical compound between weeks 6 and 8, preferably in week 7; (iv) the tumor immunotherapy agent is preferably administered in combination with the chemotherapy agent, preferably simultaneously, in the first week, preferably on the day of the first administration of the chemotherapy agent, and every three weeks during the induction period; Use according to embodiment 67.

[0080] 69. Following the run-in period, (v) 1 to 4 doses of said radiopharmaceutical compound every 3 weeks; and (vi) 1 to 4 administrations of the tumor immunosuppressant every 3 weeks. The use according to embodiment 68, further comprising a maintenance period comprising:

[0081] 70. The PD-1, PD-L1 or CTLA-4 inhibitor is, for example, nivolumab (Bristol-Myers Squibb), ipilimumab, PDR001 / spartalizumab (Novartis), Keytruda / pembrolizumab / MK-3475 / lambrolizumab (Merk & 70. The use according to any one of embodiments 67 to 69, wherein the anti-PD1, anti-PD-L1 or anti-CTLA-4 antibody is selected from the group consisting of: anti-PD1, anti-PD-L1 or anti-CTLA-4 antibody ...

[0082] 71. The use according to embodiment 70, wherein the PD-1, PD-L1 or CTLA-4 inhibitor is tislelizumab, preferably administered at a dose of about 200 mg to about 500 mg, more preferably about 200 mg to about 400 mg, even more preferably about 200 mg to about 300 mg, even more preferably about 200 mg or about 300 mg, even more preferably 200 mg.

[0083] 72. The subject has not previously received systematic treatment for SCLC, particularly ES-SCLC, and in particular the subject has not previously received chemotherapy for treating SCLC, particularly ES-SCLC, and the radiopharmaceutical compound is 177 Lu]Lu-DOTA-TATE, said one or more chemotherapeutic agents being carboplatin and etoposide, said use further comprising administering a therapeutically effective amount of tislelizumab to 177The use according to any one of embodiments 51 to 71, further comprising the step of administering in combination, preferably simultaneously, with administration of LU]Lu-DOTA-TATE.

[0084] 73. (iii) The carboplatin and etoposide are administered during the induction period, preferably in the first week after the first administration of carboplatin and / or etoposide, for example on any of the 3rd, 4th or 5th days of the first week. 177 The first administration of [LU]Lu-DOTA-TATE and the second administration of [LU]Lu-DOTA-TATE between weeks 6 and 8, preferably week 7. 177 LU] of the second dose of Lu-DOTA-TATE [ 177 in combination with two doses of LU]Lu-DOTA-TATE, preferably administered simultaneously; (iv) tislelizumab is administered in combination with carboplatin and etoposide, preferably simultaneously, in week 1, preferably on the day of the first dose of carboplatin, and every 3 weeks during the run-in period; Use according to embodiment 72.

[0085] 74. The use comprises a run-in period followed by (v) three-weekly 177 1 to 4 doses of]Lu-DOTA-TATE, and (vi) 1 to 4 doses of tislelizumab every 3 weeks The use according to embodiment 73, further comprising a maintenance period comprising:

[0086] 75. The use according to any one of embodiments 51-74, wherein said radiopharmaceutical compound is administered in a dose (i.e. daily dose, dose for each administration, non-cumulative dose) ranging between 0.925 GBq (25 mCi) and 29.6 GBq (800 mCi), preferably between 1.48 GBq (40 mCi) and 18.5 GBq (500 mCi), preferably between 1.85 GBq (50 mCi) and 14.8 GBq (400 mCi), more preferably between 3.7 GBq (100 mCi) and 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).

[0087] The present disclosure relates to a method for treating small cell lung cancer (SCLC), in particular expanded stage small cell lung cancer (ES-SCLC), in a human subject in need thereof, by administering to said subject a therapeutically effective amount of a radiopharmaceutical compound comprising a somatostatin receptor binding molecule in combination, preferably simultaneously, with a therapeutically effective amount of one or more chemotherapeutic agents.

[0088] General definition The use of the articles "a," "an," and "the" both in the specification and in the claims are to be construed to cover both the singular and the plural, unless otherwise indicated in the specification or clearly contradicted by context. The terms "comprising," "having," "being of" (e.g., a complex of a radionuclide linked to a chelating agent and a cell receptor binding organic moiety), "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including but not limited to"), unless otherwise indicated. Furthermore, whenever "comprising" or another open-ended term is used in an embodiment, it should be understood that the same embodiment may be more narrowly claimed using the intermediate term "consisting essentially of" or the closed term "consisting of."

[0089] The term "about" or "ca." is used herein to mean that the following value may vary by ±20%, preferably ±10%, more preferably ±5%, even more preferably ±2%, and even more preferably ±1%.

[0090] Unless otherwise defined, "%" in this specification has the meaning of weight percentage (wt%), also referred to as weight % (w / w%).

[0091] A "total concentration" refers to the sum of one or more individual concentrations.

[0092] "Aqueous solution" refers to one or more solutes in water.

[0093] The phrases "treatment of" and "treating" include the prevention, amelioration, or arrest of a disease, disorder, or a symptom thereof. In particular, with respect to the treatment of tumors, the term "treatment" may refer to the inhibition of tumor growth or the reduction in tumor size.

[0094] As used herein, "expanded-stage small cell lung cancer" (also referred to as "ES-SCLC") refers to small cell lung cancer (SCLC) that has spread to other parts of the body, such as the contralateral lung, bone, brain, or bone marrow tissue.

[0095] In accordance with the International System of Units, "MBq" is the abbreviation for the unit of radioactivity "megabecquerel."

[0096] As used herein, "PET" stands for positron emission tomography.

[0097] As used herein, "SPECT" stands for single photon emission computed tomography.

[0098] As used herein, "MRI" stands for magnetic resonance imaging.

[0099] As used herein, "CT" stands for computed tomography.

[0100] As used herein, the term "effective amount" or "therapeutically effective amount" of a compound refers to that amount of compound that elicits a biological or medical response in a subject, such as, for example, amelioration of symptoms, alleviation of a disease state, delaying or slowing the progression of a disease, or prevention of a disease.

[0101] The terms "patient" and "subject" are used interchangeably and refer to humans, including, for example, subjects with cancer.

[0102] "Commercial use" refers to a pharmaceutical product, e.g. a pharmaceutical solution, capable of (preferably has) obtaining marketing approval by a health authority, e.g. the US-FDA or EMA, by complying with all pharmaceutical quality and stability requirements required by the health authority, capable of (preferably has) being manufactured on a commercial scale from or in a pharmaceutical manufacturing facility, followed by quality control testing procedures, and capable of (preferably has been) being supplied to an end use, e.g. in a remote location, e.g. a hospital or a patient.

[0103] "Combination therapy," "co-administration," "combined administration," or "co-administration" refers to the combined administration of at least two therapeutic agents, where a first agent, typically a radiopharmaceutical compound, is administered to the same subject in need thereof either simultaneously with a second agent or separately within a time interval that allows the combined partners to exhibit a cooperative or synergistic effect to treat a disorder, such as, for example, cancer. These delivery methods are within the scope described herein, but are not intended to imply that the therapeutic agents must be administered simultaneously and / or formulated for delivery together. A radiopharmaceutical compound may be administered simultaneously with, prior to, or subsequent to one or more other additional therapeutic or therapeutic agents. The term is also meant to encompass treatment regimes in which the agents are not necessarily administered by the same route of administration.

[0104] As used herein, the term "radiopharmaceutical" refers to a pharmaceutical compound that is labeled with a radionuclide element, typically a metal. Radiopharmaceutical compounds may be used in peptide receptor radionuclide therapy (PRRT).

[0105] As used herein, the term "PRRT" or "peptide receptor radionuclide therapy" refers to the use of radiolabeled peptides (e.g., 177 This refers to molecular targeted radiation therapy that involves systemic administration of 1000 ng / Lu-Dotatate.

[0106] Radiopharmaceutical Compounds for Use in the Treatment Methods of the Disclosure Radiopharmaceutical compounds for use in the therapeutic methods of the present disclosure are somatostating receptor (SSTR) binding compounds that comprise a radionuclide and have specific binding affinity to an SSTR, for example at least the somatostatin receptor subtype 2 (SSTR2).

[0107] In a specific embodiment, the radiopharmaceutical compound for use as described herein 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 that provides a covalent bond between C and P; P is a somatostatin receptor-binding peptide covalently attached, e.g., directly through its N-terminus or indirectly through S, to C. It is a compound of the formula:

[0108] Such radiopharmaceutical compounds may be selected from octreotide, octreotate, lanreotide, vapreotide, and pasireotide, preferably selected from octreotide and octreotate.

[0109] In some embodiments of the present disclosure, the radionuclide M is selected from radionuclide isotopes suitable for nuclear medicine therapy or peptide receptor radionuclide therapy (PRRT).

[0110] Examples of such radionuclides M suitable for PRRT include, without limitation: 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.

[0111] As used herein, the term "chelating agent" refers to an organic moiety comprising a functional group capable of forming a non-covalent bond with a radionuclide, thereby forming a stable radionuclide complex. In the context of this disclosure, chelating agents include 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (tetraxetane), trizoxetane, 1,4,7,10-tetraazacyclododecane, 1(glutarate)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DOTAGA), and the like. 3A), triethylenetetramine TETA, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), NOTAGA, 1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane (NODAGA), NODASA, NODAPA, and 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA, e.g., AAZTA5). In many embodiments of the present disclosure, the chelator is DOTA.

[0112] Such chelators are linked to the somatostatin receptor binding peptide either directly or via a linker molecule, preferably directly. The linking bond can be either a covalent or non-covalent bond between the cell receptor binding organic moiety (and linker) and the chelator, preferably the bond is a covalent bond.

[0113] As used herein, the term "somatostatin receptor binding peptide" refers to a peptide moiety that has specific binding affinity to a somatostatin receptor. Such somatostatin receptor binding peptides may be selected from octreotide, octreotate, lanreotide, vapreotide, and pasireotide, and are preferably selected from octreotide and octreotate.

[0114] According to many embodiments of the disclosed methods, the somatostatin receptor binding peptide linked to a chelator is selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), satreotide tetraxetane, 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.

[0115] In one embodiment, the radiopharmaceutical compound of the present disclosure 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 Lu-oxodotreotide).

[0116] Thus, the cell receptor binding moiety and the chelator may together form the following molecule: DOTA-OC: [DOTA 0 ,D-Phe 1 ]Octreotide, DOTA-TOC:[DOTA 0 ,D-Phe 1 ,Tyr 3 ]Octreotide, edotreotide (INN), These are expressed by the following equations. [ka]

[0117] DOTA-NOC: [DOTA 0 ,D-Phe 1 ,1-Nal 3 ]Octreotide, DOTA-TATE: [DOTA 0 ,D-Phe 1 ,Tyr3 ]Octreotate, DOTA-Tyr 3 -Octreotate, DOTA-d-Phe-Cys-Tyr-d-Trp-Lys-Thr-Cys-Thr (cyclo 2,7), and oxodotreotide (INN), which are represented by the following formula: [ka]

[0118] DOTA-LAN: [DOTA 0 ,D-β-Nal 1 ]Lanreotide, DOTA-VAP: [DOTA 0 ,D-Phe 1 ,Tyr 3 ] Vapreotide.

[0119] Satreotide Trizoxetan [ka]

[0120] Satreotide Tetraxetan [ka]

[0121] Typical "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.

[0122] More specifically, in many embodiments of the present disclosure, the complex formed by the radionuclide linked to the chelator according to the present invention and the cell receptor binding moiety is 177 Lu]Lu-DOTA-TATE, which is lutetium ( 177It is also called [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-threoninato cyclic (2→7)-disulfide (4-)](177Lu) lutetium acid (1-) hydrogen and is expressed by the following equation. [ka]

[0123] The radiolabeled somatostatin receptor binding compound is typically formulated for administration to a subject in need thereof in a therapeutically effective amount.

[0124] 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.

[0125] In many embodiments of the present disclosure, the radiolabeled somatostatin receptor binding compound may be present at a concentration that provides a volumetric activity, for example, at a concentration of about 370 MBq / mL (10 mCi / mL), including between 100 MBq / mL and 1000 MBq / mL, including between 250 MBq / mL and 500 MBq / mL.

[0126] Pharmaceutically acceptable excipients can be any of those conventionally used, limited only by physicochemical considerations, such as solubility and lack of reactivity with the active compound.

[0127] In particular, the one or more pharmaceutcially acceptable excipients may be selected from a number of different classes of such pharmaceutcially acceptable excipients, examples of which include radiolytic stabilizers, buffering agents, sequestering agents, and mixtures thereof.

[0128] As used herein, "radiolytic stabilizers" refers to stabilizers that protect organic molecules from radiolysis, e.g., when gamma rays emitted from a radionuclide break the bonds between the atoms of organic molecules to form radicals, these radicals are then removed by stabilizers to prevent the radicals from undergoing any other chemical reactions that may result in undesirable, potentially ineffective, or even toxic molecules. These stabilizers are therefore also referred to as "free radical scavengers", or "radical scavengers" for short. Other alternative terms for these stabilizers are "radiostability enhancers", "radiolytic stabilizers", or simply "quenchers".

[0129] As used herein, "sequestering agent" refers to a chelating agent suitable for complexing free radionuclide metal ions (not complexed to the radiolabeled peptide) in the formulation.

[0130] Buffers include acetate buffers, citrate buffers, and phosphate buffers.

[0131] According to many embodiments of the present disclosure, the pharmaceutical composition is an aqueous solution, such as, for example, an injectable formulation. According to specific embodiments, the pharmaceutical composition is an infusion solution.

[0132] 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., pages 238-250 (1982), and SHP Handbook on Injectable Drugs, Trissel, 15th ed., pages 622-630 (2009)).

[0133] The following clauses refer to various embodiments of aqueous pharmaceutical solutions suitable for use in the combination methods of the present disclosure. The clauses provided below are non-limiting.

[0134] 76.(a)(ai) Radioactive nuclides and (aii) a cell receptor-binding organic moiety linked to a chelator; A complex formed by (b) at least one stabilizer against radiolysis wherein said radionuclide is present in a concentration providing a volumetric activity of at least 100 MBq / mL, preferably at least 250 MBq / mL.

[0135] 77. The aqueous pharmaceutical solution according to embodiment 76, 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, and even more preferably at least 2.7 mg / mL.

[0136] 78. The aqueous pharmaceutical solution according to any one of the preceding embodiments, wherein the radionuclide is present in a concentration providing a volumetric activity of 100-1000 MBq / mL, preferably 250-500 MBq / mL.

[0137] 79. The aqueous pharmaceutical solution according to any one of the preceding 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.

[0138] 80. The aqueous pharmaceutical solution according to any one of the preceding embodiments, wherein component (b) is only one stabilizer against radiolysis, i.e. only the first stabilizer.

[0139] 81. The aqueous pharmaceutical solution according to any one of the preceding 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.

[0140] 82. The aqueous pharmaceutical solution according to any one of embodiments 80-81, wherein the first stabilizer is present in a concentration of 0.2-5 mg / mL, preferably 0.5-5 mg / mL, more preferably 0.5-2 mg / mL, even more preferably 0.5-1 mg / mL, even more preferably 0.5-0.7 mg / mL.

[0141] 83. The aqueous pharmaceutical solution according to embodiments 80-81, wherein the second stabilizer is present in a concentration of 0.5-10 mg / mL, more preferably 1.0-8.0 mg / mL, even more preferably 2.0-5.0 mg / mL, even more preferably 2.2-3.4 mg / mL.

[0142] 84. The aqueous pharmaceutical solution according to any one of the preceding 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.

[0143] 85. An aqueous pharmaceutical solution according to any one of the preceding embodiments, which is ethanol-free.

[0144] 86. The aqueous pharmaceutical solution according to any one of embodiments 80-84, wherein the first stabilizer is selected from gentisic acid and ascorbic acid, preferably the first stabilizer is gentisic acid.

[0145] 87. The aqueous pharmaceutical solution according to any one of embodiments 81-86, wherein the second stabilizer is selected from gentisic acid and ascorbic acid, preferably the second stabilizer is ascorbic acid.

[0146] 88. The pharmaceutical aqueous solution according to any one of embodiments 81-82, 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 of the first stabilizer (mg / mL) to the concentration of the second stabilizer (mg / mL) is 1:3 to 1:7, preferably 1:4 to 1:5.

[0147] 89. 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 The pharmaceutical aqueous solution of any one of the preceding embodiments, wherein

[0148] 90. The pharmaceutical aqueous solution according to any one of the preceding 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.

[0149] 91. The aqueous pharmaceutical solution according to any one of the preceding embodiments, wherein the chelating agent is selected from DOTA (tetrazoxetan), trizoxetan, DOTAGA, DTPA, NTA, EDTA, DO3A, TETA, NOTA, NOTAGA, NODAGA, NODASA, NODAPA, and AAZTA (e.g. AAZTA5), preferably DOTA.

[0150] 92. The pharmaceutical aqueous solution of any one of the preceding embodiments, wherein the cell receptor binding moiety and the chelator together form a molecule 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.

[0151] 93. A radionuclide, a cell receptor binding moiety, and a chelator are combined in a complex [ 177 Lu]Lu-DOTA-TOC(177 Lu-Edotreotide) or [ 177 Lu]Lu-DOTA-TATE( 177 Lu-oxodotreotide), preferably 177

[0023] Lu]Lu-DOTA-TATE together form the aqueous pharmaceutical solution according to any one of the preceding embodiments.

[0152] 94. The aqueous pharmaceutical solution according to any one of the preceding embodiments, further comprising a buffer, preferably said buffer being an acetate buffer, preferably in an amount to provide a concentration of 0.3-0.7 mg / mL (preferably about 0.48 mg / mL) acetic acid and 0.4-0.9 mg / mL (preferably about 0.66 mg / mL) sodium acetate.

[0153] 95. The aqueous pharmaceutical solution according to any one of the preceding embodiments, further comprising a sequestering agent, preferably wherein said sequestering agent is diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, preferably in an amount to provide a concentration of 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL).

[0154] 2. The pharmaceutical aqueous solution according to any one of the preceding embodiments, having a shelf life of at least 24 hours at or below 96.25°C, at least 48 hours at or below 25°C, at least 72 hours at or below 25°C, between 24 hours and 120 hours at or below 25°C, between 24 hours and 96 hours at or below 25°C, between 24 hours and 84 hours at or below 25°C, between 24 hours and 72 hours at or below 25°C, in particular having a shelf life of 72 hours at or below 25°C.

[0155] 97. The aqueous pharmaceutical solution according to any one of the preceding embodiments, wherein the solution is 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.

[0156] 98. A pharmaceutical aqueous solution according to any one of the preceding embodiments, which is ready for use.

[0157] 99. An aqueous pharmaceutical solution according to any of the above embodiments, for commercial use.

[0158] 100. (a) (ai) A radionuclide present in a concentration that provides a volumetric activity of 250-500 MBq / mL 177 Lutetium (Lu-177), and (aii) a chelator-linked somatostatin receptor binding the organic moiety 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; 1. An aqueous pharmaceutical solution comprising:

[0159] 101.(c) An aqueous pharmaceutical solution according to embodiment 100, further comprising diethylenetriaminepentaacetic acid (DTPA) or a salt thereof at a concentration of 0.01 to 0.10 mg / mL.

[0160] 102.(d) The aqueous pharmaceutical solution according to embodiment 100 or 101, further comprising acetic acid in a concentration of 0.3-0.7 mg / mL and sodium acetate in a concentration of 0.4-0.9 mg / mL.

[0161] 103. An aqueous pharmaceutical solution according to any one of the preceding embodiments, wherein a stabilizer is present in solution during complexation of components (ai) and (aii).

[0162] 104. An aqueous pharmaceutical solution according to any one of embodiments 81 to 103, wherein only the first stabilizer is present during the complexation of components (ai) and (aii), preferably in an amount that results 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.

[0163] 105. An aqueous pharmaceutical solution according to any one of embodiments 81 to 104, wherein a portion of the amount of the second stabilizer is already present in the solution during complexation of components (ai) and (aii), and another portion of the amount of the second stabilizer is added after complexation of components (ai) and (aii).

[0164] 106. The aqueous pharmaceutical solution according to any one of embodiments 81-105, wherein the second stabilizer is added after complexation of components (ai) and (aii).

[0165] 107. The aqueous pharmaceutical solution according to any one of embodiments 81 to 106, wherein the second stabilizer is added after complexation of components (ai) and (aii) in an amount that results in a concentration in the final solution of preferably 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.

[0166] 108. The aqueous pharmaceutical solution according to any one of the preceding embodiments, further comprising a sequestering agent to remove any uncomplexed Lu, added after complexation of components (ai) and (aii), preferably said sequestering agent being diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, preferably in an amount to give a concentration of 0.01-0.10 mg / mL (preferably about 0.05 mg / mL) in the final solution.

[0167] In most cases, the specific radioactivity concentration is 370MBq / mL (±5%). 177 Lu]Lu-DOTA-TATE or [ 177 An infusion solution of [Lu]Lu-DOTA-TOC is used in the combination method of the present disclosure.

[0168] A particular process for producing the aqueous pharmaceutical solution defined in any one of the preceding embodiments may comprise the following process steps: (1) A complex of a radionuclide with a chelator-linked cell receptor binding organic moiety is formed by: (1.1) preparing an aqueous solution comprising a radionuclide; (1.2) preparing an aqueous solution comprising a chelator-linked cellular 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; (2) The complex solution obtained in step (1) is diluted with: (2.1) preparing an aqueous dilution solution optionally comprising a second stabilizer; and (2.2.) Mixing the complex solution obtained in step (1) with the diluted solution obtained in step (2.1).

[0169] The methods of treatment disclosed herein provide for combination therapy with said radiopharmaceutical compounds.

[0170] More specifically, the radiopharmaceutical compound is preferably 177 Lu]Lu-DOTA-TATE( 177 Lu-oxodotreotide) may be used in accordance with the present disclosure to treat SCLC, particularly ES-SCLC, in a subject in need thereof, by administering a therapeutically effective amount of said radiopharmaceutical compound to said subject.

[0171] In one embodiment, the radiopharmaceutical compound is administered in a dose ranging between 0.925 GBq (25 mCi) and 29.6 GBq (800 mCi), preferably between 1.48 GBq (40 mCi) and 18.5 GBq (500 mCi), preferably between 1.85 GBq (50 mCi) and 14.8 GBq (400 mCi), more preferably between 3.7 GBq (100 mCi) and 11.1 GBq (300 mCi), and 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).

[0172] In another embodiment, the radiopharmaceutical compound used is administered 1 to 8 times, preferably 2 to 7 times, more preferably 4 to 6 times per treatment during the induction phase. The administration of the radiopharmaceutical compound used may comprise a treatment interval of 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks, or 6 weeks, or 7 weeks.

[0173] In a specific embodiment, during the induction period, when a radiopharmaceutical compound (preferably [177LuLu]-DOTATE) is administered in combination, preferably simultaneously, with chemotherapeutic agents (preferably carboplatin and etoposide), the treatment interval for administration of said radiopharmaceutical compound is 6 to 8 weeks, e.g., 7 weeks, and during the maintenance period, when chemotherapy is stopped, the treatment interval for administration of said radiopharmaceutical compound is shortened, e.g., comprises 2 to 4 weeks, preferably 3 weeks.

[0174] In a specific embodiment, the total (cumulative) dose administered to a subject does not exceed 55.5 (1500 mCi).

[0175] In a specific embodiment, the total (cumulative) dose is greater than 800 mCi, for example between 1000 and 1500 mCi.

[0176] In certain embodiments, during the induction period when chemotherapeutic agents are co-administered, the dosage is lower than during the maintenance period (after the chemotherapy period), e.g., each dosage comprises between 100 mCi and 200 mCi during the induction period and between 150 mCi and 250 mCi during the maintenance period.

[0177] Chemotherapy used in combination The present disclosure provides a combination therapy of PRRT and chemotherapy to provide a synergistic anti-tumor effect, thereby treating subjects with SCLC, particularly ES-SCLC.

[0178] As used herein, the term "chemotherapy" is used in the treatment of diseases of an oncological nature using drugs that stop the growth of cancer cells by killing the cells or stopping their division. Chemotherapy includes, but is not limited to, alkylating agents, antimetabolites, anti-microtubule agents, topoisomerase inhibitors, and cytotoxic antibiotics.

[0179] Thus, the methods of the present disclosure comprise the step of administering one or more chemotherapeutic agents in combination, preferably simultaneously, with said radiopharmaceutical compound.

[0180] In a preferred embodiment, the one or more chemotherapeutic agents for use in combination with the radiopharmaceutical compounds disclosed herein are selected from among alkylating agents, more preferably cisplatin and derivatives such as cisplatin or carboplatin.

[0181] For over 20 years, the current standard of care for treating ES-SCLC patients is platinum chemotherapy (carboplatin or cisplatin) with etoposide. Thus, in a specific embodiment, the one or more chemotherapeutic agents for use in combination with the radiopharmaceutical compounds disclosed herein are carboplatin with etoposide.

[0182] In a specific embodiment, the combination therapy comprises administration of 3-4 cycles of one or more chemotherapeutic agents, such as, for example, carboplatin and etoposide, for example, every 3 weeks.

[0183] In a specific embodiment, the combination therapy comprises 3-4 cycles of carboplatin and etoposide administered every 3 weeks, where carboplatin is administered at an area under the curve (AUC) of 5 and etoposide is administered at 100 mg / m2.

[0184] In a specific embodiment, the first administration of the one or more chemotherapeutic agents is administered less than 15 days, preferably less than 10 days, and more preferably less than 7 days before or after the first administration of the radiopharmaceutical.

[0185] In a specific embodiment, carboplatin is initially administered on day 1, etoposide is initially administered on days 1-3, and a radiopharmaceutical compound (preferably 177 [Lu]Lu-DOTA-TATE) is initially administered on days 3-5.

[0186] In a specific embodiment, the one or more chemotherapeutic agents (typically carboplatin and etoposide) are administered during the run-in period, preferably with a first administration of the radiopharmaceutical compound on week 1, e.g., any of days 3, 4, or 5 of week 1, prior to the first administration of the chemotherapeutic agent, and with a second administration of the radiopharmaceutical compound (typically 177 [Lu]Lu-DOTA-TATE), preferably administered simultaneously.

[0187] As used herein, "induction period" refers to the period during which the one or more chemotherapeutic agents, preferably carboplatin and etoposide, are administered to a subject, where the period is up to 11 weeks, e.g., from day 1 of week 1 to day 7 at the end of week 11.

[0188] In a specific embodiment, the combination therapy comprises an induction period and a maintenance period.

[0189] As used herein, "maintenance period" refers to the period beginning after the induction phase or after a period of coadministration of PRRT and chemotherapy, in which chemotherapy is discontinued but PPRT is continued, for example, beginning on day 1 of week 12 and continuing through week 25 or longer.

[0190] In a specific embodiment, the combination therapy comprises an induction period and a maintenance period, during which the subject receives: (i) a chemotherapy agent (e.g., carboplatin and etoposide), preferably with an area under the curve (AUC) of 5 on day 1 and every 3 weeks, and 4 cycles of etoposide at 100 mg / m2 on days 1-3 and every 3 weeks; and (ii) During weeks 1 and 7, preferably on days 3, 4, or 5 of week 1, a radiopharmaceutical compound (e.g., 177 Lu]Lu-DOTA-TATE), and During the maintenance phase, chemotherapy is discontinued and subjects receive the following: (iii) For example, at weeks 13, 16, 19, and 22, the radiopharmaceutical compound (e.g., 177 Lu]Lu-DOTA-TATE) for 1 to 4 doses.

[0191] Immuno-oncology (I / O) therapy Recently, immuno-oncological therapy has been added to the standard treatment scheme for treating patients with SCLC in combination with carboplatin-etoposide. In particular, atezolizumab is administered in combination with carboplatin-etoposide, followed by administration of atezolizumab in the maintenance phase (Horn L, Mansfield AS, Szczesna A, et al (2018) N Engl J Med; 379 (23): 2220-9).

[0192] In specific embodiments, the combination therapy disclosed in the previous section further comprises the combined, preferably simultaneous, administration of a therapeutically effective amount of one or more immuno-oncology (IO) therapeutic agents, preferably selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, TIGIT inhibitors, GITR antagonists, TGF-b inhibitors, IL15 / IL15RA complexes, CD40 / CD40L complexes, OX40 inhibitors, 4-1BB / CD137 complexes, ICOS inhibitors, CD47 inhibitors, VISTA inhibitors, GD-2 inhibitors, B7 / H3 inhibitors, cytokines (e.g., interferons, interlukins), cellular immunotherapy, and cancer vaccines, more preferably PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, or combinations thereof. In some embodiments, the inhibitors used herein are antibodies.

[0193] As used herein, immuno-oncology therapeutics (I / O agents, used synonymously with I / O therapy) refer to any agent or therapy that utilizes the body's immune system to fight cancer. I / O therapy may specifically target cancer cells via the immune system, such as therapeutic cancer vaccines, CAR-T therapy, and targeted antibody therapy. I / O therapy may not necessarily target cancer cells directly, but may treat cancer by enhancing the immune system's ability to attack cancer cells, such as checkpoint inhibitors and cytokines.

[0194] In specific embodiments, I / O therapeutics that may be used in this manner include immune checkpoint inhibitors, preferably selected from the group consisting of PD-1, PD-L1, or CTLA4 inhibitors, LAG-3 inhibitors, and TIM-3 inhibitors.

[0195] Examples of I / O therapeutic agents are further disclosed in WO 2016 / 207732 and WO 2020 / 021465, the contents of which are incorporated herein by reference in their entireties.

[0196] More specifically, the term "PD-1" has its general meaning in the art and refers to the programmed death-1 receptor. The term "PD-1" also refers to a type I transmembrane protein that belongs to the CD28-B7 signaling receptor family, including CD28, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and inducible costimulatory molecule (ICOS), and that interacts with PD-L1.

[0197] The term "anti-PD-1 antibody" or "anti-PD-L1" has its general meaning in the art and refers to an antibody that has binding affinity for PD-1 or PD-L1, respectively, and antagonist activity for PD-1, i.e., it inhibits the signaling cascade associated with PD-1 and inhibits PD-1 ligand binding (PD-L1; PD-L2). Such anti-PD-1 or anti-PD-L1 antibodies preferentially inactivate PD-1 with higher affinity and potency, respectively, than its interaction with other subtypes or isotypes of the receptor of the CD28-B7 signaling family (CD28; CTLA-4; ICOS). Tests and assays for determining whether a compound is a PD-1 inhibitor are well known to those of skill in the art.

[0198] Examples of said PD-1, PD-L1 or CTLA-4 inhibitors are e.g. tislelizumab, nivolumab (Bristol-Myers Squibb), ipilimumab, PDR001 / spartalizumab (Novartis), Keytruda / pembrolizumab / MK-3475 / lambrolizumab (Merk & and anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibodies selected from the group consisting of: ...

[0199] As used herein, the term "antibody" refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds an antigen. Thus, the term "antibody" encompasses not only whole antibody molecules, but also antibody fragments and variants (including derivatives) of antibodies and antibody fragments.

[0200] As used herein, the term "antibody" also includes bispecific or multispecific molecules. An antibody may be derivatized or linked to another functional molecule, such as, for example, another peptide or protein (e.g., another antibody or ligand for a receptor), to generate a bispecific molecule that binds at least two different binding sites or target molecules. An antibody may in fact be derivatized or linked to two or more other functional molecules to generate a multispecific molecule that binds more than two different binding sites and / or target molecules; such multispecific molecules are also intended to be encompassed by the term "bispecific molecule" as used herein. To generate a bispecific molecule, an antibody of the invention may be functionally linked (e.g., by chemical conjugation, genetic fusion, non-covalent binding, etc.) to one or more other binding molecules, such as another antibody, antibody fragment, peptide, or binding mimetic, such that a bispecific molecule results. Furthermore, in embodiments in which the bispecific molecule is multispecific, the molecule may further include a third binding specificity in addition to the first and second target epitopes. In one embodiment, the bispecific molecule disclosed herein comprises as binding specificity at least one antibody or antibody fragment thereof, including, for example, a Fab, Fab', F(ab')2, Fv, Unibody or single chain Fv. The antibody may also be a dimer of a light or heavy chain, or any minimal fragment thereof, such as an Fv or single chain construct as described in U.S. Patent No. 4,946,778 to Ladner et al.

[0201] In natural antibodies, two heavy chains are linked to each other by disulfide bonds, and each heavy chain is linked to a light chain by a disulfide bond. There are two types of light chains: lambda (λ) and kappa (k). There are five major heavy chain classes (or isotypes), IgM, IgD, IgG, IgA, and IgE, that determine the functional activity of the antibody molecule. Each chain contains different sequence domains. Light chains contain two domains: a variable domain (VL) and a constant domain (CL). Heavy chains contain four domains: one variable domain (VH) and three constant domains (CH1, CH2, and CH3, collectively referred to as CH). The variable regions of both the light chain (VL) and the heavy chain (VH) determine binding recognition and specificity to the antigen. The light chain (CL) and heavy chain (CH) constant region domains confer important biological properties such as antibody chain assembly, secretion, placental transport, complement fixation, and Fc receptor (FcR) binding.

[0202] Fv fragment is the N-terminal part of the Fab fragment of an immunoglobulin and consists of one light chain and one heavy chain variable part. The specificity of an antibody lies in the structural complementarity of the antibody binding site with the antigenic determinant. The antibody binding site is composed of residues mainly from hypervariable regions or complementarity determining regions (CDRs). Sometimes, residues from non-hypervariable regions or framework regions (FRs) may participate in the antibody binding site or affect the structure of the entire domain and thus the binding site. Complementarity determining regions or CDRs refer to amino acid sequences that together define the binding affinity and specificity of the native Fv region of a native immunoglobulin binding site. The light and heavy chains of an immunoglobulin each have three CDRs, designated L-CDR1, L-CDR2, L-CDR3, and H-CDR1, H-CDR2, H-CDR3. Thus, an antigen binding site typically contains six CDRs, comprising a set of CDRs from each of the heavy and light chain V regions. Framework region (FR) refers to the amino acid sequence between the CDRs. Thus, the variable regions of the light and heavy chains typically comprise four framework regions and three CDRs of the following sequence: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.

[0203] Residues in antibody variable domains are conventionally numbered according to a system devised by Kabat et al., which is described in Kabat et al., 1987, in Sequences of Proteins of Immunological Interest, US Department of Health and Human Services, NIH, USA (hereinafter "Kabat et al."). The Kabat residue designations do not necessarily correspond directly to the linear numbering of the amino acid residues in the SEQ ID NO:. The actual linear amino acid sequence may contain fewer or more amino acids than the strict Kabat numbering, which corresponds to the shortening or insertion of structural elements, whether framework or complementarity determining regions (CDRs) of the basic variable domain structure. The correct Kabat numbering of residues may be determined for a given antibody by alignment of the homologous residues in the antibody sequence with the "standard" Kabat numbering sequence. The CDRs of the heavy chain variable domain are located at residues 31-35 (H-CDR1), residues 50-65 (H-CDR2), and residues 95-102 (H-CDR3) according to the Kabat numbering system. The CDRs of the light chain variable domain are located at residues 24-34 (L-CDR1), residues 50-56 (L-CDR2), and residues 89-97 (L-CDR3) according to the Kabat numbering system.

[0204] As used herein, an "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds PD-1 is substantially free of antibodies that specifically bind to antigens other than PD-1). However, an isolated antibody that specifically binds PD-1 may have cross-reactivity to other antigens, such as related PD-1 molecules in other species. Moreover, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0205] In a preferred embodiment, said I / O agent for use in combination with the radiopharmaceutical compounds disclosed herein is selected from among PD1 inhibitors, in particular anti-PD1 antibodies, anti-PD-L1 antibodies or anti-CTLA4 antibodies, more preferably BGB-A317 / tislelizumab (Beigene), nivolumab (Bristol-MyersSquibb), ipilimumab, PDR001 / spartalizumab (Novartis), Keytruda / pembrolizumab / MK-3475 / lambrolizumab (Merk & Schneider, Germany), Co), pidilizumab, durvalumab / MEDI4736, atezolizumab / MPDL3280A / Tecentriq / RG7446 (Roche), avelumab, MEDI0680 (AMP-514, Mediimmune), REGN2810 / cemiplimab (Regeneron), TSR-042 / dostarlimab / dostarlimab-gxly (Tesaro), PF-06801591 / sananlimab (Pfizer), BGB-A317 / tislelizumab (Beigene), BGB-108, INCSHR1210 / camrelizumab (Incyte), and AMP-224 (Amplimmune).

[0206] In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule described in U.S. Patent Application Publication No. 2015 / 0210769, which is incorporated by reference in its entirety.

[0207] In one embodiment, the anti-PD-1 antibody molecule is BGB-A317 / tislelizumab, which is discosed in WO 2015 / 035606, US 2015 / 315274, US 2015 / 079109, and US 2018 / 111995. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), heavy or light chain variable region sequences, or heavy or light chain sequences of BGB-A317 / tislelizumab.

[0208] Heavy chain [ka] -HCDR1: GFSLTSYGVH (SEQ ID NO: 2) -HCDR2: VIYADGSTNYNPSLKS (SEQ ID NO: 3) -HCDR3: ARAYGNYWYIDV (SEQ ID NO: 4)

[0209] Light chain [ka] - LCDR1: KSSESVSNDVA (SEQ ID NO: 6) - LCDR2: YAFHRFT (SEQ ID NO: 7) - LCDR3: HQAYSSPYT (SEQ ID NO: 8)

[0210] In some embodiments, the PD-1 inhibitor is PDR001. PDR001 is also known as spartalizumab. Nivolumab (clone 5C4) and other anti-PD-1 antibodies are disclosed in U.S. Pat. No. 8,008,449 and WO 2006 / 121168, which are incorporated by reference in their entireties. Pembrolizumab and other anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369(2):134-44, U.S. Pat. No. 8,354,509, and WO 2009 / 114335, which are incorporated by reference in their entireties. MEDI0680 and other anti-PD-1 antibodies are disclosed in U.S. Pat. No. 9,205,148, and WO 2012 / 145493, which are incorporated by reference in their entireties. Additional known anti-PD-1 antibodies include, for example, those described in WO 2015 / 112800, WO 2016 / 092419, WO 2015 / 085847, WO 2014 / 179664, WO 2014 / 194302, WO 2014 / 209804, WO 2015 / 200119, U.S. Patent No. 8,735,553, U.S. Patent No. 7,488,802, U.S. Patent No. 8,927,697, U.S. Patent No. 8,993,731, and U.S. Patent No. 9,102,727, which are incorporated by reference in their entireties.

[0211] In one embodiment, the anti-PD-1 antibody molecule is nivolumab (Bristol-Myers Squibb), also known as MDX-1106, MDX-1106-04, ONO-4538, BMS-936558, or OPDIVO®. Nivolumab (clone 5C4) and other anti-PD-1 antibodies are disclosed in U.S. Patent No. 8,008,449 and WO 2006 / 121168, which are incorporated by reference in their entireties.

[0212] In one embodiment, the anti-PD-1 antibody molecule is pembrolizumab (Merck & Co), also known as lambrolizumab, MK-3475, MK03475, SCH-900475, or KEYTRUDA®. Pembrolizumab and other anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369(2):134-44, U.S. Patent No. 8,354,509, and WO 2009 / 114335, which are incorporated by reference in their entireties.

[0213] In one embodiment, the anti-PD-1 antibody molecule is MEDI0680 (Medimmune), also known as AMP-514. MEDI0680 and other anti-PD-1 antibodies are disclosed in U.S. Patent No. 9,205,148 and WO 2012 / 145493, which are incorporated by reference in their entireties. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), heavy or light chain variable region sequences, or heavy or light chain sequences of MEDI0680.

[0214] In one embodiment, the anti-PD-1 antibody molecule is REGN2810 / cemiplimab (Regeneron). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), heavy or light chain variable region sequences, or heavy or light chain sequences of REGN2810.

[0215] In one embodiment, the anti-PD-1 antibody molecule is PF-06801591 (Pfizer). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), heavy or light chain variable region sequences, or heavy or light chain sequences of PF-06801591.

[0216] In one embodiment, the anti-PD-1 antibody molecule is INCSHR1210 (Incyte), also known as INCSHR01210 or SHR-1210. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), heavy chain or light chain variable region sequences, or heavy chain or light chain sequences of INCSHR1210.

[0217] In one embodiment, the anti-PD-1 antibody molecule is TSR-042 (Tesaro), also known as ANB011. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), heavy or light chain variable region sequences, or heavy or light chain sequences of TSR-042.

[0218] Additional known anti-PD-1 antibodies include, for example, those described in WO 2015 / 112800, WO 2016 / 092419, WO 2015 / 085847, WO 2014 / 179664, WO 2014 / 194302, WO 2014 / 209804, WO 2015 / 200119, U.S. Patent No. 8,735,553, U.S. Patent No. 7,488,802, U.S. Patent No. 8,927,697, U.S. Patent No. 8,993,731, and U.S. Patent No. 9,102,727, which are incorporated by reference in their entireties.

[0219] In one embodiment, the anti-PD-1 antibody is an antibody that competes for binding with one of the anti-PD-1 antibodies described herein and / or binds to the same epitope on PD-1.

[0220] In one embodiment, the PD-1 inhibitor is a peptide that inhibits the PD-1 signaling pathway, such as those described in U.S. Patent No. 8,907,053, which is incorporated by reference in its entirety. In one embodiment, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In one embodiment, the PD-1 inhibitor is AMP-224 (B7-DCIg (Amplimmune), e.g., as disclosed in WO 2010 / 027827 and WO 2011 / 066342, which are incorporated by reference in their entireties).

[0221] In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of about 200 mg to about 500 mg (e.g., about 300 mg to about 400 mg). In some embodiments, the PD-1 inhibitor is administered once every three weeks. In some embodiments, the PD-1 inhibitor is administered once every four weeks. In other embodiments, the PD-1 inhibitor is administered at a dose of about 200 mg to about 400 mg (e.g., about 300 mg) once every three weeks. In yet other embodiments, the PD-1 inhibitor is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every four weeks.

[0222] In a specific embodiment, the combination therapy comprises administration of an I / O therapeutic, eg, an anti-PD1 inhibitor, preferably tislelizumab, every 3-4 weeks, such as every 3 weeks.

[0223] In a specific embodiment, the first administration of the I / O therapeutic agent, e.g., an anti-PD1 inhibitor, preferably tislelizumab, is administered less than 15 days, preferably less than 10 days, more preferably less than 7 days before or after the first administration of the radiopharmaceutical.

[0224] In a specific embodiment, the PD1 inhibitor (preferably tislelizumab) is first administered on day 1 along with the first administration of one or more chemotherapeutic agents, and the radiopharmaceutical compound (preferably177 Lu]Lu-DOTA-TATE) is initially administered on days 3-5.

[0225] In a specific embodiment, the I / O therapeutic agent (typically an anti-PD1 inhibitor, more preferably tislelizumab) is administered in combination with the one or more chemotherapeutic agents during the run-in period, preferably with a first administration of the radiopharmaceutical compound on week 1 of the first administration of the chemotherapeutic agent, e.g., on any of days 3, 4, or 5 of week 1, and a second administration of the radiopharmaceutical compound between weeks 6 and 8 (typically 177 [Lu]Lu-DOTA-TATE), preferably administered simultaneously.

[0226] In a specific embodiment of the method of using the radiopharmaceutical compound, the one or more chemotherapeutic agents are administered, preferably in combination with and preferably simultaneously with two administrations of the radiopharmaceutical compound during the induction period, with a first administration of the radiopharmaceutical compound in the first week of the first administration of the chemotherapeutic agent, e.g., on any of days 3, 4 or 5 of week 1, and a second administration of the radiopharmaceutical compound between weeks 6 and 8, and the tumor immunotherapy agent is administered, preferably in combination with and preferably simultaneously with the chemotherapeutic agent, in week 1, preferably on the day of the first administration of the chemotherapeutic agent, every three weeks during the induction period.

[0227] In a specific embodiment, the combination therapy comprises an induction period and a maintenance period, wherein the maintenance period comprises: (i) 1 to 4 administrations of said radiopharmaceutical compound every 3 weeks; and (ii) 1 to 4 administrations of the tumor immunomodulator every 3 weeks.

[0228] In a specific embodiment, the combination therapy comprises an induction period and a maintenance period, during which the subject receives: (i) a chemotherapy agent (e.g., carboplatin and etoposide), preferably with an area under the curve (AUC) of 5 on day 1 and every 3 weeks, and 4 cycles of etoposide at 100 mg / m on days 1-3 and every 3 weeks; (ii) During weeks 1 and 7, preferably on days 3, 4, or 5 of week 1, a radiopharmaceutical compound (e.g., 177 Lu]Lu-DOTA-TATE), and (iii) 4 cycles of an I / O agent (e.g., an anti-PD1 inhibitor, typically tislelizumab) preferably at 200 mg on day 1 and every 3 weeks. During the maintenance period, chemotherapy is discontinued and subjects receive: (iv) For example, at weeks 13, 16, 19, and 22, the radiopharmaceutical compound (e.g., 177 1 to 4 doses of [Lu]Lu-DOTA-TATE), (v) 200 mg of an I / O drug (e.g., an anti-PD1 inhibitor, typically tislelizumab) every 3 weeks, preferably 2 to 4 doses of an anti-PD1 inhibitor.

[0229] Efficacy of combination therapy In certain aspects, the combined effect of the radiopharmaceutical compound (PRRT) and chemotherapy increases the overall response rate by at least 10%, 20%, 30%, 40%, or at least 50% compared to chemotherapy alone and / or compared to PRRT in combination with radiation therapy.

[0230] In certain embodiments, the combination therapy of the present disclosure may inhibit, delay, and / or reduce tumor growth in a subject. In certain embodiments, tumor growth is delayed by at least 10%, 20%, 30%, or 50% compared to an untreated control. In certain embodiments, tumor growth is delayed by at least 20% compared to an untreated control. In certain embodiments, tumor growth is delayed by at least 10%, 20%, 30%, or 80% compared to tumor growth expected without treatment. In certain embodiments, tumor growth is delayed by at least 20% compared to tumor growth expected without treatment.

[0231] In certain embodiments, administering a composition comprising a radiopharmaceutical composition to a subject eligible for said treatment can prolong the survival of the subject. In certain embodiments, the prolongation of survival is compared to an untreated control or to a control treated with standard of care for ES-SCLC subjects, typically chemotherapy with carboplatin and etoposide, optionally in combination with an I / O therapy such as an anti-PD-1 antibody, anti-PD-L1 antibody, or anti-CTLA4 antibody. In certain embodiments, the prolongation of survival is compared to the expected survival of the subject without treatment. In certain embodiments, survival is prolonged by at least 10%, 20%, or 30% compared to an untreated control or to a control treated with standard of care for ES-SCLC subjects, typically chemotherapy with carboplatin and etoposide, optionally in combination with an I / O therapy such as an anti-PD-1 antibody, anti-PD-L1 antibody, or anti-CTLA4 antibody. In certain embodiments, survival is prolonged by at least 20% compared to an untreated control. In certain embodiments, survival is increased by at least 10%, 20%, or 30% compared to the expected survival of a subject without treatment. In certain embodiments, survival is increased by at least 20% compared to the expected survival of a subject without treatment. In certain embodiments, survival is increased by at least 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, or 3 years compared to untreated controls or compared to controls, particularly ES-SCLC subjects, treated with standard of care for SCLC, typically chemotherapy with carboplatin and etoposide, optionally in combination with an I / O therapeutic agent such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA4 antibody. In certain embodiments, survival is increased by at least 1 month, 3 months, or 6 months compared to untreated controls. In certain aspects, survival is extended by at least 1 week, 1 week, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, or 3 years compared to the expected survival of a subject without treatment, or compared to the expected survival of a control, particularly an ES-SCLC subject, treated with standard of care for SCLC, typically chemotherapy with carboplatin and etoposide, optionally in combination with an I / O therapeutic agent such as an anti-PD-1, anti-PD-L1, or anti-CTLA4 antibody.In certain aspects, survival is extended by at least 1 month, 3 months, or 6 months compared to the expected survival of a subject without treatment, or compared to the expected survival of a control, particularly an ES-SCLC subject, treated with standard of care for SCLC, typically chemotherapy with carboplatin and etoposide, optionally in combination with an I / O therapy, such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA4 antibody.

[0232] Methods for Selecting Targets for Combination Therapy In certain embodiments of the present disclosure, the small cell lung cancer is an SSTR positive disease. In one embodiment, the subject is selected for treatment with SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging with the same organic compound as used in PRRT, but with a radiometal suitable for imaging, i.e., an imaging radiopharmaceutical compound. Exemplary radiometals suitable for use as contrast agents in imaging include: 111 In, 133m In, 99m Tc, 94m Tc, 67 Ga, 66 Ga, 68 Ga, 52 Fe, 72 As, 97 Ru, 203 Pb, 62 Cu, 64 Cu, 61 Cu 177 Lu, 86 Y, 51 Cr, 52m Mn, 157 Gd, 169 Yb, 172 Tm, 117m Sn, 123 I, 124 I, 125 I, 18 F, Al 18 F, 152 Tb, 155 Tb, 82 Rb, 89 Zr, 43 Sc, 44 Sc.

[0233] According to a preferred embodiment, the radiometal suitable for imaging is 67 Ga, 68 Ga or 64 Cu, preferably 68 It's Ga.

[0234] In one embodiment, in particular 177 When [Lu]Lu-DOTA-TATE is used for PRRT in combination therapy, subjects will be 68 Selected by assessing Ga-DOTA-TATE uptake.

[0235] Therefore, the present disclosure also relates to a method for determining whether a human patient with SSTR-positive SCLC, in particular ES-SCLC, is eligible for said combination therapy disclosed herein, said method comprising: (i) administering an effective amount of an imaging radiopharmaceutical compound as an imaging agent for imaging uptake of said radiopharmaceutical compound; (ii) acquiring a PET / MRI or PET / CT image of the patient; (iii) comparing with a control image; The present invention relates to a method for producing a semiconductor device comprising the steps of:

[0236] The objective of the above method is to select for combination therapy patients with SSTR-positive tumors, i.e., tumors that can be detected by injecting an imaging radiopharmaceutical SSTR-binding compound, typically labeled with DOTA-TATE, as a contrast agent and then assessing its uptake by PET / MRI or PET / CT imaging.

[0237] Advantageously, SSTR-positive patients exhibit a statistically better response to treatment compared to a randomized patient population (i.e., a patient population not selected by the selection step of the method) and / or exhibit fewer side effects to treatment compared to a randomized patient population (i.e., a patient population not selected by the selection step of the method).

[0238] In certain embodiments, 68 Ga-DOTA-TATE is provided in a kit called NETSPOT® (Gallium Ga 68 Dotatate (USAN)). This kit has been approved in the United States (USA) (2016), Canada (2019), and Switzerland (2019). 68 A kit for the preparation of radiopharmaceuticals of 1,2-Dimethyl-2,4-Diphenyl-2,4-dimethyl-1,2,4-tetrahydro-2,4-hexanediaminetetraacetate (Ga) and 1,2-Dimethyl-2,4-hexanediaminetetraacetate (Ga) for the following indications: 68 It is a radioactive diagnostic agent that is radiolabeled with 1000 ng / mL (Ga) and then used in conjunction with PET to localize SSTR-positive neuroendocrine tumors (NETS) (NETSPOT® PI).

[0239] In one embodiment, subject selection occurs 10-28 days, preferably about 14 days, prior to the first administration of the radiopharmaceutical compound.

[0240] In certain embodiments, the imaging radiopharmaeutical is administered at a dose of between 1.5MBq / kg (0.040mCi / kg) and 2.5MBq / kg (0.067mCi / kg), preferably about 2MBq / kg body weight (0.054mCi / kg), with a minimum dose of 100MBq (2.7mCi) and a maximum dose of 200MBq (5.4mCi), typically administered by intravenous injection, preferably slow intravenous injection.

[0241] 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 identify whether lesions identified by conventional imaging, e.g., MRI, CT, SPECT or PET, are also identified by the imaging radiopharmaceutcal compound uptake, i.e., 68Ga-DOTA-TATE uptake. Typically, PET / MRI or PET / CT imaging is performed between 30 and 120 minutes, preferably between 60 and 90 minutes, after intravenous administration of the imaging radiopharmaceutical compound to the subject.

[0242] In a specific embodiment of the method, a subject is selected for the combination therapy of the present disclosure and meets the following criteria: in said subject, 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 such as, for example, MRI, CT, SPECT or PET, are also identified by imaging radiopharmaceutical compound uptake, for example 68Ga-DOTA-TATE uptake, as determined by PET / MRI or PET / CT imaging in said subject.

[0243] In a specific embodiment, the term "lesion" refers to a tumor lesion measurable 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.

[0244] In a particular embodiment, the subject is newly diagnosed with SCLC, in particular ES-SCLC.

[0245] In a particular embodiment, said subject has SSTR-positive SCLC, in particular ES-SCLC.

[0246] In another embodiment, the subject has not received prior systemic treatment for SCLC, particularly ES-SCLC, and in particular said subject has not received prior chemotherapy for the treatment of SCLC, particularly ES-SCLC. In a particularly specific embodiment, said subject has not been identified as having relapsed or refractory SCLC, particularly ES-SCLC, after first-line chemotherapy. EXAMPLES

[0247] Example 1: Clinical Trial for Treating ES-SCLC Subjects Provided herein are methods for determining whether or not a patient with newly diagnosed extended stage small cell lung cancer (ES-SCLC) has a pulmonary function that is associated with a decreased risk of developing pulmonary edema. 177 This is an example protocol describing a prospective, phase Ib, dose-finding study evaluating the safety and activity of [Lu]Lu-DOTA-TATE in combination with carboplatin, etoposide, and tislelizumab in the induction phase, and in combination with tislelizumab in the maintenance phase.

[0248] 1. Protocol Overview Objective: This study aimed to 177 "Our goal is to establish a safe and well-tolerated dose of [Lu]Lu-DOTA-TATE and evaluate the preliminary activity of combination therapy. The studies are essential to evaluate possible new treatment options for patients with this aggressive cancer type."

[0249] The primary objective was to evaluate the efficacy and safety of ES-SCLC in patients with newly diagnosed ES-SCLC. 177 The objective of this study was to establish the recommended doses of [Lu]Lu-DOTA-TATE in combination with carboplatin, etoposide, and tislelizumab during induction therapy, and in combination with tislelizumab during maintenance therapy.

[0250] Secondary objectives are listed below: In patients with newly diagnosed ES-SCLC,177 To characterize the safety and tolerability of [Lu]Lu-DOTA-TATE in combination with carboplatin, etoposide, and tislelizumab during induction therapy, and in combination with tislelizumab during maintenance therapy. In patients with newly diagnosed ES-SCLC, 68 To evaluate the safety and tolerability of Ga]Ga-DOTA-TATE In patients with newly diagnosed ES-SCLC, 177 To evaluate the preliminary antitumor activity of [Lu]Lu-DOTA-TATE In patients with newly diagnosed ES-SCLC, 177 Characterize the pharmacokinetics (PK) and dosimetry of [Lu]Lu-DOTA-TATE - Characterize the pharmacokinetics and immunogenicity of tislelizumab in patients with newly diagnosed ES-SCLC

[0251] Study design This is in participants with newly diagnosed ES-SCLC [ 177 This is a multicenter, open-label, phase Ib study between [Lu]Lu-DOTA-TATE in combination with carboplatin, etoposide, and tislelizumab during induction therapy and in combination with tislelizumab during maintenance therapy.

[0252] Each participant's study will consist of a screening period, a treatment period including an induction and maintenance period, and a follow-up period.

[0253] Eligible participants will be enrolled in cohorts of 3 to 6 and will receive: During the induction period, carboplatin at an area under the curve (AUC) of 5 on day 1 and etoposide at 100 mg / m2 on days 1-3 were administered every 3 weeks at weeks 1, 4, 7, and 10 for 4 cycles. During the induction and maintenance periods, 200 mg of tislelizumab on day 1 of every 3 weeks During the implementation period, two [ 177administration of ]Lu-DOTA-TATE, followed by 1 to 4 doses on day 1 of week 13, day 1 of week 16, day 1 of week 19, and day 1 of week 22 during the maintenance period, depending on the dose evaluated.

[0254] [ 177 Up to six different dose level combinations of [Lu]Lu-DOTA-TATE will be evaluated in the study as follows: Dose level 1 (DL1): 100 mCi during the induction period 177 Lu]Lu-DOTA-TATE, and 100 mCi of [ 177 Lu]Lu-DOTA-TATE Dose level 2a (DL2a): 150 mCi during both the induction and maintenance periods 177 Lu]Lu-DOTA-TATE Dose level 2b (DL2b): 150 mCi during the induction period 177 Lu]Lu-DOTA-TATE, and 200 mCi of [ 100 Lu]Lu-DOTA-TATE Dose level 3a (DL3a): 200 mCi during both the induction and maintenance periods 177 Lu]Lu-DOTA-TATE Dose level 3b (DL3b): 200 mCi during the induction period 177 Lu]Lu-DOTA-TATE, and 250 mCi of [ 177 Lu]Lu-DOTA-TATE Dose level 4 (DL4): 250 mCi during both the induction and maintenance periods 177 Lu]Lu-DOTA-TATE

[0255] The dose escalation portion of this study will be guided by the rate of dose-limiting toxicity (DLT) observed within the first 6 weeks (42 days) of treatment. In addition to DLTs, the totality of safety data available at the time will be evaluated for each dose escalation decision. Dose escalation / deescalation will be performed using a Bayesian optimal interval approach (BOIN).

[0256] Rationale: This is in patients with ES-SCLC [ 177 As this is the first study of [Lu]Lu-DOTA-TATE, its efficacy and safety in this population have yet to be established. However, it is thought that the effect of [Lu]Lu-DOTA-TATE on tumor cells expressing somatostatin receptors (SSTRs) is not yet known. 177 Based on the mechanism of action of [Lu]Lu-DOTA-TATE and the available preclinical and clinical data, it is quite likely that patients with ES-SCLC would benefit from targeted radioligand therapy. This study is essential to provide a potential new treatment option for ES-SCLC, and given the unmet medical need and limited treatment options, the benefit / risk assessment for patients with ES-SCLC in this Phase Ib study is considered favorable.

[0257] [Table X1]

[0258] [Table X2]

[0259] 2. Detailed study design Each participant's study will consist of a screening period, a treatment period including an induction and maintenance period, and a follow-up period.

[0260] Screening Period During a screening period of up to 28 days prior to the start of SCLC treatment, participants' eligibility will be determined according to the protocol's predefined inclusion and exclusion criteria. 68 Imaging with [Ga]Ga-DOTA-TATE should be performed as soon as possible during screening to avoid delaying participant enrollment.

[0261] Participants who meet all eligibility criteria at screening may be enrolled in the study. 177Orders for Lu]Lu-DOTA-TATE should be placed immediately after all eligibility criteria have been verified and participants have been confirmed as eligible.

[0262] [ 68 All participants who received 1Ga]Ga-DOTA-TATE were 68 Patients will be followed up by dedicated telephone calls 2 days after administration of Ga]Ga-DOTA-TATE to assess the occurrence of AEs.

[0263] Duration of treatment The treatment period will consist of an induction period and a maintenance period. Eligible participants will be enrolled in cohorts of 3-6 and will receive: During the run-in period, every 3 weeks, carboplatin at an area under the curve (AUC) of 5 on day 1 and 100 mg / mm on days 1 to 3. 2 4 cycles of etoposide During the induction and maintenance periods, 200 mg of tislelizumab on day 1 of every 3 weeks During the implementation period 177 Two doses of [Lu]Lu-DOTA-TATE: on either days 3, 4, or 5 of week 1 and day 3 of week 7, followed by one to four doses depending on the dose evaluated on days 13, 16, 19, and 22 during the maintenance period.

[0264] The study is expected to enroll approximately 39 participants in total. The investigators will not continue to enroll cohorts until they receive written confirmation from the sponsor that the results of the previous cohort have been evaluated and it is OK to begin the new cohort.

[0265] [ 177 Up to six different dose level combinations of [Lu]Lu-DOTA-TATE will be evaluated in the study as follows: Dose level 1 (DL1): 100 mCi during the induction period 177 Lu]Lu-DOTA-TATE, and 100 mCi of [ 177 Lu]Lu-DOTA-TATE Dose level 2a (DL2a): 150 mCi during both the induction and maintenance periods 177 Lu]Lu-DOTA-TATE Dose level 2b (DL2b): 150 mCi during the induction period 177 Lu]Lu-DOTA-TATE, and 200 mCi of [ 100 Lu]Lu-DOTA-TATE Dose level 3a (DL3a): 200 mCi during both the induction and maintenance periods 177 Lu]Lu-DOTA-TATE Dose level 3b (DL3b): 200 mCi during the induction period 177 Lu]Lu-DOTA-TATE, and 250 mCi of [ 177 Lu]Lu-DOTA-TATE Dose level 4 (DL4): 250 mCi during both the induction and maintenance periods 177 Lu]Lu-DOTA-TATE At dose level 1, participants received 177 Lu]Lu-DOTA-TATE was administered four times (i.e., a total of [ 177 Six doses of 600mCi of [Lu]Lu-DOTA-TATE were administered; cumulative dose 600mCi. Higher doses may result in a cumulative dose of over 800mCi. 177 Prior to administration of a dose of [Lu]Lu-DOTA-TATE, the following checks are performed: For dose level 2a: The third dose during the maintenance period 177 After administration of [Lu]Lu-DOTA-TATE (i.e., the fifth [ 177 After administration of Lu-DOTA-TATE) For dose levels 2b and 3a: The second dose during the maintenance period 177 After administration of [Lu]Lu-DOTA-TATE (i.e., the fourth [ 177 After administration of Lu-DOTA-TATE) For dose levels 3b and 4: The first dose during the maintenance period 177 After administration of [Lu]Lu-DOTA-TATE (i.e., the third [ 177After administration of Lu-DOTA-TATE)

[0266] The investigator should determine: • Participants demonstrate evidence of disease stabilization or response (i.e., as assessed by radiological or clinical benefit). ●[ 177 Lu]Lu-DOTA-TATE treatment is well tolerated.

[0267] If participants meet all the above criteria, 177 If the patient agreed to continue the maintenance treatment with Lu]Lu-DOTA-TATE, the investigator 177 One to three additional cycles with a cumulative dose of [Lu]Lu-DOTA-TATE >800 mCi may be administered. Up to six cycles of radioligand treatment, corresponding to a maximum of 1500 mCi, are permitted (see next section for rationale).

[0268] [ 177 For renal protection, each 177 At the time of administration of [Lu]Lu-DOTA-TATE, an infusion of 2.5% lysine-arginine amino acid (AA) solution is administered concomitantly. Antiemetics should be administered to prevent infusion-related nausea and vomiting.

[0269] In the approved GEP-NET indication, more frequent dosing compared with Q8W dosing 177 To assess absorbed doses in vital organs and tumor lesions when administered [Lu]Lu-DOTA-TATE, the first three participants (1, 2a, 3a, and 4) at each dose level received a second [ 177 Each participant will undergo additional dosimetry / PK assessments during the first week after administration of [Lu]Lu-DOTA-TATE, i.e., once during the study treatment period. 177 In the exceptional circumstances where it is not possible to perform dosimetry in a particular participant after the second [Lu]Lu-DOTA-TATE administration, dosimetry should be completed as soon as possible after the second [Lu]Lu-DOTA-TATE administration.177 Dosimetry analyses of [Lu]Lu-DOTA-TATE administration, in conjunction with participants' global assessment of safety and efficacy, will be used as supportive data for the more frequent regimen.

[0270] Up to six additional patients may be enrolled at dose levels already tested to provide additional safety, tolerability, and pharmacokinetic data.

[0271] Each participant will be treated until disease progression per RECIST 1.1 or discontinued for another reason. For participants receiving tislelizumab in the maintenance phase, treatment beyond the first investigator-assessed disease progression as defined by RECIST v1.1 will be permitted only if the participant has an investigator-assessed clinical response, tolerates the study drug, and certain conditions are met.

[0272] The end-of-treatment visit must occur within 28 days after the last dose of study treatment.

[0273] Rationale for study design Despite initial responses to first-line treatment for patients with newly diagnosed ES-SCLC, prognosis remains poor, with overall survival approximately 10-12 months. There is an unmet medical need for novel therapeutic options that would improve outcomes for patients with this aggressive disease.

[0274] SSTR expression has been demonstrated in SCLC by both histology and imaging methods, and in patients with this tumor type [ 177The study provides a biological rationale for the use of radioligand therapy with [Lu]Lu-DOTA-TATE (Reisinger I, Bohuslavitzki KH, Brenner W, et al (1998) J Nucl Med; 39(2): 224-7, Reubi JC, Waser B, Schaer JC, et al (2001) Eur J Nucl Med; 28(7): 836-46, Lehman JM, Hoeksema MD, Staub J, et al (2019) Int J Cancer; 144: 1104-14). This study supports the use of [Lu]Lu-DOTA-TATE in other SSTR-positive tumors. 177 Based on the efficacy of [Lu]Lu-DOTA-TATE, it should result in synergistic antitumor responses in SSTR-positive ES-SCLC. 177 To evaluate the combination of [Lu]Lu-DOTA-TATE with established first-line therapies in ES-SCLC.

[0275] This was combined with carboplatin, etoposide, and tislelizumab in patients with newly diagnosed ES-SCLC. 177 This is the first clinical study to evaluate [Lu]Lu-DOTA-TATE. The primary objective is to evaluate the efficacy and safety of [Lu]Lu-DOTA-TATE in induction and maintenance phases with the aim of selecting the appropriate dose in this setting. 177 The aim of the study was to evaluate several doses of [Lu]Lu-DOTA-TATE. 177 The first cycle of [Lu]Lu-DOTA-TATE will be assessed for DLT and dose escalation / deescalation will be performed based on the Bayesian optimal interval approach (BOIN) (Liu S, Yuan Y (2015) Bayesian optimal interval designs for phase I clinical trials; 64 (3): 507-23; Yuan Y, Hess KR, Hilsenbeck SG, et al (2016) Clin Cancer Res; 22 (17): 4291-301).

[0276] The secondary objective of the study was to 177The study was selected to assess the overall safety of [Lu]Lu-DOTA-TATE and to evaluate preliminary signs of antitumor activity of the combination. For the evaluation of antitumor activity, progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and DoR will be evaluated since these are the most relevant endpoints. In addition, 177 As [Lu]Lu-DOTA-TATE is a radioligand compound, its dosimetry and pharmacokinetics will be evaluated. Evaluation of SSTR expression will be performed as part of the exploratory objectives.

[0277] The study has a non-randomized, open-label design and is considered suitable for a Phase I dose-escalation trial. As is the standard approach for Phase I trials in cancer patients, the study will be conducted at multiple sites in multiple countries.

[0278] In summary, this multicenter, open-label clinical trial demonstrated the efficacy and safety of ES-SCLC in participants with newly diagnosed ES-SCLC. 177 To establish a safe and well-tolerated dose of [Lu]Lu-DOTA-TATE in combination with carboplatin, etoposide, and tislelizumab during induction therapy, and with tislelizumab during maintenance therapy. 177 To investigate the safety, preliminary antitumor activity, pharmacokinetics, and dosimetry of [Lu]Lu-DOTA-TATE.

[0279] Rationale for dose / regimen and duration of treatment [ 177 Rationale for dose and schedule selection of [Lu]Lu-DOTA-TATE In established GEP-NET indications 177The approved adult regimen of [Lu]Lu-DOTA-TATE consists of four doses (7.4 GBq / 200 mCi each) administered every 8 weeks (cumulative dose: 29.6 GBq / 800 mCi). This regimen has been shown to be safe and to lead to significant improvements in progression-free survival (PFS) and quality of life in patients with GEP-NETs (Strosberg J, Leeuwenkamp O, Siddiqui MK (2021) Cancer Treat Rev; 93: 102141; Strosberg J, Wolin E, Chasen B, et al (2018). J Clin Oncol; 36 (25): 2578-84).

[0280] In contrast to well-differentiated GEP-NETs, ​​which generally have an indolent course, ES-SCLC is a highly aggressive disease, and patients progress rapidly even with established drug regimens. In the IMPower133 study, patients in the atezolizumab treatment group had a PFS of 5.2 months (Horn L, Mansfield AS, Szczesna A, et al (2018) N Engl J Med; 379 (23): 2220-9), and in the CASPIAN study, patients in the durvalumab treatment group had a PFS of 5.1 months (Paz-Ares L, Dvorkin M, Chen Y, et al (2019) Lancet; 394: 1929-39). Due to the short PFS in this patient population, [ 177 The standard 8-week interval for administration of [Lu]Lu-DOTA-TATE would not be sufficient to deliver an effective cumulative radioactive dose. 177 The dosing interval of [Lu]Lu-DOTA-TATE was shortened. Due to the potential overlap of myelotoxicity of the combination regimens during the induction period, the regimens were evaluated every 6 weeks, whereas during the chemotherapy-free maintenance period, 177 The dosing interval of [Lu]Lu-DOTA-TATE will be shortened to every 3 weeks. The Q3W regimen will also be synchronized with the tislelizumab treatment schedule.

[0281] This is in patients with ES-SCLC [ 177Because this is the first study of the combination of [Lu]Lu-DOTA-TATE with carboplatin, etoposide, and tislelizumab, the starting dose of the first cohort was set at 1 mg / kg for both induction and maintenance periods to minimize safety risks of overlapping toxicities. 177 The starting dose of 100 mCi was chosen as [Lu]Lu-DOTA-TATE. The starting dose of 100 mCi is supported by a phase II study that assessed this dose as being well tolerated in patients previously treated with chemotherapy, radioligand therapy, and who presented with risk factors or abnormalities in renal and bone marrow function (Paganelli G, Sansovini M, Ambrosetti A, et al (2014) Eur J Nucl Med Mol Imaging; 41: 1845-51). In this study, [ 177 A dose of 100 mCi (compared to the approved dose of 200 mCi for [Lu]Lu-DOTA-TATE) reduced absorbed dose in vital organs while maintaining efficacy. 177 This is the dose reduction level implemented to address toxicity due to Lu]Lu-DOTA-TATE ([ 177 Lu]Lu-DOTA-TATE Clinical Trial Investigator Brochure).

[0282] Given the favorable safety profile of 800 mCi, and given the differences in disease aggressiveness and prognosis between patients with SCLC and those with GEP-NETs, ​​as reflected in a median overall survival of 12.3 months in ES-SCLC versus 48 months in patients with GEP-NETs (Strosberg J, Caplin M, Kunz P, et al (2021) Final overall survival in the phase 3 NETTER-1 study of lutetium-177-DOTATATE in patients with midgut neuroendocrine tumors

[4112] Poster presented at the American Society of Clinical Oncology Annual Meeting, held virtually June 4-8, 2021), the possibility of exceeding a cumulative dose of 800 mCi in patients with SCLC may be considered (Horn L, Mansfield AS, Szczesna A, et al (2018) N Engl J Med; 379 (23): 2220-9). Furthermore, [ 177 There is an accumulating body of evidence from the literature indicating that, if additional doses of [Lu]Lu-DOTA-TATE are required, they can be administered without additional safety signals, suggesting that, given careful evaluation of the patient, cumulative doses may exceed 800 mCi to maximize benefit without compromising safety (Strosberg J, Leeuwenkamp O, Siddiqui MK (2021) Cancer Treat Rev; 93: 102141). Thus, [ 177 The frequency of administration of [Lu]Lu-DOTA-TATE may vary depending on the dose level evaluated, the physician's judgment, and patient tolerability.

[0283] Recently, a population analysis was performed on adult patient populations from two studies (Erasmus and NETTER-1) to identify covariates influencing kidney and bone marrow dosimetry. The results showed a significant effect of renal function and dose on kidney and bone marrow dosimetry, which is in agreement with the publication by Svensson (Svensson J, Berg G, Wangberg B, et al (2015) Eur J Nucl Med Mol Imaging; 42: 947-55). In both studies, dosimetry assessments were performed after the first dose, and [ 177 Lu]Lu-DOTA-TATE was administered on average every 8 weeks. 177 Given the fact that excretion of [Lu]Lu-DOTA-TATE occurs mainly via the renal route, metabolism is very low (if at all), and the drug does not interact with drug transporters, its distribution and uptake in healthy tissues in patients with SCLC are not expected to be significantly different from patients with GEP-NETs. In this study, increasing the dosing frequency may affect acute toxicity, for example, time to bone marrow (BM) recovery. Therefore, it is proposed to perform dosimetry evaluation after the second dose instead of after the first dose to evaluate how a more frequent regimen correlates with dosimetry and acute toxicity (i.e., time to BM recovery).

[0284] Rationale for choice of chemotherapy and tislelizumab dose and schedule All chemotherapy doses and schedules were based on product labeling, literature, and local guidelines.

[0285] For tislelizumab, a recommended dose for the pivotal clinical trial was determined based on a comprehensive analysis of pharmacokinetic, safety, and efficacy data from the first-in-human study, BGB-A317_Study_001, as well as data from other clinical trials. A fixed dose of 200 mg administered intravenously once every 3 weeks was selected for further evaluation.

[0286] The incidence of treatment-related and serious adverse events observed in patients receiving 2 mg / kg and 5 mg / kg every 2 weeks was similar to that in patients receiving 2 mg / kg and 5 mg / kg every 3 weeks, suggesting no clear dose-dependence across these regimens.Similarly, confirmed overall response rates (ORR) in patients receiving 2 mg / kg and 5 mg / kg tislelizumab every 2 weeks ranged from 10% to 15%, compared with 15% to 38% in patients receiving 2 mg / kg and 5 mg / kg every 3 weeks.

[0287] Pharmacokinetic data from the Phase Ia study BGB-A317_Study_001 showed that CL of tislelizumab was independent of body weight, ethnicity, or gender, and serum exposures observed at the 200 mg dose were between those observed at doses of 2 mg / kg and 5 mg / kg (a dose range with comparable safety and efficacy rates).

[0288] Furthermore, no unexpected treatment-related adverse events occurred in the 200 mg fixed-dose cohort (BGB-A317_Study_001, Phase Ia, Part 3) when compared with the weight-based cohort. Among treated evaluable patients (n=13), 3 patients (23%) had a BOR of partial response (PR), 4 patients (31%) had a BOR of stable disease, and 6 patients (46%) had a BOR of progressive disease (PD). Thus, clinical activity with a manageable and tolerable safety profile is expected to be maintained in patients receiving 200 mg tislelizumab once every 3 weeks.

[0289] Furthermore, in a Phase II study of Tislelizumab in combination with platinum-based chemotherapy as first-line treatment for advanced lung cancer, all patients received 200 mg of Tislelizumab combined with 4 to 6 cycles of a platinum doublet. Demonstrated to promote antitumor activity, especially in the SCLC patient group, the drug was generally well tolerated, and distinct immune-related and cell cycle-related gene signatures were associated with efficacy across the cohort (Wang Z, Zhao J, Ma Z, et al (2020) A Phase 2 Study of Tislelizumab in Combination With Platinum-Based Chemotherapy as First-line Treatment for Advanced Lung Cancer in Chinese Patients. Lung Cancer; 147: 259-68).

[0290] In conclusion, based on the above rationale, a definitive dose of 200 mg of tislelizumab was selected in this ES-SCLC study.

[0291] Treatment with tislelizumab in this study will continue until disease progression. However, selected participants will be allowed to continue tislelizumab treatment after radiological progression according to RECIST v1.1. In light of the fact that second-line treatment of ES-SCLC has an unfavorable benefit-risk profile manifested by low efficacy and high toxicity, and the possibility of pseudoprogression / tumor immune infiltration as a result of immunotherapy that may not be reflected unbiasedly on the first radiographic evaluation, at the discretion of the investigator and in consultation with the medical monitor, participants may be considered to receive treatment beyond radiographic disease progression according to RECIST v1.1. Participants who continue treatment beyond radiographic disease progression according to RECIST v1.1 will be closely monitored clinically and tumor evaluations will continue as scheduled until clinical benefit is lost.

[0292] Rationale for choice of combination agent In this study,177 [Lu]Lu-DOTA-TATE is administered in combination with an established combination of platinum-based chemotherapy and checkpoint inhibitors. As discussed above, there is a significant unmet need for new agents with novel mechanisms of action and no overlapping toxicities that can be combined with established therapies in patients with ES-SCLC. Multiple targeted agents that have been investigated in the past two decades, including those targeting tyrosine kinase (TKI) such as epidermal growth factor receptor (EGFR) TKI and BCR-ABLTKI, mammalian target of rapamycin (mTOR) signaling pathway, and vascular endothelial growth factor (VEGF) signaling pathway, have not been successful in demonstrating survival benefit in this disease (Mamdani H, Induru R, Jalal SI (2015) Transl Lung Cancer Res; 4 (5): 533-44). Platinum chemotherapy (carboplatin or cisplatin) with etoposide has been the standard of care for SCLC for over 20 years (Farago AF, Keane FK (2018) Transl Lung Cancer Res; 7(1): 69-79).

[0293] Recently, immune checkpoint inhibitors have been added to the standard treatment scheme. The combination of atezolizumab and carboplatin-etoposide (C / E), followed by atezolizumab during maintenance, improved OS by approximately 2 months compared to C / E (12.3 vs. 10.3 months, HR=0.70, p=0.007) and PFS by approximately 1 month (5.2 vs. 4.3 months, HR=0.77, p=0.02) (Horn L, Mansfield AS, Szczesna A, et al (2018) N Engl J Med;379(23):2220-9). On this basis, this combination has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as first-line (1L) treatment for ES-SCLC. Similarly, the FDA and EMA recently approved the PD-L1 inhibitor durvalumab in combination with platinum and etoposide for the 1L treatment of ES-SCLC, following results from the randomized phase III CASPIAN trial that showed an improvement in median overall survival from 10.3 to 13.0 months (Paz-Ares L, Dvorkin M, Chen Y, et al (2019) Lancet;394:1929-39).

[0294] Currently, the standard first-line treatment for patients with ES-SCLC is four cycles of platinum-based chemotherapy (cisplatin or carboplatin) and etoposide combined with a checkpoint inhibitor (CPI) (atezolizumab or durvalumab) (NCCN Guidelines Small Cell Lung Cancer Version 3.2021; Dingemans AMC, Fruh M, Ardizzoni A, et al (2021) Ann Oncol; 32 (7): 839-53). However, despite the addition of immunotherapy to first-line (1L) treatment, ES-SCLC remains a refractory disease. As SCLC is a radiosensitive tumor of neuroendocrine origin with intermediate to high expression of SSTR-2 receptor target, preclinical and clinical evidence supports the use of immunotherapy in patients with ES-SCLC. 177We support the investigation of radioligand targeted therapy with]Lu-DOTA-TATE in combination with carboplatin, etoposide, and checkpoint inhibitors, with the aim of improving clinical outcomes for patients with ES-SCLC in the first-line clinical treatment setting.

[0295] The choice of tislelizumab as an immune checkpoint inhibitor component in the combination scheme was based on data from clinical trials of tislelizumab, which demonstrated that tislelizumab is comparable to other checkpoint inhibitors in terms of safety and preliminary activity in patients with advanced solid tumors. Furthermore, it was shown that the combination of tislelizumab with various standard of care chemotherapy in the first-line treatment of lung cancer did not result in any new safety signals compared to other checkpoint inhibitors plus chemotherapy. In a phase II study (BGB-A317-206) of tislelizumab combined with platinum-based chemotherapy as first-line treatment of patients with advanced lung cancer, in a cohort of 17 patients with SCLC, tislelizumab (Q3W, day 1) plus cisplatin / carboplatin (Q3W, day 1), and etoposide (Q3W, days 1, 2, and 3) were administered. Promising antitumor activity was observed, with an ORR of 77%, a median PFS of 6.9 months, and a median OS of 15.6 months. The regimen was generally well tolerated, and distinct immune- and cell cycle-related gene signatures were associated with efficacy across the cohort (Wang Z, Zhao J, Ma Z, et al (2020) Lung Cancer; 147: 259-68).

[0296] Currently, tislelizumab is being studied in a randomized, double-blind, placebo-controlled, multicenter, Phase III study (BGB-A317-312) to compare the efficacy of tislelizumab plus cisplatin or carboplatin and etoposide as first-line treatment with placebo plus cisplatin or carboplatin and etoposide (Arm B) in approximately 364 patients with previously untreated ES-SCLC. Although the study has not yet been published, data collected from previous studies indicate that tislelizumab, whether as monotherapy or in combination with platinum-based chemotherapy, has established a manageable safety profile, with the most common side effects being consistent with the known class effects of other anti-PD-1 antibodies.

[0297] In addition to anticancer drugs, this study 68 Ga]Ga-DOTA-TATE is used as the imaging PET agent. The choice of this compound is based on 177 Lu]Lu-DOTA-TATE and [ 68 The mechanism of action is based on [Ga]Ga-DOTA-TATE, a diagnostic therapeutic drug pair that targets SSTR receptors to provide targeted imaging and targeted radiotherapy.

[0298] 3. Drugs used in clinical trials

[0299] [Table 1]

[0300] [ 177 Lu]Lu-DOTA-TATE Lutathera® has a volumetric activity of 370 MBq / mL at the reference time (calibration time (tc)). 177 The total amount of radioactivity per single-dose vial of sterile radiopharmaceutical supplied as a ready-to-use infusion solution containing [Lu]Lu-DOTA-TATE is 7,400 MBq / 7.4 GBq (200 mCi) ± 10% at the time of injection.

[0301] Tislelizumab Tislelizumab is a monoclonal antibody formulated for intravenous administration in single-use vials (20R glass, United States Pharmacopeia [USP] Type I) containing a total of 100 mg of antibody in 10 mL of isotonic solution. Tislelizumab is filled aseptically into single-use glass vials with rubber stoppers and capped with aluminum flip-off seal caps. Each vial is packaged in a single carton box.

[0302] 200 mg of tislelizumab will be administered on day 1 of each 21-day cycle (once every 3 weeks).

[0303] [ 68 Ga]Ga-DOTA-TATE NETSPOT® contains 40mcg of DOTA-TATE 68 This is a kit for preparing the radiopharmaceutical [Ga]Ga-DOTA-TATE. 68 [Ga]Ga-DOTA-TATE is used as an imaging agent to characterize the SSTR during screening.

[0304] gallium( 68 After being radiolabeled with 1,000 ng / g, it serves as a radioactive diagnostic agent by positron emission tomography (PET) to localize somatostatin receptor-positive tumors.

[0305] For adults, the recommended amount of radioactivity administered for PET imaging is 2MBq / kg body weight (0.054mCi / kg), with a minimum dose of 100MBq (2.7mCi) and a maximum dose of 200MBq (5.4mCi).

[0306] After reconfiguration, [ 68 Administer [Ga]Ga-DOTA-TATE by slow intravenous injection. Images may be acquired 40-90 min after intravenous administration. All participants will be scanned during the screening period.

[0307] Chemotherapy (carboplatin and etoposide) Carboplatin and etoposide are not considered investigational drugs in the study because they are part of the standard of care in the patient population.

[0308] During the run-in period, participants received carboplatin AUC5 and etoposide 100 mg / m on day 1 of each 21-day cycle from cycle 1 to cycle 4. 2 Patients were given etoposide 100mg / m 2 The IV dose will also be given on days 2 and 3 of each of the four cycles.

[0309] Agents should be administered sequentially on day 1. See Table 2 for timing and sequence of tislelizumab and chemotherapy administration.

[0310] [Table 2]

[0311] [ 177 On days when Lu]Lu-DOTA-TATE is administered with other investigational drugs, 177 Lu]Lu-DOTA-TATE was always administered last.

[0312] Additional study treatment Participants can click 177 After each administration of [Lu]Lu-DOTA-TATE, patients will receive a 2.5% Lys-Arg amino acid infusion for renal protection.

[0313] The 2.5% Lys-Arg solution should be administered intravenously at an infusion rate of 250 ml / h. 177 It should be started 30 minutes before the start of the [Lu]Lu-DOTA-TATE infusion and continued for a total of 4 hours (extension to 6 hours is permitted if there is an adverse reaction requiring interruption of the infusion or slowing of the infusion rate).

[0314] The composition of the 2.5% Lys-Arg solution is shown below.

[0315] [Table 3]

[0316] each[ 177 On the day of [Lu]Lu-DOTA-TATE administration, an intravenous bolus of antiemetic should be administered with sufficient lead time according to local prescribing information before starting the infusion of 2.5% Lys-Arg solution. The choice of antiemetic is at the investigator's discretion according to local regulations (recommended options: granisetron (3 mg), or ondansetron (8 mg), or tropisetron (5 mg)). The use of steroids as prophylactic antiemetic therapy should be avoided if possible due to the possibility of downregulation of somatostatin receptors.

[0317] The clinical trial design is shown in Figure 1.

Claims

1. A radiopharmaceutical compound for use in treating small cell lung cancer (SCLC) in a human subject in need thereof, said radiopharmaceutical compound being a compound of the formula: M-C-S-P During the ceremony, M is ９０ Y, １３１ I, １２１ Sn, １８６ Re, １８８ Re, ６４ Cu, ６７ Cu, ５９ Fe, ８９ Sr, １９８ Au, ２０３ Hg, ２１２ Pb, １６５ Dy, １０３ Ru, １４９ Tb, １６１ Tb, ２１３ Bi, １６６ Ho, １６５ Er, １６９ Er, １５３ Sm, １７７ Lu, ２１３ Bi, ２２３ Ra, ２２５ Ac, ２２７ Ac, ２２７ Th, ２１１ At, ６７ Cu, １８６ Re, １８８ Re, １６１ Tb, １７５ Yb, １０５ Rh, １６６ Dy, １９９ Au, ４４ Sc, １４９ Pm, １５１ Pm, １４２ Pr, １４３ Pr, ７６ As, １１１ Ag, and ４７ selected from Sc, preferably M is １７７ Lu, C-S-P is selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), satreotide tetraxetane, DOTA-LAN, and DOTA-VAP, preferably C-S-P is selected from DOTA-TOC and DOTA-TATE, more preferably C-S-P is DOTA-TATE; the radiopharmaceutical compound is administered in combination with i) one or more chemotherapeutic agents including at least carboplatin and etoposide, and ii) a PD-1 inhibitor or a PD-L1 inhibitor; Radiopharmaceutical compounds.

2. 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 radiopharmaceutical compound of claim 1, which is 1Lu-oxodotreotide.

3. The radiopharmaceutical compound of claim 1, wherein the SCLC is expanded stage small cell lung cancer (ES-SCLC).

4. The radiopharmaceutical compound of claim 1, wherein the subject has not previously received chemotherapy for treating SCLC.

5. 10. The radiopharmaceutical compound of claim 1, wherein the subject has newly diagnosed SCLC.

6. The target is the same organic compound as used in radiopharmaceutical treatment, but with a radioactive metal suitable for imaging, preferably ６８ Ga, ６７ Ga or ６４ Cu, more preferably ６８ 10. The radiopharmaceutical compound of claim 1, selected for therapy with Ga-based SPECT / CT or PET / CT or SPECT / MRI, PET / MRI imaging.

7. The subject is preferably diagnosed with a positron emission tomography (PET) scan imaging at least one target lesion or non-target lesion. ６８ 10. The radiopharmaceutical compound of claim 1, which has been diagnosed as SSTR positive by a [Ga]Ga-DOTA-TATE imaging PET scan.

8. 10. The radiopharmaceutical compound of claim 1, wherein said one or more chemotherapeutic agents are carboplatin and etoposide.

9. 2. The radiopharmaceutical compound of claim 1, wherein the radiopharmaceutical compound is administered 1 to 8 times, preferably 2 to 7 times, such as 4 to 6 times, each administration of the radiopharmaceutical compound being up to 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks, or even 6 weeks.

10. 2. The radiopharmaceutical compound of claim 1, wherein the one or more chemotherapeutic agents are administered in combination, preferably simultaneously, with two administrations of the radiopharmaceutical compound during the run-in period, preferably a first administration of the radiopharmaceutical compound in the first week of the first administration of the chemotherapeutic agent, for example on any of days 3, 4 or 5 of week 1, and a second administration of the radiopharmaceutical compound between weeks 6 and 8, preferably in week 7.

11. The radiopharmaceutical compound of claim 10, further comprising a maintenance period following said induction period, said maintenance period comprising 1 to 4 administrations of said radiopharmaceutical compound, preferably every 3 weeks.

12. (i) the one or more chemotherapeutic agents are administered during the run-in period, preferably in combination with two administrations of the radiopharmaceutical compound, with a first administration of the radiopharmaceutical compound in week 1, e.g., on any of day 3, 4, or 5 of week 1, following the first administration of the chemotherapeutic agent, and a second administration of the radiopharmaceutical compound between weeks 6 and 8, preferably in week 7; (ii) The radiopharmaceutical compound of claim 1, wherein said PD-1 inhibitor or PD-L1 inhibitor is administered preferably in combination with said chemotherapeutic agent, preferably simultaneously, in week 1, preferably on the day of the first administration of the chemotherapeutic agent, and every three weeks during said run-in period.

13. Following the introductory period, (i) 1 to 4 administrations of said radiopharmaceutical compound every 3 weeks; and (ii) 1 to 4 administrations of the PD-1 inhibitor or PD-L1 inhibitor every 3 weeks 13. The radiopharmaceutical compound of claim 12, further comprising a maintenance period comprising:

14. The PD-1 inhibitor or PD-L1 inhibitor is, for example, nivolumab (Bristol-Myers Squibb), ipilimumab, PDR001 / spartalizumab (Novartis), Keytruda / pembrolizumab / MK-3475 / lambrolizumab (Merck & Co), pidilizumab, durvalumab / MEDI4736, atezolizumab / MPDL3280A / Tecentriq / RG7446 (Roche), avelumab, MEDI0680 (AMP-514, Medimmune), REGN2810 / cemiplimab (Regeneron), TSR-042 / dostarlimab / dostarlimab-gxly (Tesa 2. The radiopharmaceutical compound of claim 1, which is an anti-PD1 antibody or an anti-PD-L1 antibody selected from the group consisting of PF-06801591 / sananlimab (Pfizer), BGB-A317 / tislelizumab (Beigene), BGB-108, INCSHR1210 / camrelizumab (Incyte), and AMP-224 (Amplimmune).

15. 2. The radiopharmaceutical compound of claim 1, wherein the radiopharmaceutical compound is administered at a dose ranging between 0.925 GBq and 29.6 GBq, preferably between 1.48 GBq and 18.5 GBq, preferably between 1.85 GBq and 14.8 GBq, more preferably between 3.7 GBq and 11.1 GBq, and even more preferably at a dose of 7.4 GBq each administration.

Images