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EP-4735056-A1 - METHODS FOR THE DIAGNOSIS AND/OR TREATMENT OF NEUROENDOCRINE CANCERS

EP4735056A1EP 4735056 A1EP4735056 A1EP 4735056A1EP-4735056-A1

Abstract

The present invention relates to methods of diagnosis and/or radiotherapy, comprising the administration of a compound of Formula (I) and a 64 Cu / 67 Cu radioisotope to deliver a targeted dose of radiation for the diagnosis and treatment of a neuroendocrine cancer, particularly neuroblastoma in children.

Inventors

  • HARRIS, Matthew John
  • PARKER, Michelle
  • LENGYELOVA, Eva
  • HEDT, Amos
  • BIGGIN, Colin

Assignees

  • Clarity Pharmaceuticals Limited

Dates

Publication Date
20260506
Application Date
20240627

Claims (20)

  1. 1. A method for the treatment of a neuroendocrine cancer, the method comprising administering to a subject in need thereof an aqueous formulation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed to a 67 Cu radioisotope in a therapeutically effective amount, Formula (I) wherein the aqueous formulation is optionally administered one, two or three additional times at the same or lower amount of the compound of Formula (I); wherein the total dose of 67 Cu radiation delivered to the bone marrow of the subject is less than about 2 Gy and the total dose of radiation delivered to the kidneys of the subject is less than about 30 Gy.
  2. 2. A method for the treatment of a neuroendocrine cancer, the method comprising administering to a subject in need thereof an aqueous formulation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed to a 67 Cu radioisotope in a therapeutically effective amount, Formula (I) wherein the dose of radiation delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.
  3. 3. A method for the treatment of a neuroendocrine cancer in a patient in need of such treatment, the method comprising: 1) optionally administering an amino acid infusion to said patient followed by an IV infusion of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed to a 67 Cu radioisotope: Formula (I) in a therapeutically effective amount of about 75 MBq/kg to about 475 MBq/kg.
  4. 4. A method for the treatment of a neuroblastoma, the method comprising administering to a subject in need thereof an aqueous formulation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed to a 67 Cu radioisotope in a therapeutically effective amount, Formula (I) wherein the aqueous formulation is optionally administered one, two or three additional times at the same or lower amount of the compound of Formula (I); wherein the total dose of 67 Cu radiation delivered to the bone marrow of the subject is less than about 2 Gy and the total dose of radiation delivered to the kidneys of the subject is less than about 30 Gy.
  5. 5. A method for the treatment of a neuroblastoma, the method comprising administering to a subject in need thereof an aqueous formulation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed to a 67 Cu radioisotope in a therapeutically effective amount, Formula (I) wherein the dose of radiation delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the neuroblastoma.
  6. 6. A method for the treatment of a neuroendocrine cancer, the method comprising administering to the subject in need thereof an aqueous formulation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a 67 Cu radioisotope in a therapeutically effective amount: Formula (I) wherein the subject does not experience any adverse events classified as Grade 3 or higher.
  7. 7. A method for the treatment of a neuroblastoma, the method comprising administering to the subject in need thereof an aqueous formulation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a 67 Cu radioisotope in a therapeutically effective amount: Formula (I) wherein the subject does not experience any adverse events classified as Grade 3 or higher.
  8. 8. A method according to claim 6 or 7, wherein the subject does not experience any adverse events classified as Grade 2 or higher.
  9. 9. A method according to claim 6 or 7, wherein the subject does not experience any adverse events classified as Grade 1 or higher.
  10. 10. A method according to claim 6 or 7, wherein the subject does not experience any adverse events classified as Grade 1, Grade 2 or Grade 3.
  11. 11. A method for the treatment of a neuroendocrine tumour, the method comprising administering to the subject in need thereof an aqueous formulation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed with a 67 Cu radioisotope in a therapeutically effective amount: Formula (I) wherein the dose of radiation is not associated with any dose limiting toxicities in the subject.
  12. 12. A method according to claim 11, wherein the subject does not experience any adverse events classified as Grade 3 or higher.
  13. 13. A method according to claim 11, wherein the subject does not experience any adverse events classified as Grade 2 or higher.
  14. 14. A method according to claim 11, wherein the subject does not experience any adverse events classified as Grade 1 as higher.
  15. 15. A method for the treatment of a neuroblastoma in a patient in need of such treatment, the method comprising: 1) optionally administering an amino acid infusion to said patient followed by an IV infusion of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed to a 67 Cu radioisotope: Formula (I) in a therapeutically effective amount of about 75 MBq/kg to about 475 MBq/kg.
  16. 16. A method for the treatment of a neuroendocrine cancer in a patient in need of such treatment, the method comprising: 1) optionally administering an amino acid infusion to said patient followed by an IV infusion of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed to a 67 Cu radioisotope: Formula (I) in a therapeutically effective amount of about 75 MBq/kg to about 475 MBq/kg, and 2) repeating the therapy cycle 1) one, two or three additional times at the same or lower amount of Formula (I) so that the overall dose delivered to the patient does not exceed a 30 Gy kidney limit based on the patients weight.
  17. 17. A method for the treatment of a neuroblastoma in a patient in need of such treatment, the method comprising: 1) optionally administering an amino acid infusion to said patient followed by an IV infusion of a compound of Formula (I) or a pharmaceutically acceptable salt thereof complexed to a 67 Cu radioisotope: Formula (I) in a therapeutically effective amount of about 75 MBq/kg to about 475 MBq/kg, and 2) repeating the therapy cycle 1) one, two or three additional times at the same or lower amount of Formula (I) so that the overall dose delivered to the patient does not exceed a 30 Gy kidney limit based on the patients weight.
  18. 18. A method according to any one of claims 1 to 17, wherein the dose of radiation delivered by the 67 Cu radioisotope to the subject is about 75 MBq/kg, about 175 MBq/kg, about 275 MBq/kg, about 375 MBq/kg or about 475 MBq/kg.
  19. 19. A method according to any one of claims 1 to 18, wherein multiple doses of the formulation as defined in any one of claims 1 to 5 are administered, wherein the doses are the same or different.
  20. 20. A method according to any one of claims 1 to 11, wherein the method further comprises the administration of an aqueous formulation containing one or more amino acids or salts thereof.

Description

Methods for the diagnosis and/or treatment of neuroendocrine cancers Field [0001] The present invention relates to methods of radioimaging and/or radiotherapy, comprising the administration of a specific chemical compounds complexed with 64Cu/67Cu radioisotopes to deliver a targeted dose of radiation for the imaging and/or treatment of a neuroendocrine cancer, particularly neuroblastoma in children. Background [0002] The neuroendocrine system of the body is responsible for creating, storing and secreting peptides and hormones. Neuroendocrine cancers often present as tumours and are typically found in the gastrointestinal or respiratory system, however neuroendocrine cancers may also be found in other sites such as the adrenal glands, the nervous system and skin. Specific sites for neuroendocrine tumours include the large bowel and appendix, small intestine, pancreas, stomach and the lungs. [0003] Neuroblastoma is a neuroendocrine cancer, where the cancer forms in early nerve tissue (i.e. neuroblasts) of the sympathetic nervous system and can be found anywhere in this system, including the adrenal glands, neck, chest and spinal cord. Neuroblastomas occur most often in infants and young children under the age of 5 and accounts for approximately 13% of pediatric cancer mortalities. Given the complexity and heterogeneity of neuroblastoma, many factors determine the outcome. For example, whether the cancer will spontaneously regress or metastasize and become refractory to therapy may relate to the age at diagnosis, stage of disease, and molecular, cellular and genetic features of the disease. [0004] Diagnosis of the neuroendocrine cancer is typically achieved by a combination of techniques, including biopsies, blood tests, endoscopies, ultrasounds, x-rays, CT scans, MRI scans and nuclear medicine imaging, such as PET scans. While techniques such as biopsies can allow for definitive diagnosis, this requires that the cancer is first located. Other techniques, such as PET scans, allow for the whole subject to be assessed at once in order to determine the presence of cancer. The use of nuclear medicine imaging requires the administration of a suitable radioactive tracer that is capable of binding to the cancer site. In order for imaging to be successful, the agent that is administered must bind selectively to the cancer site, retain and deliver the radioisotope to the cancer site, persist for a sufficient time to allow for images of sufficient quality to be obtained and also induce little or no side effects to the subject. Treatment of cancer is typically accompanied by various side effects and adverse events that are associated with the form of treatment. Often, adverse events that are experienced by the patient may be severe enough to limit or end the prescribed course of treatment early, or otherwise cause detrimental effects to the patient. [0005] Patients are classified into low, intermediate, and high-risk categories. In general, those with low-risk disease have excellent event free survival and overall survival (OS) rates with observation only or minimal therapeutic interventions. The outcome of patients with intermediate-risk disease, who are treated primarily with surgery and chemotherapy, has improved to the point where many groups are focused on using biologic markers to help further decrease therapy in this group of children. [0006] Patients with high-risk disease comprise approximately half of all new neuroblastoma cases each year. This group requires treatment with multimodal therapy, including induction chemotherapy, surgery, radiotherapy, high-dose chemotherapy with autologous stem cell rescue, and biologic and immunotherapeutic maintenance therapy in order to improve their survival odds. However, even with this aggressive therapeutic strategy, a significant number of patients will still relapse and eventually die of this disease. [0007] Despite recent advances in understanding of the pathogenesis of neuroblastoma, patients suffering from high-risk refractory or relapsed disease have no established curative treatment options. Patients with relapsed disease often develop metastatic tumors resistant to standard therapies and treatment goals are often not curative but aimed at prolonging survival and symptom control. The 1- and 4-year OS rates remain at only 57% and 20%, respectively. To improve outcomes in these patients, novel treatment strategies are needed. The substitution of 123I for 131I in meta-iodobenzylguanidine (MIBG) enables a therapeutic radiopharmaceutical suitable for treatment of neuroblastoma and other neuroendocrine tumors. However, the use of 131I-MIBG for neuroblastoma remains experimental and it is currently used only in a clinical trial setting. In addition, 131I-MIBG therapy is an extremely involved and logistically difficult process due to the long half-life (8 days) of 131I. Although single-agent molecular radiotherapy with 131I-MIBG has shown to have some efficacy in the rela