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EP-4507744-B1 - THERAGNOSTIC METHOD FOR CANCER PATIENTS

EP4507744B1EP 4507744 B1EP4507744 B1EP 4507744B1EP-4507744-B1

Inventors

  • VALENTINI, Serena

Dates

Publication Date
20260506
Application Date
20230303

Claims (20)

  1. A radiopharmaceutical composition, comprising as the active ingredient copper-64 in ionic form ( 64 Cu 2+ ), in combination with suitable excipients and/or diluents in a saline solution, having a radioconcentration higher than 925 MBq/mL at calibration time, for use in the treatment of a neoplasm, wherein radiopharmaceutical composition is used at a dose from 7 MBq/kg to 210 MBq/kg, optionally from 13 MBq/kg to 105 MBq/kg.
  2. A radiopharmaceutical composition, comprising as the active ingredient copper-64 in ionic form ( 64 Cu 2+ ), in combination with suitable excipients and/or diluents in a saline solution, having a radioconcentration comprised between 50 and 3,500 MBq/mL at calibration time, for use in the treatment of a neoplasm, wherein radiopharmaceutical composition is used at a dose from 7 MBq/kg to 210 MBq/kg, optionally from 13 MBq/kg to 105 MBq/kg, wherein the composition is administered intravenously by infusion.
  3. The radiopharmaceutical composition for use according to claim 1 or 2, wherein the treatment is preceded by a phase of evaluation of the eligibility of a subject for the treatment.
  4. The radiopharmaceutical composition for use according to any of the preceding claims, wherein the radioconcentration at calibration time is comprised between 930 MBq/mL and 3,500 MBq/mL, optionally comprised between 1,000 MBq/mL and 2,800 MBq/mL, or between 1,850 MBq/mL and 2,775 MBq/mL.
  5. The radiopharmaceutical composition for use according to any of the preceding claims, wherein the radioconcentration at calibration time is 2,775 MBq/mL, optionally 1,850 MBq/mL.
  6. The radiopharmaceutical composition for use according to claims 2 or 3, wherein the radioconcentration at calibration time is comprised between 50 MBq/mL and 920 MB/mL at calibration time, optionally comprised between 100 MBq/mL and 600 MBq/mL at calibration time. or between 200 MBq/mL and 450 MBq/mL at calibration time, optionally it is 350 MBq/mL at calibration time.
  7. The radiopharmaceutical composition for use according to any of the preceding claims, having a specific activity comprised between 500 and 50,000 MBq of 64 Cu/micrograms of copper, optionally between 1,000 and 10,000 MBq of 64Cu/micrograms of copper.
  8. The radiopharmaceutical composition for use according to any of the preceding claims, wherein the neoplasm is a benign neoplasm, an in situ neoplasm, a malignant neoplasm or a neoplasm of uncertain or unknown behavior.
  9. The radiopharmaceutical composition for use according to any of the preceding claims, wherein the malignant neoplasm is head-neck or brain cancer, in particular glioma, glioblastoma or astrocytoma.
  10. The radiopharmaceutical composition for use according to any of claims 1-8, wherein the malignant neoplasm is prostate cancer or metastatic prostate cancer.
  11. The radiopharmaceutical composition for use according to any of claims 1-8, wherein the malignant neoplasm is breast or ovary cancer, esophagus, stomach, intestines or colon cancer, lung cancer, leukemia or lymphoma, a neuroendocrine tumor or melanoma.
  12. The radiopharmaceutical composition for use according to any of the preceding claims 1, 3-5, 7-11, wherein the composition is administered by an enteral, parenteral, inhalation, oral or transcutaneous route, optionally by intramuscular, intradermal, subcutaneous, intratumoral, intracavity and intrathecal or intravenous route and any medical device system, optionally intravenously by injection or intravenously by infusion.
  13. The radiopharmaceutical composition for use according to claims 1, 5, 11 and 12, wherein the radioconcentration at calibration time is equal to 2,775 MBq/mL.
  14. The radiopharmaceutical composition for use according to claim 2 and 6, wherein the radioconcentration at calibration time is equal to 925 MBq/mL and the composition is administered by infusion.
  15. The radiopharmaceutical composition for use according to claim 3, wherein the phase of evaluating the eligibility of the subject for the treatment comprises the determination of the 64 Cu uptake by the neoplastic cells.
  16. The radiopharmaceutical composition for use according to claim 3, wherein the determination of the 64 Cu uptake by the neoplastic cells is carried out by measuring the target to background ratio (TBR) value through PET imaging, where a TBR value equal or higher than 5 is considered as evidencing an uptake of 64 Cu by the neoplastic cells.
  17. The radiopharmaceutical composition for use according to claim 3, wherein the radiopharmaceutical composition is used at a dose between 3 MBq/kg and 14 MBq/kg, optionally between from 5.3 MBq/kg and 13 MBq/kg to evaluate the eligibility of the patient for the treatment.
  18. The radiopharmaceutical composition for use according to any of the preceding claims for use in the treatment of a neoplasm, wherein the treatment is followed by a phase of monitoring the response of a subject to the treatment.
  19. The radiopharmaceutical composition for use according to claim 3, wherein the phase of evaluation of the eligibility of a subject is preceded by a determination of the copper level in a blood sample of the subject and said phase of evaluation of the eligibility is practiced only if serum copper level detected in a blood sample of the patient is over 60, optionally 150 µg/dL.
  20. The radiopharmaceutical composition for use according to any one of the preceding claims, wherein the treatment is repeated for 1 to 7 times per each cycle.

Description

FIELD OF THE INVENTION The present invention relates to a radiopharmaceutical composition comprising as the active ingredient copper-64 in ionic form (64Cu2+) in combination with suitable excipients and/or diluents, having a radioconcentration comprised between 50 and 3,500 MBq/mL at calibration time, optionally equal to, lower or higher than 925 MBq/mL at calibration time, for use in a method for treating a subject affected by a neoplasm. BACKGROUND OF THE INVENTION Copper, essential trace element with many physiological functions, plays an important role in tumor angiogenesis and can stimulate endothelial cell proliferation (Hu, 1998). Copper metabolism, that is tightly regulated through sophisticated homeostatic mechanism in physiological conditions, is profoundly altered in neoplastic disease together with its cellular deposition-from cytoplasm in normal tissue to intranuclear and perinuclear zones in tumors (Fuchs et al., 1989). In the past twenty years, many preclinical studies have demonstrated an effect of copper on cancer development; in particular, a copper's alteration has been observed in tumor bearing in mice and rats. Furthermore, a highly significant increase in both serum copper level and ceruloplasmin level was observed in patients with various types of tumors compared to healthy subjects (Fisher and Shifrine, 1978, Scanni et al., 1979). In particular, several authors reported an increased copper content in serum of patients affected by different tumor types such as lung cancer (Bai et al., 2019), cervical cancer (Zhang et al., 2018) and prostate cancer (Saleh et al., 2019). In addition, in glioma patients both serum copper and ceruloplasmin values showed a significantly higher concentration compared to healthy subjects or subjects affected by non-tumorous neurological diseases (Manjula et al., 1992). Currently, the importance of copper in carcinogenesis and metastasis formation and in resistance to treatment has been explored. In addition, research work on copper deregulation in oncology and the recent understanding of copper metabolism have led to the development of numerous therapeutic strategies targeting this trace element. Despite numerous research studies and the improvement of knowledge on copper metabolism over the years, some shadow areas persist (Lelièvre et al., 2020). The deregulated levels of copper in tumor patients can be observed thanks to the radioactive isotope Copper-64 (64Cu). This is one of the copper isotopes that is showing its potential in the nuclear medicine field for the PET (Positron Emission Tomography) imaging, which can be or PET/CT (Computed Tomography) or PET/MRI (Magnetic Resonance Imaging). Once injected to the patient, this isotope follows the abnormal distribution of copper in the human body that can be visualized by PET. Copper-64 is the only copper isotope that possesses three decay modalities and it has a half-life (12.7 h) that allows to obtain efficient clinical imaging at delayed scan times, exploiting better target-to-background signal; furthermore, it allows for the convenient distribution of the radiopharmaceuticals after its synthesis at centralized production sites, and for easier management of scheduled activities at the clinical nuclear medicine facilities. 64Cu can undergo β+ emission to nickel-64, β- emission to zinc-64. Both daughter nuclides are stable. In addition to beta minus, 64Cu decays also by Auger electron emission, these electrons have an average energy of 2 keV, 126 nm range in tissue (Howell, 1992) and are considered high-LET (Linear Energy Transfer) radiation. The capability to reach the cell nuclei and to emit Auger electrons in proximity of the DNA leads to tumor cell death and this mechanism may enhance cancer therapy. The beta plus emission gives it the capability to be a diagnostic agent, indeed different literature evidences showed the capability of 64Cu in the form of Copper Chloride (64CuCl2) to be a good diagnostic imaging agent in different cancer types, such as breast, prostate or melanoma, both in preclinical studies (Peng et al., 2006; Cai et al., 2014, Qin et al., 2014), but also in clinical settings. In patients affected by prostate cancer, 64CuCl2 PET/CT seems to show superior characteristics comparing to the clinical standard 18F-FCH (Capasso et al., 2015; Piccardo et al., 2017) and also in glioblastoma patients 64CuCl2 showed the potential to become a diagnostic agent (Panichelli et al., 2016). Instead, as mentioned above, the potential promising therapeutic use is given by the auger electron emission, but still less evidences are present in literature. During the last few years, in the field of nuclear medicine unprecedented advances have been shown: one of the main driving forces is the so-called "theragnostic" concept that combines the use of a diagnostic biomarker with a therapeutic option. Recent developments have significantly broadened the scope of radionuclide imaging and therapies that now extends