Methods for treating sstr positive cancer
A radiopharmaceutical composition with a targeting ligand and stabilizer enhances tumor targeting for SSTR-positive cancers, improving treatment efficacy by minimizing healthy tissue damage.
Patent Information
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- RAYZEBIO INC
- Filing Date
- 2026-04-10
- Publication Date
- 2026-07-10
AI Technical Summary
Current treatments for SSTR-positive cancers lack effective targeted therapies that can selectively deliver radionuclides to tumor sites while minimizing damage to surrounding healthy tissues.
A radiopharmaceutical composition comprising a targeting ligand, such as a monocyclic peptide, conjugated with a radionuclide and a metal chelating agent, is used to selectively target SSTR-positive tumors, utilizing a stabilizer to enhance stability and delivery.
The composition effectively delivers radionuclides to tumor sites, enhancing treatment efficacy while reducing harm to healthy tissues.
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Abstract
Description
CN Title: Method for Treating SSTR-Positive Cancers CN Abstract: This paper provides a method for treating SSTR+ cancers using a radiopharmaceutical composition. The radiopharmaceutical composition may comprise one or more stabilizers, an aqueous medium, and a conjugate containing a targeting ligand and a radionuclide bound to a metal chelating agent. The targeting ligand may be a small molecule compound or a peptide, such as a monocyclic peptide. The targeting ligand may be configured to bind to a tumor target. The stabilizer may include a radiodesorption stabilizer, a free metal chelating agent, and / or a pH stabilizer. This paper further provides methods for preparing the radiopharmaceutical composition and methods for treating cancer by administering the radiopharmaceutical composition. 1 Abstract
Claims
WSGR Docket No.59541-743.602 CLAIMS WHAT IS CLAIMED IS:
1. A method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject an effective amount of225Ac- DOTA-TATE in the form of a liquid radiopharmaceutical composition, wherein the subject has previously received a177Lu-labelled somatostatin analog (SSA) therapy, wherein the liquid radiopharmaceutical composition is administered to the subject in an amount equivalent to about 10.2 MBq per dose, and wherein the liquid radiopharmaceutical composition is administered at a 7- to 9-week interval per cycle with a maximum cumulative dose at about 40,800 kBq.
2. A method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject an effective amount of225Ac- DOTA-TATE in the form of a liquid radiopharmaceutical composition, wherein the subject has previously received a177Lu-labelled somatostatin analog (SSA) therapy, wherein the liquid radiopharmaceutical composition is administered to the subject in an amount equivalent to about 10.2 MBq per dose as an initial dose, and wherein at least one subsequent dose of the liquid radiopharmaceutical composition is administered to the subject at about 50% of the initial dose.
3. The method of claim 2, wherein the at least one subsequent dose is an amount equivalent to about 5.1 MBq per dose.
4. A method of treating a somatostatin receptor-positive (SSTR+) neuroendocrine tumor in a subject in need thereof, comprising administering to the subject an effective amount of225Ac- DOTA-TATE in the form of a liquid radiopharmaceutical composition, wherein the subject has previously received a177Lu-labelled somatostatin analog (SSA) therapy, wherein the liquid radiopharmaceutical composition is administered to the subject in an amount equivalent to about 10.2 MBq per dose as an initial dose, and wherein if the subject has an adverse reaction to the initial dose, the liquid radiopharmaceutical composition is administered to the subject at a reduced dose that is about 50% of the initial dose.
5. The method of claim 4, wherein if the subject has an adverse reaction to the initial dose, the liquid radiopharmaceutical composition is withheld for a period of time prior to the administering of the reduced dose.
6. The method of claim 5, wherein if the subject does not have an adverse reaction to the reduced dose that is about 50% of the initial dose, the liquid radiopharmaceutical composition is administered at a second reduced dose that is about 75% of the initial dose.WSGR Docket No.59541-743.602 7. The method of claim 6, wherein if the subject does not have an adverse reaction second reduced dose, the liquid radiopharmaceutical composition is administered at the initial dose.
8. The method of any one of claims 4 to 7, wherein the adverse reaction is selected from: i) NCI CTCAE (v5.0) grade 2, 3, or 4 thrombocytopenia; ii) NCI CTCAE (v5.0) grade 3 or 4 anemia or neutropenia; iii) renal toxicity comprising eGFR <50mL / min / 1.73m2, 40% increase in baseline serum creatinine, or 40% decrease in baseline eGFR; iv) hepatotoxicity comprising NCI CTCAE (v5) grade 3 or 4 bilirubinemia or hypoalbuminemia <3g / dL with a decreased prothrombin ratio less than 70%; and / or v) NCI CTCAE (v5.0) grade 3 or 4 non-hematologic toxicity.
9. The method of any one of claims 1 to 8, wherein the SSTR+ neuroendocrine tumor in the subject has progressed following the177Lu-labelled somatostatin analog (SSA) therapy.
10. The method of any one of claims 1 to 9, wherein the SSTR+ neuroendocrine tumor is an inoperable, advanced, well-differentiated, SSTR+ gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that have progressed following treatment with177Lu-labelled somatostatin analogue (177Lu-SSA) therapy.
11. The method of any one of claims 1 to 10, wherein the subject has previously received a177Lu- SSA therapy selected from177Lu-DOTA-TATE,177Lu-DOTA-TOC, and / or177Lu-HA-DOTA- TATE.
12. The method of claim 11, wherein the177Lu-SSA therapy is administered for a minimum of two cycles.
13. The method of any one of claim 1 to 12, wherein the177Lu-SSA therapy is administered for a maximum of four cycles.
14. The method of any one of claims 11 to 13, wherein: 177Lu-DOTA-TATE is administered at a dose of about 6.66 GBq to about 8.14 GBq per cycle; 177Lu-DOTA-TOC is administered at a dose of about 6.75 GBq to about 8.25 GBq per cycle; or 177Lu-HA-DOTA-TATE is administered at a dose of 6.66 GBq to about 8.14 GBq per cycle.
15. The method of any one of claims 11 to 14, wherein: 177Lu-DOTA-TATE is administered at a cumulative dose of about 26.64 GBq to about 32.56 GBq; 177Lu-DOTA-TOC is administered at a cumulative dose of about 27 GBq to about 33 GBq; or 177Lu-HA-DOTAT-ATE is administered at a cumulative dose of about 26.64 GBq to about 32.56 GBq.
16. The method of any one of claims 1 to 15, wherein the liquid radiopharmaceutical composition is administered at an 8-week interval.
17. The method of any one of claims 1 to 16, wherein the liquid radiopharmaceutical composition is administered at least at a 7-week interval.WSGR Docket No.59541-743.602 18. The method of any one of claims 1 to 17, wherein the liquid radiopharmaceutical composition is administered for a maximum of 4 cycles.
19. The method of any one of claims 2 to 18, wherein the subject is administered a maximum cumulative dose of about 40,800 kBq of the liquid radiopharmaceutical composition.
20. The method of any one of claims 1 to 19, wherein the liquid radiopharmaceutical composition is administered less than 150 hours from its manufacture.
21. The method of any one of claims 1 to 19, wherein the liquid radiopharmaceutical composition is administered less than 72 hours from its manufacture.
22. The method of any one of claims 1 to 21, wherein the subject has a Ki-67 index of at most 20%.
23. The method of any one of claims 1 to 22, wherein the subject has a creatinine clearance of at least 50 or 60 mL / min.
24. The method of any one of claims 1 to 23, wherein the subject meets one or more of the following criteria: (i) wherein the subject has an eGFR of at least 50mL / min / 1.73m2; (ii) wherein the subject has a hemoglobin concentration of at least 5.0 mmol / L; (iii) wherein the subject has an absolute neutrophil count of at least 1000 cells / μL; (iv) wherein the subject has a platelet count of at least 75 x 109 / L; (v) wherein the subject has a platelet count of at least 100 x 109 / L; (vi) wherein the subject has a total bilirubin level of at most three times the upper limit of normal; and / or (vii) wherein the subject has a serum albumin level of at least 3.0 g / dL.
25. The method of any one of claims 1 to 24, wherein the subject has a SSTR+ neuroendocrine tumor having a Krenning score of 3 or 4.
26. The method of any one of claims 1 to 25, wherein the subject does not have a hypersensitivity to 225Actinium,68Gallium, or64Copper.
27. The method of any one of claims 1 to 26, wherein the subject does not have liver cirrhosis.
28. The method of any one of claims 1 to 27, wherein the subject has not received a radioembolization.
29. The method of any one of claims 1 to 28, wherein the patient has received at least one SSTR- PET prior to administering the225Ac-DOTA-TATE.
30. The method of claim 29, wherein the SSTR-PET comprises a68Ga or64Cu based imaging agent.
31. The method of claim 29 or 30, wherein the patient has at least one SSTR-PET positive measurable site of disease and no measurable metastatic lesions that are SSTR imaging-negative.
32. The method of any one of claims 1 to 31, wherein the SSTR+ neuroendocrine tumor is a functional tumor and the subject is administered a long-acting SSA, wherein the long-acting somatostatin analog (SSA) is administered at a stable dose for at least 12 weeks prior to administering the225Ac-DOTA-TATE.WSGR Docket No.59541-743.602 33. The method of any one of claims 1 to 31, wherein the SSTR+ neuroendocrine tumor is a functional or a nonfunctional tumor, and wherein the subject has not received a long-acting somatostatin analog (SSA) within 4 weeks prior to administering the225Ac-DOTA-TATE.
34. The method of claim 32 or 33, wherein the long-acting SSA is octreotide long-acting release or lanreotide.
35. The method of any one of claims 1 to 31, wherein the subject is receiving a short-acting somatostatin analog (SSA), wherein the short-acting SSA is administered at least 24 hours before or at least 24 hours after administering the225Ac-DOTA-TATE.
36. The method of any one of claims 1 to 35, wherein the subject is administered an intravenous amino acid solution prior to administering the225Ac-DOTA-TATE.
37. The method of claim 36, wherein the amino acid solution comprises arginine and lysine.
38. The method of claim 36, wherein the amino acid solution is a 1-2 liter solution comprising between 18-25g arginine and 18-25g lysine.
39. The method of any one of claims 36 to 38, wherein the amino acid solution is administered at least 30 minutes prior to administering the225Ac-DOTA-TATE.
40. The method of any one of claims 36 to 39, wherein the amino acid solution is administered for a period of at least 4 hours.
41. The method of any one of claims 1 to 40, further comprising administering an antiemetic to the subject.
42. The method of claim 41, wherein the antiemetic is selected from granisetron, ondansetron, and tropisetron.
43. The method of claim 41 or 42, wherein the antiemetic is administered prior to the administering of the amino acid solution.
44. The method of any one of claims 1 to 43, wherein the177Lu-SSA therapy is administered at least one year prior to administering the225Ac-DOTA-TATE.
45. The method of any one of claims 1 to 43, wherein the177Lu-SSA therapy is administered at most one year prior to administering the225Ac-DOTA-TATE.
46. The method of any one of claims 1 to 45, wherein the subject has received long acting somatostatin analogs (SSA) prior to administering the225Ac-DOTA-TATE.
47. The method of claim 46, wherein the long acting SSA comprises octreotide or lanreotide.
48. The method of any one of claims 1 to 47, wherein the somatostatin receptor-positive (SSTR+) neuroendocrine tumor is gastro-enteropancreatic neuroendocrine tumor (GEP-NET).
49. The method of any one of claims 1 to 48, wherein the somatostatin receptor-positive (SSTR+) neuroendocrine tumor is an inoperable, advanced, somatostatin receptor expressing (SSTR+), well-differentiated gastro-enteropancreatic neuroendocrine tumor (GEP-NET) that has progressed following prior177Lu-SSA therapy (such as177Lu-DOTA-TATE,177Lu-DOTA-TOC, or177Lu-HA-DOTA-TATE).WSGR Docket No.59541-743.602 50. The method of any one of claims 1 to 49, wherein the subject has an elevated level of a chromogranin A.
51. The method of any one of claims 1 to 50, wherein the subject has an elevated level of a 5- hydroxyindole acetic acid.
52. The method of claim 50 or 51, wherein the chromogranin A is detected in a urine sample from the subject.
53. The method of claim 51 or 52, wherein the 5-hydroxyindole acetic acid is detected in a urine sample from the subject.
54. The method of any one of claims 1 to 53, wherein the SSTR+ neuroendocrine tumor is located in a gastrointestinal organ or a pancreas.
55. The method of claim 54, wherein the SSTR+ neuroendocrine tumor is located in a gastrointestinal organ.
56. The method of claim 54 or 55, wherein the gastrointestinal organ is an ileum, a duodenum, or a jejunum.
57. The method of any one of claims 1 to 52, wherein the SSTR+ neuroendocrine tumor is located in an ileum, a duodenum, a jejunum, or a pancreas.
58. The method of any one of claims 1 to 57, wherein the225Ac-DOTA-TATE is present in the radiopharmaceutical composition at a concentration equivalent to about 5 mCi / L to about 50 mCi / L.
59. A method of treating a somatostatin receptor-positive (SSTR+) cancer in a subject in need thereof, comprising administering to the subject an effective amount of225Ac-DOTA-TATE in the form of a liquid radiopharmaceutical composition.
60. The method of claim 59, wherein the cancer is a neuroendocrine cancer, a lymphatic cancer, a pancreatic cancer, a pituitary cancer, a breast cancer, a lung cancer, a stomach cancer, medulloblastoma, or neuroblastoma.
61. The method of claim 59, wherein the cancer is a neuroendocrine cancer.
62. The method of any one of claims 59 to 61, wherein at least 20% of measurable lesions in the subject are SSTR+.
63. The method of claim 62, wherein at least 50% of measurable lesions in the subject are SSTR+.
64. The method of claim 62, wherein at least 20%, at least 30%, at least 50%, at least 75%, or at least 99% of measurable lesions in the subject are SSTR+.
65. The method of claim 62, wherein 20% to 100% measurable lesions in the subject are SSTR+.
66. The method of any one of claims 59 to 61, wherein at least 20% of lesions in the subject are SSTR+ as determined by imaging or immunohistochemistry.
67. The method of claim 66, wherein 20% to 100% of lesions in the subject are SSTR+ as determined by imaging or immunohistochemistry.WSGR Docket No.59541-743.602 68. The method of any one of claims 59 to 67, wherein the subject has received a radiotherapy that comprises beta-particle emitting radionuclide prior to the administering of the radiopharmaceutical composition.
69. The method of claim 68, wherein the radiotherapy that comprises beta-particle emitting radionuclide comprises177Lu-DOTA-TATE,177Lu-DOTA-TOC, or77Lu-HA-DOTA-TATE therapy.
70. The method of any one of claims 61 to 69, wherein the neuroendocrine cancer is a neuroendocrine lung cancer or a neuroendocrine pancreatic cancer.
71. The method of any one of claims 61 to 69, wherein the neuroendocrine cancer is a carcinoid tumor in the lungs, gastrointestinal tract or thymus, pancreatic neuroendocrine tumor (e.g., gastrinoma, insulinoma, glucagonoma, VIPoma) medullary thyroid carcinoma, merkel cell carcinoma, pheochromocytoma of the adrenal gland, adrenal cancer, small cell carcinoma (such as in the lungs), or large cell carcinoid tumor (such as in the lungs).
72. The method of any one of claims 59 to 69, wherein the cancer is a SSTR2+ lung neuroendocrine tumor.
73. The method of any one of claims 59 to 69, wherein the cancer is small cell lung cancer (SCLC).
74. The method of any one of claims 59 to 69, wherein the cancer is somatostatin receptor expressing (SSTR+) extensive stage small cell lung cancer (ES-SCLC).
75. The method of claim 73 or 74, wherein the SCLC is untreated, recurrent or refractory.
76. The method of claim 73 or 74, wherein the subject has received at most 1 cycle of platinum- etoposide and PD-L1 inhibitor therapy.
77. The method of any one of claims 59 to 76, wherein the cancer is untreated.
78. The method of any one of claims 59 to 76, wherein the cancer is recurrent or refractory.
79. The method of any one of claims 59 to 78, wherein the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 1kBq / kg to about 0.2GBq / kg body weight per dose.
80. The method of any one of claims 59 to 78, wherein the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 5kBq / kg to about 50,000kBq / kg body weight per dose, about 20k Bq / kg to about 5,000kBq / kg body weight per dose, about 50k Bq / kg to about 500 kBq / kg body weight per dose, or about 50k Bq / kg to about 200 kBq / kg body weight per dose.
81. The method of any one of claims 59 to 78, wherein the radiopharmaceutical composition is administered to the subject in an amount equivalent to about 60 kBq / kg to about 150 kBq / kg body weight per dose.
82. The method of any one of claims 59 to 78, wherein the radiopharmaceutical composition is administered to the subject at a radioactivity of about 1 μCi to 1,000 μCi, about 10 μCi to 500 μCi, about 100 μCi to 500 μCi, about 100 μCi to 300 μCi, about 125 μCi to 275 μCi, about 50 μCi to 125 μCi, or about 10 μCi to 50 μCi.WSGR Docket No.59541-743.602 83. The method of any one of claims 59 to 78, wherein the radiopharmaceutical composition is administered to the subject at a radioactivity of about 125 μCi to 275 μCi (e.g., about 125 μCi, 175 μCi, 225 μCi, or 275 μCi).
84. The method of any one of claims 59 to 83, wherein the radiopharmaceutical composition is administered at a 4 to 6-week interval.
85. The method of any one of claims 1 to 84, wherein the SSTR+ tumor or cancer is characterized as having an H-score of at least 11.
86. A method of treating a disease in a subject in need thereof, comprising (a) determining a level of SSTR expression in a sample of the subject; and (b) administering to the subject an effective amount of225Ac-DOTA-TATE in the form of a liquid radiopharmaceutical composition.
87. The method of claim 86, wherein the level of SSTR expression in a sample is determined by calculating an H-Score, and wherein the H-Score is between 11 and 300.
88. The method of any one of claims 1 to 87, wherein the SSTR is somatostatin receptor type 1 (SSTR1), somatostatin receptor type 2 (SSTR2), somatostatin receptor type 3 (SSTR3), somatostatin receptor type 4 (SSTR4), and / or somatostatin receptor type 5 (SSTR5).
89. The method of any one of claims 1 to 87, wherein the SSTR is somatostatin receptor type 2 (SSTR2).
90. The method of any one of claims 1 to 89, wherein the liquid radiopharmaceutical composition comprises: (a)225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof, wherein the225Ac- DOTA-TATE or the pharmaceutically acceptable salt thereof is present in the radiopharmaceutical composition at a concentration equivalent to 10 mCi / L to 50 mCi / L; (b) a pH stabilizer, wherein the pH stabilizer is present in the radiopharmaceutical composition at a concentration of 10 mM to 500 mM; (c) a free metal chelator, wherein the free metal chelator is present in the radiopharmaceutical composition at a concentration of 0.01 mg / mL to 5 mg / mL; and (d) water; wherein the radiopharmaceutical composition is a solution, and wherein the radiopharmaceutical composition retains at least 80 % of the225Ac content as225Ac-DOTA-TATE or the pharmaceutically acceptable salt thereof after 48 hours.
91. The method of claim 90, wherein a pH of the liquid radiopharmaceutical composition is about 4.0 to about 8.
0.
92. The method of claim 90 or 91, wherein the225Ac-DOTA-TATE or the pharmaceutically acceptable salt thereof is present in the radiopharmaceutical composition at a concentration equivalent to 10 mCi / L to 25 mCi / L.WSGR Docket No.59541-743.602 93. The method of any one of claims 90 to 92, wherein the radiopharmaceutical composition retains at least 80 % of the225Ac content as225Ac-DOTA-TATE or the pharmaceutically acceptable salt thereof after 48 hours at about 20ºC to about 25°C.
94. The method of any one of claims 1 to 90, wherein the liquid radiopharmaceutical composition comprises: (a)225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof, wherein the225Ac- DOTA-TATE or the pharmaceutically acceptable salt thereof is present in the radiopharmaceutical composition at a concentration equivalent to 5 mCi / L to 50 mCi / L; (b) sodium ascorbate, wherein the sodium ascorbate is present in the radiopharmaceutical composition at a concentration of 40 mM to 250 mM; (c) diethylenetriamine pentaacetate (DTPA), wherein the DTPA is present in the radiopharmaceutical composition at a concentration of 0.01mg / mL to 5mg / mL; and (d) an aqueous vehicle, wherein the aqueous vehicle is a saline solution; wherein the radiopharmaceutical composition is a solution, and wherein the radiopharmaceutical composition retains at least 90 % of the225Ac content as225Ac-DOTA-TATE or the pharmaceutically acceptable salt thereof after 120 hours at about 20ºC to about 25°C.
95. The method of any one of claims 90 to 94, wherein the radiopharmaceutical composition is formulated as a unit dose form that contains about 5-25 mL of the solution.
96. The method of any one of claims 90 to 94, wherein the radiopharmaceutical composition is formulated as a unit dose form that contains about 12 mL of the solution.
97. The method of any one of claims 90 to 96, wherein the radiopharmaceutical composition is formulated for IV infusion.
98. The method of any one of claims 90 to 97, wherein the225Ac-DOTA-TATE or the pharmaceutically acceptable salt thereof has a structure illustrated as.
99. The method of any one of claims 1 to 98, wherein the administering of the225Ac-DOTA-TATE (e.g., in the form of a liquid radiopharmaceutical composition) increases a progression freeWSGR Docket No.59541-743.602 survival in the subject of at least 2 months in comparision to a subject who receives a standard of care (SoC) cancer therapy.
100. The method of claim of 99, wherein the SoC cancer therapy is177Lu-SSA therapy, or chemotherapy (such as streptozocin, temozolamide, or capecitabine).
101. The method of claim of 99, wherein the SoC cancer therapy is everolimus, sunitinib, or high dose somatostatin analog (SSA) therapy.
102. The method of any one of claims of 99 to 101, wherein the administering of the225Ac- DOTA-TATE increases a progression free survival in the subject of at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 36 months, in comparision to a subject who receives a SoC cancer therapy.
103. The method of any one of claims 1 to 102, further comprising administering to the subject an additional anti-cancer agent. wherein the additional anti-cancer agent is a local or regional cancer treatment.