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CN-122003254-A - Methods for diagnosing and/or treating neuroendocrine cancer

CN122003254ACN 122003254 ACN122003254 ACN 122003254ACN-122003254-A

Abstract

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

Inventors

  • M.J. HARRIS
  • M. Parker
  • E. Rengelova
  • A. Hurt
  • C. Compared to gold

Assignees

  • 透明医药有限公司

Dates

Publication Date
20260508
Application Date
20240627
Priority Date
20230627

Claims (20)

  1. 1. A method for treating neuroendocrine cancer comprising administering to a subject in need thereof a therapeutically effective amount of an aqueous formulation of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with a 67 Cu radioisotope, Formula (I) Wherein the aqueous formulation is optionally additionally administered once, twice or three times in the same or lower amounts of the compound of formula (I); Wherein the total dose of 67 Cu radiation delivered to the subject's bone marrow is less than about 2 Gy and the total dose of radiation delivered to the subject's kidneys is less than about 30 Gy.
  2. 2. A method for treating neuroendocrine cancer comprising administering to a subject in need thereof a therapeutically effective amount of an aqueous formulation of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with a 67 Cu radioisotope, Formula (I) Wherein the radiation dose delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the cancer.
  3. 3. A method for treating neuroendocrine cancer in a patient in need of such treatment, the method comprising: 1) Optionally administering to the patient an amino acid infusion followed by IV infusion of about 75 MBq/kg to about 475 MBq/kg of a therapeutically effective amount of a compound of formula (I) complexed with a 67 Cu radioisotope, or a pharmaceutically acceptable salt thereof: Formula (I).
  4. 4. A method for treating neuroblastoma comprising administering to a subject in need thereof a therapeutically effective amount of an aqueous formulation of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with a 67 Cu radioisotope, Formula (I) Wherein the aqueous formulation is optionally additionally administered once, twice or three times in the same or lower amounts of the compound of formula (I); Wherein the total dose of 67 Cu radiation delivered to the subject's bone marrow is less than about 2 Gy and the total dose of radiation delivered to the subject's kidneys is less than about 30 Gy.
  5. 5. A method for treating neuroblastoma comprising administering to a subject in need thereof a therapeutically effective amount of an aqueous formulation of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with a 67 Cu radioisotope, Formula (I) Wherein the radiation dose delivered by the radioisotope is sufficient to reduce the size of one or more lesions associated with the neuroblastoma.
  6. 6. A method for treating neuroendocrine cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an aqueous formulation of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with a 67 Cu radioisotope: Formula (I) Wherein the subject does not experience any adverse events classified as grade 3 or above.
  7. 7. A method for treating neuroblastoma, the method comprising administering to a subject in need thereof a therapeutically effective amount of an aqueous formulation of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with a 67 Cu radioisotope: Formula (I) Wherein the subject does not experience any adverse events classified as grade 3 or above.
  8. 8. The method of claim 6 or 7, wherein the subject does not experience any adverse events classified as class 2 or more.
  9. 9. The method of claim 6 or 7, wherein the subject does not experience any adverse events classified as class 1 or more.
  10. 10. The method of claim 6 or 7, wherein the subject does not experience any adverse events classified as class 1, class 2 or class 3.
  11. 11. A method for treating a neuroendocrine tumor, the method comprising administering to a subject in need thereof a therapeutically effective amount of an aqueous formulation of a compound of formula (I) or a pharmaceutically acceptable salt thereof complexed with a 67 Cu radioisotope: Formula (I) Wherein the radiation dose is independent of any dose limiting toxicity in the subject.
  12. 12. The method of claim 11, wherein the subject does not experience any adverse events classified as grade 3 or more.
  13. 13. The method of claim 11, wherein the subject does not experience any adverse events classified as class 2 or more.
  14. 14. The method of claim 11, wherein the subject does not experience any adverse events classified as class 1 or more.
  15. 15. A method for treating neuroblastoma in a patient in need of such treatment, the method comprising: 1) Optionally administering to the patient an amino acid infusion followed by IV infusion of about 75 MBq/kg to about 475 MBq/kg of a therapeutically effective amount of a compound of formula (I) complexed with a 67 Cu radioisotope, or a pharmaceutically acceptable salt thereof: Formula (I).
  16. 16. A method for treating neuroendocrine cancer in a patient in need of such treatment, the method comprising: 1) Optionally administering to the patient an amino acid infusion followed by IV infusion of about 75 MBq/kg to about 475 MBq/kg of a therapeutically effective amount of a compound of formula (I) complexed with a 67 Cu radioisotope, or a pharmaceutically acceptable salt thereof: The compound of formula (I), And 2) The treatment cycle 1) is repeated one, two or three additional times with the same or lower amount of formula (I) such that the total dose delivered to the patient based on patient weight does not exceed 30 Gy kidney limitations.
  17. 17. A method for treating neuroblastoma in a patient in need of such treatment, the method comprising: 1) Optionally administering to the patient an amino acid infusion followed by IV infusion of about 75 MBq/kg to about 475 MBq/kg of a therapeutically effective amount of a compound of formula (I) complexed with a 67 Cu radioisotope, or a pharmaceutically acceptable salt thereof: The compound of formula (I), And 2) The treatment cycle 1) is repeated one, two or three additional times with the same or lower amount of formula (I) such that the total dose delivered to the patient based on patient weight does not exceed 30 Gy kidney limitations.
  18. 18. The method of any one of claims 1-17, wherein the radiation dose delivered to the subject by the 67 Cu radioisotope is about 75 MBq/kg, about 175 MBq/kg, about 275 MBq/kg, about 375 MBq/kg, or about 475 MBq/kg.
  19. 19. The method according to any one of claims 1 to 18, wherein a plurality of 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. The method of any one of claims 1 to 11, wherein the method further comprises administering an aqueous formulation comprising one or more amino acids or salts thereof.

Description

Methods for diagnosing and/or treating neuroendocrine cancer FIELD The present invention relates to methods of radiation imaging and/or radiation therapy comprising administering a specific compound complexed with a 64Cu/67 Cu radioisotope to deliver a targeted dose of radiation for imaging and/or therapy of neuroendocrine cancer, particularly neuroblastoma in children. Background The body's neuroendocrine system is responsible for the production, storage and secretion of peptides and hormones. Neuroendocrine cancers often appear as tumors and are often present in the gastrointestinal system or respiratory system, but neuroendocrine cancers may also be present in other sites, such as the adrenal gland, nervous system and skin. Specific sites of neuroendocrine tumors include the large intestine and appendix, the small intestine, pancreas, stomach and lung. Neuroblastoma is a neuroendocrine cancer in which the cancer forms in early neural tissue of the sympathetic nervous system (i.e., neuroblasts) and can be present anywhere in the system, including the adrenal gland, neck, chest and spinal cord. Neuroblastomas occur most frequently in infants under 5 years of age and young children and account for about 13% of childhood cancer deaths. In view of the complexity and heterogeneity of neuroblastomas, many factors determine the outcome. For example, whether cancer spontaneously regresses or metastasizes and becomes resistant to treatment may be related to the age at diagnosis, the stage of the disease, and the molecular, cellular and genetic characteristics of the disease. Diagnosis of neuroendocrine cancer is typically accomplished by a combination of techniques, including biopsy, blood testing, endoscopy, ultrasound, x-ray, CT scanning, MRI scanning, and nuclear medicine imaging (such as PET scanning). While techniques such as biopsy may allow for definitive diagnosis, the technique requires locating the cancer first. Other techniques, such as PET scanning, allow the entire subject to be evaluated at one time to determine the presence of cancer. The use of nuclear medicine imaging requires the administration of a suitable radiotracer that is capable of binding to the cancer site. For imaging to be successful, the administered agent must selectively bind to the cancer site, retain and deliver the radioisotope to the cancer site for a sufficient time to allow an image of sufficient quality to be obtained, and also induce little or no side effects to the subject. Treatment of cancer is often accompanied by various side effects and adverse events, which are related to the form of treatment. In general, adverse events experienced by a patient may be severe enough to limit or prematurely end a prescribed course of treatment or otherwise cause deleterious effects to the patient. Patients fall into low risk, medium risk and high risk categories. In general, patients with low risk diseases have excellent event-free survival and Overall Survival (OS) with only observed or minimal therapeutic intervention. The outcome of patients with intermediate risk diseases who are primarily treated with surgery and chemotherapy has improved to the point where many teams have focused on the use of biomarkers to help further reduce treatment in this class of children. Patients with high risk disease account for approximately half of all new neuroblastoma cases annually. To increase the chance of survival, this class requires treatment with multimode therapies, including induction chemotherapy, surgery, radiation therapy, high dose chemotherapy and autologous stem cell rescue, as well as biological and immunotherapy maintenance therapies. However, even with this aggressive treatment strategy, a significant number of patients relapse and eventually die from the disease. Despite recent advances in understanding the pathogenesis of neuroblastomas, patients with high risk refractory or recurrent disease have no established curative treatment options. Patients with recurrent disease often develop metastatic tumors that are resistant to standard therapies, and the goal of treatment is often not cure, but rather to extend survival and control symptoms. OS rates were maintained at only 57% and 20% for 1 year and 4 years, respectively. To improve the outcome in these patients, new therapeutic strategies are needed. Replacement of 131 I with 123 I in m-iodobenzoguanidine (migg) enables therapeutic radiopharmaceuticals suitable for the treatment of neuroblastomas and other neuroendocrine tumors. However, the use of 131 I-migg for neuroblastomas remains experimental and is currently only used in clinical trial settings. Furthermore, 131 I-mig treatment is an extremely complex and difficult procedure to schedule due to the long half-life of 131 I (8 days). Although single agent molecular radiotherapy with 131 I-migg has been shown to have some efficacy in recurrent or refractory populations, the total remission rate (ORR) is only 36%, the median ti