Intratumoral alpha-emitter irradiation in combination with vascular inhibitors

Abstract

1. A vascular inhibitor for use as a medicament for the treatment of a tumor in a patient, wherein an administration pattern of the medicament comprises administering a therapeutically effective amount of the vascular inhibitor to the patient in one or more sessions, and implanting seeds (204) carrying radium-224 into the tumor for intratumoral alpha emitter radiotherapy less than two weeks after administering the vascular inhibitor.

Description

[Technical field]

[0001] The present invention relates generally to tumor therapy, and in particular to the combination of intratumoral alpha emitter irradiation and vascular inhibitors. [Background technology]

[0002] Cancer is the leading cause of death in many countries around the world. Accordingly, enormous amounts of resources are spent on the treatment of cancer, and a wide variety of such treatments have been proposed. One type of tumor treatment is tumor ablation, which kills tumor cells in situ. Several ablation methods have been proposed, such as thermal, microwave, laser, electrical, photodynamic, chemical (e.g., using reactive oxygen species (ROS)) and radioactive ablation, which may be applied externally (e.g., external beam radiation therapy) or internally (e.g., brachytherapy), and may include various types of radiation, such as alpha, beta and gamma radiation. A discussion of these methods can be found, for example, in Keisari, Yona. "Tumor abolition and antitumor immunostimulation by physico-chemical tumor ablation." Front Biosci 22 (2017): 310-347. The ablation method used for any particular patient is generally selected according to the type of tumor, its location, its stage and / or other parameters of the tumor. Many other cancer treatment modalities are used, such as surgery, chemotherapy, immunotherapy, DNA repair inhibitors, targeted therapy, hormonal treatment, antiangiogenic therapy, and epigenetic modification. In general, the specific method used for each patient is selected according to the type, location, or stage of the tumor. Several combinations of the above-mentioned types of therapy have been tested in preclinical and clinical trials. Some of these methods involve the modulation of tumor vasculature, such as antiangiogenic therapy, which involves the inhibition of the growth of new blood vessels in the patient.

[0003] Ionizing radiation destroys cells by causing damage to their DNA. The biological effectiveness of different types of irradiation in killing cells is determined by the type and severity of DNA damage they cause. Alpha particles are a powerful tool of radiotherapy since they induce clustered double-strand breaks in DNA that cells cannot repair. Unlike conventional types of irradiation, the destructive effect of alpha particles is also largely unaffected by low cellular oxygen levels, making them equally effective against hypoxic cells whose presence in tumors is the main cause of failure of conventional radiotherapy based on photons or electrons. Also, the short-range alpha particles (less than 100 micrometers) in tissues ensure that surrounding healthy tissues are spared when the atoms that emit them are confined to the tumor volume. On the other hand, short-range alpha irradiation has so far been limited in its use to cancer treatment, due to the lack of a practical way to place alpha-emitting atoms in sufficient concentrations throughout the tumor volume.

[0004] Diffusing alpha-emitters Radiation Therapy (DaRT), described for example in Kelson's U.S. Patent No. 8,834,837, expands the therapeutic window of alpha radiation by using radium-223 or radium-224 atoms that undergo several radioactive decay chains, with predominant half-lives of 3.6 days for radium-224 and 11.4 days for radium-223. In DaRT, radium atoms are bound to sources (also called "seeds") implanted in the tumor with sufficient strength that they do not leave the source to be wasted (by being removed from the tumor through the blood), but a significant proportion of their daughter radionuclides (radon-220 in the case of radium-224 and radon-219 in the case of radium-223) leave the source and enter the tumor upon radium decay. These radionuclides, as well as their own radioactive daughter atoms and further daughter radionuclides derived therefrom, spread around the source by diffusion up to radial distances of several millimeters before decaying by alpha emission. Thus, the extent of destruction in the tumor increases in proportion to the radionuclides that remain in the source together with their daughters.

[0005] U.S. Patent Publication 2020 / 0276164 to Waugh et al., entitled "Pharmaceutical Combinations for the Treatment of Cancer," describes the treatment of metastatic prostate cancer with androgen deprivation therapy using a combination of a vascular endothelial growth factor (VEGF) signaling inhibitor and an interleukin-8 signaling inhibitor, in combination with radiation therapy. U.S. Patent Publication 2020 / 0093968 to Kaplan, entitled "Flexible and / or Elastic Brachytherapy Seed or Strand," describes a flexible brachytherapy strand that provides brachytherapy to drugs. Summary of the Invention

[0006] An aspect of some embodiments of the present invention relates to tumor treatment based on a combination between vascular inhibitors that destroy blood vessels and / or prevent the development and / or growth of new blood vessels and intratumoral diffuse alpha-emitter radiotherapy (DaRT). The term intratumoral refers herein to a treatment in which an alpha-emitter radionuclide is implanted in a seed within the tumor at one or more initial locations, and the alpha-emitter radionuclide or its daughter radionuclide migrates to other locations in the tumor where alpha-radiative decay occurs. The migration of the radionuclide from the seed may be by diffusion or by decay, where the radionuclide on the seed initiates multiple chains of radioactive decays. Thus, in accordance with an embodiment of the present invention, there is provided a vascular inhibitor for use as a medicament for the treatment of a tumour in a patient, wherein the administration pattern of the medicament comprises administering a therapeutically effective amount of the vascular inhibitor to the patient in one or more sessions, and implanting seeds carrying radium-224 into the tumour for intratumoural alpha-emitter radiotherapy less than two weeks before or after administering the vascular inhibitor. The pharmaceutical administration pattern may include initiating administration of the vascular inhibitor less than 5 days after implantation of the seed. The pharmaceutical administration pattern may include initiating administration of the vascular inhibitor at least 12 hours after implantation of the seed. The pharmaceutical administration pattern may include initiating administration of the vascular inhibitor at least 72 hours after implantation of the seed. The pharmaceutical administration pattern may include initiating administration of the vascular inhibitor at least 12 hours prior to implantation of the seed. The pharmaceutical administration pattern may include initiating administration of the vascular inhibitor at least 72 hours prior to implantation of the seed.

[0007] The vascular inhibitor may include an antiangiogenic agent. The antiangiogenic agent may include a vascular endothelial growth factor (VEGF) blocker. In some embodiments, the VEGF blocker includes an antibody against vascular endothelial growth factor (VEGF). The antibody against VEGF may include bevacizumab. The VEGF blocker may include a vascular endothelial growth factor (VEGF) decoy receptor. The VEGF decoy receptor may include Ziv-aflibercept. The VEGF blocker may include an antibody against a VEGF receptor. The antiangiogenic agent may include a kinase inhibitor. The kinase inhibitor may include at least one of sorafenib, sunitinib, regorafenib, and lenvatinib. The antiangiogenic agent may include an immunomodulatory imide drug (IMiD). In some embodiments, the immunomodulatory imide drug (IMiD) comprises at least one of thalidomide, pomalidomide, and lenalidomide. The antiangiogenic agent may include an antiangiogenic microRNA, an endothelin receptor blocker, and / or bosentan. In some embodiments, the antiangiogenic agent includes an mTOR inhibitor, rapamycin, a fibroblast growth factor inhibitor, and / or brivanib. The antiangiogenic agent may include an angiopoietin inhibitor. The antiangiogenic agent may include a platelet derived growth factor inhibitor. The antiangiogenic agent may include ponatinib. The antiangiogenic agent may include a hepatocyte growth factor (HGF) / c-MET inhibitor. The antiangiogenic agent may include a natural antiangiogenic factor, or a derivative or mimic of a natural antiangiogenic factor. The antiangiogenic agent may include endostatin. The antiangiogenic agent may include one or more beta adrenergic agonists. The antiangiogenic agent may include propranolol. The antiangiogenic agent may include an angiogenesis inhibitor. The anti-angiogenic agent may include metformin or chloroquine. The anti-angiogenic agent may include a cannabinoid. The anti-angiogenic agent may include a matrix metalloproteinase inhibitor. The anti-angiogenic agent may include an inhibitor of the pro-angiogenic activity of integrins. The vascular inhibitor may include a vascular disrupting agent. The vascular disrupting agent may include combretastatin A-4 phosphate (CA4P).

[0008] The source may include a support having a length of at least 1 millimeter; and radium-224 atoms bound to the support such that when the source is implanted into a tumor, no more than 20% of the radium-224 atoms leave the support and enter the tumor within 24 hours without decay, but upon decay at least 5% of the daughter radionuclides of the radium-224 atoms leave the support upon decay. Further provided in accordance with an embodiment of the present invention is a method of treating a patient having a tumor, comprising: treating the tumor with intratumoral alpha-emitter radiation therapy; and administering a vascular inhibitor to the patient within two weeks of initiating treatment of the tumor with intratumoral alpha-emitter radiation therapy. Administering a vascular inhibitor may include administering a vascular endothelial growth factor (VEGF) blocker. Treating a tumor with intratumoral alpha emitter radiotherapy may include treating a colorectal cancer tumor. Administering a vascular inhibitor may include administering bevacizumab and / or ranibizumab. Administering a vascular inhibitor may include administering an antiangiogenic drug. Administering a vascular inhibitor may include administering a vascular endothelial growth factor (VEGF) inhibitor. Administering a vascular inhibitor may include administering a vascular disrupting agent. Treating a tumor with intratumoral alpha emitter radiotherapy may include implanting a plurality of seeds in the tumor, each having a length of at least 1 millimeter. Administering a vascular inhibitor may include administering less than 5 days after implantation of the seeds. Administering a vascular inhibitor may include administering at least 12 hours after implantation of the seeds.

[0009] There is further provided in accordance with an embodiment of the present invention a kit for treatment of a patient, comprising at least one source of alpha-emitting atoms for at least partially introducing into a body of a subject, mounted thereon, at least one vascular inhibitor; and a package containing the at least one source and the at least one vascular inhibitor. There is further provided, in accordance with an embodiment of the present invention, an alpha emitting device designed for use in alpha emitter radiotherapy treatment of a tumor in a patient, wherein an alpha emitter radiotherapy treatment pattern comprises treating the tumor with the alpha emitter device, followed by administration of a therapeutically effective amount of a vascular inhibitor in one or more sessions less than six weeks after initiation of alpha emitter radiotherapy. An alpha emitter radiation therapy treatment pattern may include treating the tumor with an alpha emitter device followed by administration of a therapeutically effective amount of a vascular inhibitor in one or more sessions less than two weeks after initiation of alpha emitter radiation therapy.

[0010] Further provided in accordance with an embodiment of the present invention is an alpha-emitting device designed for use in populations whose tumors have been treated by administering an alpha-emitter device followed by a therapeutically effective amount of a vascular inhibitor in one or more sessions less than six weeks after the initiation of alpha-emitter radiation therapy. The various options and alternatives set out in the following description and claims can be used alternatively or together in any suitable combination, unless the options are specifically contradictory. [Brief description of the drawings]

[0011] [Figure 1] 1 is a flow chart of a treatment method according to one embodiment of the present invention. [Diagram 2] 1 is a schematic diagram of a kit for the combination of alpha emitter irradiation and vascular inhibitors, according to one embodiment of the present invention. [Diagram 3] 1 is a graph showing the results of an experiment testing the effect of combining alpha-emitter irradiation with bevacizumab administered after implantation of alpha-emitter irradiated seeds in accordance with one embodiment of the present invention. [Figure 4] 1 is a graph showing the results of an experiment testing the effect of combining alpha-emitter irradiation with bevacizumab administered four days prior to implantation of alpha-emitter irradiated seeds in accordance with one embodiment of the present invention. [Figure 5A-5B] 2 is a graph showing the results of experiments performed by applicant to examine the effect of the method of FIG. 1 on the effective diameter of DaRT seeds and leakage of radioactive atoms from tumors. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] An aspect of some embodiments of the present invention relates to a combined tumor treatment comprising a therapeutically effective treatment of diffuse alpha-emitter radiation therapy (DaRT) and a vascular inhibitor. Applicants have found that the combination of a vascular inhibitor with specific tumor ablation applying DaRT has a substantially greater therapeutic effect than each of the treatments separately. The effective range of destruction around the radionuclide-bearing DaRT source is limited to a few millimeters and depends on the biological attributes of the tumor. Contrary to the conventional belief that the disorganized structure of tumor vasculature increases the spread of DaRT-associated radionuclides in tumors compared to normal tissues, and therefore the use of vascular inhibitors would reduce the effective range of destruction, applicants have found that vascular inhibitors increase the effective range of DaRT treatment. Applicants believe that the increase in the effective range of DaRT resulting from vascular inhibitors is due to a reduction in blood vessels or prevention of angiogenesis, which allows leakage from the tumor through the bloodstream, thus allowing accumulation of alpha-emitting atoms in the tumor that increases the effectiveness of alpha-emitter irradiation treatment. First, it should be noted that applicants believed that vascular inhibitors should only be taken a few days after the initiation of DaRT treatment so that they would not interfere with the first phase of radionuclide spread in the tumor. However, after further investigation, applicants determined that their effects were beneficial even if vascular inhibitors were administered prior to initiating DaRT treatment.

[0013] Intratumoral alpha emitter radiotherapy utilizes alpha-emitting atoms for the treatment of tumors by using seeds (also called "sources") covered with radioactive atoms. The alpha-emitting atoms are released locally in a time- and spatially-slow manner. That is, by migration and convection, the atoms gradually diffuse in the tumor. At the initial time, most of the radioactivity is concentrated near the source. Over time, this distribution changes such that some of the alpha-emitting atoms reach more distant locations in the decay chain of the source radionuclide in the tumor. In addition to the change in the distance traveled over time, at each time point, there is a different distribution of activity as a function of distance from the source. That is, for each given time point and distance traveled, there is a different amount of activity along the straight line between the source and the maximum distance traveled, with shorter distances from the source showing higher activity. This allows for non-uniform and non-instantaneous destruction of tumor tissue. It has been shown that alpha-emitting atoms diffuse more efficiently in tumor tissue compared to normal tissue, possibly due to the abnormal tumor vasculature of tumors. However, as the radioactive decay chain progresses, with dispersion of the alpha-emitting atoms in the tumor away from the radioactive seed, there is an increased chance that the atoms will be eliminated by the bloodstream. By administering a vasculature inhibitor to the tumor, leakage of the radionuclide from the tumor can be reduced.

[0014] Treatment FIG. 1 is a flow chart of a method of treatment 100 according to an embodiment of the invention. Following identification of a tumor in a patient (102), an alpha emitter irradiation treatment (also referred to herein as alpha emitter radiotherapy) of the tumor is selected for the tumor (103). The selection of the treatment may include selecting in response to the type of tumor, the activity of radium-224 in the source to be implanted in the tumor, and the interval between sources. The source having the selected activity is then implanted inside the tumor (104). Also, a therapeutically effective dose of one or more vascular inhibitors is administered to the patient in one or more sessions (108). In some embodiments, after the alpha emitter radiation treatment is completed, the efficacy of the treatment is evaluated (110). In some embodiments, after the evaluation, surgery is performed to remove any remaining primary tumor (112). Surgery is performed after tumor shrinkage due to treatment, for example, in patients who were not eligible for surgery prior to treatment. Alternatively, or in addition, surgery (112) is performed prior to the DaRT treatment.

[0015] Tumor type The therapeutic method 100 may be used in the treatment of any tumor type, including cancerous tumors, benign neoplasms, in situ neoplasms (pre-malignant), malignant neoplasms (cancer), and neoplasms of uncertain or unknown behavior. In some embodiments, the method of Figure 1 is used to treat relatively solid neoplastic lesions, such as breast cancer, renal cancer, pancreatic cancer, skin cancer, head and neck cancer, colorectal cancer, ovarian cancer, bladder cancer, brain cancer, and prostate cancer. In other embodiments, the therapeutic method 100 of Figure 1 is used to treat non-solid tumors. The method of Figure 1 may be used for both primary and secondary tumors.

[0016] Exemplary tumors that may be treated by the method of FIG. 1 include, but are not limited to, tumors of the digestive tract (colon cancer, rectal cancer, colorectal cancer, colorectal adenocarcinoma, hereditary nonpolyposis 1, hereditary nonpolyposis 2, hereditary nonpolyposis 3, hereditary nonpolyposis 6; colorectal cancer, hereditary nonpolyposis 7, small intestine and / or large intestine cancer, esophageal cancer, calluses with esophageal cancer, gastric cancer, pancreatic cancer, pancreatic endocrine tumors). , endometrial cancer, dermatofibrosarcoma protuberans, gallbladder cancer, biliary tract tumors, prostate cancer, prostate adenocarcinoma, kidney cancer (e.g., Wilms' tumor type 2 or type 1), liver cancer (e.g., hepatoblastoma, hepatocellular carcinoma, hepatocellular carcinoma), bladder cancer, embryonal rhabdomyosarcoma, germ cell tumor, trophoblastic tumor, testicular germ cell tumor, immature teratoma of the ovary, uterus, epithelial ovarian, sacrococcygeal tumor, choriocarcinoma, placental trophoblastic tumor, epithelial adult tumor, ovarian cancer, serous ovarian cancer, ovarian sex cord tumor, cervical cancer, small cell and non-small cell lung cancer, nasopharynx, breast cancer (e.g., ductal carcinoma, invasive ductal carcinoma; breast cancer, susceptibility to breast cancer, type 4 breast cancer, breast cancer 1, breast cancer 3;breast cancer-ovarian cancer), squamous cell carcinoma (e.g., in the head and neck), vulvar cancer, neurogenic tumor, astrocytoma, ganglioneuroblastoma, neuroblastoma, glioma, adenocarcinoma, adrenal tumor, hereditary adrenocortical carcinoma, malignant brain tumor (tumor), various other cancers (e.g., bronchogenic large cell, ductal, epidermoid, large cell, medullary, mucoepidermoid, oat cell, small cell, spindle cell, spinous cell, transitional cell, anaplastic, carcinosarcoma, choriocarcinoma, cystadenocarcinoma), ependymoblastoma, epithelioma, erythroleukemia (e.g., Friend, lymphoblastic), fibroblastoma, giant cell tumor, glial tumor, glioblastoma (e.g., polymorphic, astrocytoma), glioma hepatoma hepatoma), heterohybridoma, heteromyeloma, histiocytoma, hybridoma (e.g., B cell), adrenal tumor, insulinoma, pancreatic islet tumor, keratoma, leiomyoblastoma, leiomyosarcoma, lymphosarcoma, melanoma, breast tumor, mast cell tumor, medulloblastoma, mesothelioma, metastatic tumor, monocytic tumor, multiple myeloma, myelodysplastic syndrome, myeloma, nephroblastoma, neural tissue glial tumor, neural tissue neural tumor, schwannoma, neuroblastoma, oligodendroglioma, osteochondroma, osteomyeloma , osteosarcoma (e.g., Ewing), papilloma, transitional cell, pheochromocytoma, pituitary tumor (invasive), plasmacytoma, retinoblastoma, rhabdomyosarcoma, sarcoma (e.g., Ewing, histiocytic, Jensen, osteogenic, reticular cell), schwannoma, subcutaneous tumor, teratocarcinoma (e.g., pluripotent), teratomas, testicular tumors, thymoma and trichoepithelioma, gastric cancer, fibrosarcoma, glioblastoma multiforme; multiple glomus tumors, Li-Fraumeni syndrome, solid lymphoma, liposarcoma, Lynch familial cancer syndrome type II (lynch These include Turcot's syndrome with rhabdoid tumor family syndrome II, male germ cell tumors, medullary thyroid, multiple meningiomas, endocrine neoplasms myxosarcoma, paraganglioma, familial nonchromaffin, pilomatricoma, papillary, familial and sporadic, rhabdoid predisposition syndrome, familial rhabdoid tumor, soft tissue sarcoma, and glioblastoma;

[0017] In some embodiments, the method of Figure 1 is applied to tumors known to be substantially affected by alpha emitter irradiation alone. In other embodiments, the method of Figure 1 is applied to tumors of a type that are not substantially affected by alpha emitter irradiation alone, e.g., do not decrease in size at all, or do not decrease in size by more than 5% or 10%. Experiments performed by applicants indicate that tumors that are substantially unaffected by alpha emitter irradiation or vascular inhibitors alone will still decrease in size when targeted with a combination of vascular inhibitors and alpha emitter irradiation according to the method of Figure 1.

[0018] While the treatment method 100 may be used with any of the tumors described above, applicant has determined that the method 100 is particularly useful for tumors such as pancreatic, melanoma, prostate, and glioblastoma, in which the required spacing between sources is relatively short, e.g., less than 4 mm, as described in PCT patent application PCT / IB2022 / 055322, entitled "Activity Levels for Diffusing Alpha-emitter Radiation Therapy," the disclosure of which is incorporated herein by reference in its entirety. Another criterion for tumors that would particularly benefit from the method of FIG. 1 is tumors that are difficult to access, such that the required spacing between sources is less than what is achievable due to limited access. For example, the method of FIG. 1 is particularly useful for glioblastoma in the head, since access to the tumor within the patient's skull is limited and the required spacing is small. Other tumors that may particularly benefit from the method of FIG. 1 are tumors that produce large amounts of vascular endothelial growth factor (VEGF) and / or have large amounts of blood vessels.

[0019] In some embodiments, whether to administer 108 the vascular inhibitor is determined in response to one or more parameters of the radiotherapy treatment. For example, the vascular inhibitor may be administered 108 only if the selected spacing between the implanted alpha-emitter sources is greater than a predetermined threshold, e.g., 3.6 mm, 3.8 mm, or 4 mm. Alternatively, after implantation of the alpha-emitter sources, the actual maximum distance between the sources and / or the average distance between the sources is determined, and the vascular inhibitor is administered if the actual distance is substantially greater (e.g., at least 20%, at least 30%, or at least 40%) than the selected spacing. In some embodiments, the minimum radiation dose expected to reach any point in the tumor is calculated for the selected radiotherapy treatment, e.g., using any of the methods described in PCT application PCT / IB2021 / 061607, entitled "Treatment Planning for Alpha-Particle Radiotherapy," the disclosure of which is incorporated herein by reference in its entirety. The calculated radiation dose, in these embodiments, is compared to the estimated required dose for the tumor type, and the vascular inhibitor is administered only if the calculated radiation dose is less than or equal to the estimated required dose by a sufficient safety margin. Instead of using the above determinations to determine whether to administer 108 a vascular inhibitor, one or more of the above determinations may be used to determine the dose and / or duration of administration of the vascular inhibitor. In some embodiments, according to this alternative, the vascular inhibitor is administered before the alpha emitter source is implanted. After the alpha emitter source is implanted, the distance between the sources is evaluated and a decision is made accordingly to continue or terminate administration of the vascular inhibitor.

[0020] In another embodiment, the selection of the parameters of the radiotherapy treatment (103) is made in response to whether the patient receives a vascular inhibitor treatment together with the radiotherapy. The activity of the source may be selected in response to whether the patient receives a vascular inhibitor treatment. For example, for patients resistant to vascular inhibitors, a source activity is selected that is higher than that used for patients to whom a vascular inhibitor is administered, for example at least 5% higher, at least 10% higher, or even at least 20% higher. Alternatively, or in addition, the distance between the sources is selected in response to whether the patient receives a vascular inhibitor treatment. In accordance with this alternative, for patients resistant to vascular inhibitors, a shorter spacing may be selected than that used for patients to whom a vascular inhibitor is administered, for example at least 0.1 millimeters shorter, at least 0.2 millimeters shorter, or even at least 0.3 millimeters shorter.

[0021] Vascular Inhibitors In some embodiments, the administered vascular inhibitor comprises an anti-angiogenic agent, which may include a vascular endothelial growth factor (VEGF) blocker. The VEGF blocking agent may include an antibody against VEGF. In some embodiments, the VEGF blocking agent includes a monoclonal antibody, such as bevacizumab (also known by the trade name Avastin), 2C3, and / or ranibizumab, that targets the VEGF factor. In other embodiments, the administered VEGF blocking agent includes an antibody against the VEGF receptor, such as ramucirumab (also known by the trade name Cyramza), that targets the VEGF receptor (VEGFR-2, also known as the kinase insert domain receptor). Alternatively, or in addition, the administered VEGF blocking agent comprises a VEGF decoy receptor, such as Ziv aflibercept (also known as a VEGF trap) and / or conbercept (sold under the trade name Lumitin). In other embodiments, the administered antiangiogenic agent includes drugs that are not VEGF blockers but have been identified as having antiangiogenic effects through biological pathways other than those of VEGF blockers. These antiangiogenic agents acting on other biological pathways are used in conjunction with DaRT, for example, in patients sensitive to VEGF blockers, in patients who do not respond to VEGF blockers, and / or in patients who are already receiving an antiangiogenic agent that acts through another pathway for a different purpose other than its antiangiogenic properties. In such cases, the antiangiogenic agent may be administered to the patient closer to the DaRT treatment, rather than at a more distant unrelated time, in order to increase the effect and scope of the DaRT treatment.

[0022] In accordance with these other embodiments, the antiangiogenic agent may include a kinase inhibitor such as sorafenib (also known as Nexavar), sunitinib (also known by the trade name Sutent), regorafenib (also known by the trade name Stivarga), and / or lenvatinib (also known by the trade name Lenvima). Alternatively, or in addition, the administered kinase inhibitor includes axitinib, vandetanib, pazopanib, cabozantinib, cilengitide, cediranib, enzastaurin, and / or vatalanib. In yet other embodiments, the administered antiangiogenic agent comprises an immunomodulatory imid drug (IMiD), such as thalidomide, pomalidomide, amiodarone, lenalidomide, iveldmide, linomide, and / or apremilast. Another option for the administered antiangiogenic agent, in some embodiments, comprises an antiangiogenic microRNA. It should be noted that at least some of these anti-angiogenic drugs further inhibit immune checkpoint expression, thus increasing the effectiveness of treatment by both preventing blood vessel regrowth and increasing the immune system's response.

[0023] Alternatively, or in addition, the administered antiangiogenic agent comprises an mTOR inhibitor, such as everolimus, rapamycin, and / or itraconazole.Further, alternatively, or in addition, the administered antiangiogenic agent comprises a fibroblast growth factor inhibitor, such as brivanib, dovitinib, and / or S49076. In other embodiments, the administered antiangiogenic agents include angiopoietin inhibitors such as vanucizumab, platelet derived growth factor inhibitors such as ponatinib, and / or hepatocyte growth factor (HGF) / c-MET inhibitors such as onartuzumab. The administered antiangiogenic agents, in other embodiments, include natural antiangiogenic factors or derivatives or mimetics thereof such as thrombospondin (TSP-1 and 2), ATB-510, 3TSR, pigment epithelium derived factor (PEDF), angiostatin, and / or endostatin.

[0024] In some embodiments, the administered antiangiogenic agent comprises one or more beta adrenergic agonists, such as carvedilol, nebivolol, propranolol, metroprolol, bisoprolol, and / or an αvβ3 integrin inhibitor. In other embodiments, the administered antiangiogenic agent comprises a drug that inhibits angiogenesis (also called angiogenesis inhibitors), such as metformin, chloroquine, carboxyamidotriazole, TNP-470, suramin, SU5416, Anecortave acetate, Verolanib, Fluoromedroxyprogesterone acetate, and / or Tasquinimod. In other embodiments, the administered anti-angiogenic agent comprises a cannabinoid such as HU-336, HU-345, a matrix metalloproteinase inhibitor such as marimastat, prinomastat, revimastat, neovastat, batimastat and / or tanomastat, an inhibitor of the pro-angiogenic activity of integrins such as Medi-522, EMD12194 (cilengitide), and / or an anti-angiogenic gene therapy such as VB-111. The administered antiangiogenic agent, in some embodiments, comprises a transforming growth factor beta (TGF-β) inhibitor. In some embodiments, the administered vascular inhibitors include endothelin receptor blockers, such as bosentan and / or atrasentan.

[0025] In some embodiments, instead of anti-angiogenic drugs, the administered vascular inhibitor comprises a vascular disrupting agent (VDA, also known as a vascular targeting agent). Although vascular disrupting agents are not known to prevent blood vessel growth, they are known to destroy blood vessels, and applicants believe that they may help extend the effective range of the DaRT source for at least some tumor types. Vascular disrupting agents are used in conjunction with DaRT, for example, in patients who are sensitive to anti-angiogenic drugs and / or in patients who are already receiving vascular disrupting agents for other reasons. In such cases, the vascular disrupting agent may be administered to the patient around the time of DaRT treatment to increase the effectiveness and range of the DaRT treatment. Vascular disrupting agents (VDAs) may include VDAs to small molecules and ligands, such as flavonoids or tubulin binding agents. Flavonoids may include endothelial permeability enhancers, such as vadimezan (also known as dimethylxanthine acetic acid (DMXAA), 5,6-dimethylxanthenone-4-acetic acid or ASA404). Tubulin binding agents may include combretastatin A-4 phosphate (CA4P), also known as dibrestat, ombrabulin (also known as AVE8062), ZD6126, ABT-571, MN-029 provided by MediciNova, OXi4503, plinabulin (NPI-2358) combretastatin, AS1404, and / or TZT-1027. The vascular inhibitor administered may comprise a single drug or may comprise a combination of several different drugs as described above, which may be administered together or in separate sessions.

[0026] Route of Administration In some embodiments, delivery of the vascular inhibitor to tumors and / or metastases is by systemic administration, for example orally or by intravenous (IV) injection or infusion, hi some embodiments, delivery of the vascular inhibitor uses a suitable method of targeted delivery. Alternatively, or in addition, the vascular inhibitor is administered in situ directly to one or more identified tumors (108). In this alternative, the vascular inhibitor may be administered by intratumoral injection. In some embodiments, the vascular inhibitor is administered from seeds carrying an alpha-emitter radionuclide, but preferably, the vascular inhibitor is administered separately from the seeds to achieve greater coverage of the tumors affected by receiving the vascular inhibitor. Prior to administering the vascular inhibitor to a patient, the size of the tumor, tumors, and / or metastases may be estimated and the amount of the vascular inhibitor selected accordingly. timing In some embodiments, the vascular inhibitor is administered in a single session (108). Alternatively, the vascular inhibitor is administered in multiple sessions, perhaps at least three, at least five, or even at least seven sessions (108). The separate sessions may be separated from each other by at least 4 hours, 8 hours, 24 hours, 48 ​​hours, or even at least 72 hours. In certain embodiments, the vascular inhibitor bevacizumab (BEV) is administered three times per week for a period of three weeks. For embodiments in which the vascular inhibitor is administered in multiple sessions (108), the following paragraphs relate to the first session of administration unless otherwise stated.

[0027] In a first type of embodiment, the vascular inhibitor is administered prior to the implantation of alpha-emitting seeds, so that the vascular inhibitor takes effect substantially throughout the duration of the radiation therapy. This type of embodiment is based on experimental results showing that the combination of DaRT and vascular inhibitor has a beneficial effect on the destruction of tumor cells, even if the vascular inhibitor is administered prior to the start of the alpha-emitter radiation treatment, e.g., the implantation of the seeds. The vascular inhibitor may be administered in this type of embodiment at least 6 hours, at least 12 hours, at least 24 hours, or even at least 48 hours, at least 72 hours, at least 96 hours, or even at least one week prior to the start of the alpha-emitter radiation treatment. Alternatively, or in addition, the vascular inhibitor is administered a short time prior to the implantation of the alpha-emitting seeds, so that the vascular inhibitor takes effect only after the dispersion of the daughter radionuclides in the tumor has begun. For example, the vascular inhibitor is administered less than 72 hours, less than 48 hours, less than 24 hours, less than 12 hours, or even less than 6 hours prior to the implantation of the seeds, according to this alternative.

[0028] In a second type of embodiment, the timing of the vascular inhibitor therapy is selected such that alpha emitter irradiation is first applied without vascular inhibitors to allow the radioactive atoms to utilize the abnormal vasculature of the tumor for optimized diffusion in the tumor, and then a vascular inhibitor is added to prevent leakage of the atoms from the tumor and repopulation of the remaining tumor cells. In this second type of embodiment, administration of the vascular inhibitor begins after implantation of the alpha-emitting source (104), followed by a limited buffer period (106). The buffer period may be selected to allow the vascular inhibitor to take effect when radioactivity in the tumor away from the seeds reaches a maximum level. For example, when diffuse alpha-emitter radiotherapy is induced by the insertion of alpha-emitter seeds, the buffer period (106) is selected to allow dispersion of alpha-emitting atoms in the tumor to a point where the number of alpha-emitting radionuclides dispersed away from the seeds is maximized. The buffer period (106) between implantation of the alpha emitter source (104) and the first session of administration of the vascular inhibitor (108) may be at least 6 hours, at least 9 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 96 hours, at least 120 hours, or even at least 144 hours. The buffer period (106) may be less than 2 weeks, less than 10 days, less than 1 week, less than 120 hours, less than 96 hours, less than 72 hours, or even less than 48 hours, such that alpha-emitting atom leakage is minimized when the vascular inhibitor is applied. In some embodiments, the buffer period (106) is less than 30 hours, less than 20 hours, or even less than 10 hours, for example in tumors that have a large number of blood vessels or that otherwise respond more rapidly to alpha-emitter radiotherapy.

[0029] In a third type of embodiment, the vascular inhibitor is administered after most of the radionuclides of the implanted seeds have undergone radioactive decay, which occurs within about two weeks. In this type of embodiment, the vascular inhibitor prevents tissue vascularization and / or repopulation of residual tumor cells from tumor cells that escaped alpha-based therapy in a wound healing response that may be caused by tissue damage following intense tumor cell killing. In some embodiments, one or more parameters of the tumor are monitored following implantation and / or activation of the alpha emitter seeds to determine the most suitable time point to apply vascular inhibitor therapy. Monitoring may include imaging the tumor using a suitable modality (e.g., X-ray, ultrasound, PET-CT, MRI, CT) to identify when the tumor begins to change due to activation of the alpha emitter radiotherapy and / or to monitor the vascularization status of the tumor. Alternatively, the monitoring may include taking a blood test to identify the level of the characteristic. It should be noted, however, that in some embodiments, the vascular inhibitor therapy is administered before the effects of the alpha emitter radiation therapy are detectable.

[0030] Alpha emitter radiation Alpha irradiation may include the insertion of seeds carrying alpha-emitting atoms, such as radium-224 or radium-223, into the tumor. The alpha-emitting atoms may be bound to the seeds such that the atoms do not leave the seeds, but do leave the seeds upon radionuclide decay that produces daughter radionuclides. The brachytherapy seeds may emit daughter radionuclide atoms at a rate of at least 0.1%, 0.5%, or even at least 1% of the number of radionuclide atoms bound to the seeds when originally used per 24 hours. In some embodiments, the daughter radionuclide atoms are slowly released from the seeds at a rate of less than 25%, less than 10%, less than 5%, or even less than 3% of the radionuclide atoms bound to the seeds per 24 hours. Instead of binding alpha-emitting atoms to the seeds such that the atoms do not exit the seeds without radionuclide decay, the alpha-emitting atoms are bound to the seeds such that the atoms controllably exit the seeds at a rate of at least 0.1% per 24 hours by means other than radionuclide decay, as described, for example, in PCT Publication WO 2019 / 193464, entitled "controlled release of radionuclides," which is incorporated herein by reference.

[0031] Diffuse alpha emitter radiation therapy (DaRT) may be performed using any of the methods and / or devices described in U.S. Patent 8,834,837, U.S. Patent Application 2009 / 0136422, U.S. Provisional Patent Application No. 62 / 913,184, filed October 10, 2019, and / or PCT Publication WO2018 / 207105, which are incorporated herein by reference. The alpha emitter radiation treatment may be initiated by inserting (104) one or more brachytherapy seeds into the tumor, the seeds carrying alpha emitting atoms on their outer surface. Alternatively, the alpha emitter radiotherapy is initiated by activating previously inserted seeds carrying alpha emitting atoms. In accordance with this alternative, the seeds may be inserted into the patient with a bioabsorbable coating that prevents alpha radiation and / or daughter radionuclides from leaving the seeds. The bioabsorbable coating may comprise polylactic acid (PLA), polyglycolide (PGA) or copolymers of PLA and PGA adapted to achieve a desired resorption rate of the coating. Alternatively, or in addition, the coating comprises copolylactic / glycolic acid (PLGA). The polymer of the coating may have a molecular weight in the range of 5,000 to 100,000. The material of the coating dissolves in the patient through any of the methods known in the art, such as one or more of ultrasonic energy, reaction with body temperature and / or reaction with bodily fluids. Further discussion of bioabsorbable polymers that may be used in accordance with embodiments of the present invention, after adjustment to a desired resorption rate, is provided in U.S. Patent 8,821,364 and U.S. Patent Application 2002 / 0055667, which are incorporated herein by reference. In some embodiments, initiation (108) involves applying a stimulus that dissolves the coating to allow alpha irradiation and / or daughter radionuclides to exit the seed. In other embodiments, initiation (108) is accomplished by dissolving the coating upon contact with tumor tissue, without further initiation required. Alpha emitter radiotherapy may be applied to the patient for at least 24 hours, at least 5 days, or even at least 10 days. In some embodiments, the radiotherapy seeds are removed from the patient after a designated treatment period. For example, the seeds may be removed during surgery for tumor removal. Alternatively, the seeds are not removed. In some embodiments, the seeds comprise a biodegradable material.

[0032] Treatment kit Figure 2 is a schematic diagram of a kit 200 for treatment of a patient according to the method of Figure 1. The kit 200 includes a sterile package 202 containing one or more alpha emitter radiotherapy seeds 204 for insertion into a tumor and one or more doses 216 of a vascular inhibitor. The seeds 204 may be provided in a vial or other casing 206 that prevents radiation from exiting the casing. In some embodiments, the casing is filled with a strong viscous liquid, such as glycerin, to prevent leakage of the radioactive atoms from the casing 206, as described in PCT Application PCT / IB2019 / 051834, entitled "Radiotherapy Seeds and Applicators," the disclosure of which is incorporated herein by reference. In some embodiments, the kit 200 further includes a seed applicator 208 that is used to introduce the seeds 204 into a patient, as described in PCT Application PCT / IB2019 / 051834. The applicator 208 may be provided with one or more seeds 204 preloaded therein. Pursuant to this option, separate seeds 204 in the casing 206 are provided if a greater number of preloaded seeds are required. Alternatively, the seeds 204 in the casing 206 are not provided in the kit 200, and only the seeds in the applicator 208 are included in the kit 200.

[0033] As shown, doses 216 of vascular inhibitor are provided preloaded in one or more needles 210. In other embodiments, doses 216 are provided in one or more containers or vials 220 and needles are provided separately within sterile packaging 202 or are not provided in kit 200 at all. In some embodiments, the kit 200 includes multiple separate compartments, separated by appropriate isolation, for materials requiring storage at different temperatures. For example, a first compartment may contain dry ice to keep the material in the first compartment at about -20°C, and a second compartment contains ice to maintain the material in the second compartment at about 4°C.

[0034] The radiotherapy seeds 204 may include a metallic or non-metallic support configured for insertion into the subject's body. The seeds 204 further include radionuclide atoms, such as, for example, radium-224, on an outer surface, as described, for example, in U.S. Patent 8,894,969, which is incorporated herein by reference. The radionuclide atoms are generally bound to the seeds such that the radionuclide atoms do not leave the support, but their daughter radionuclides may leave the seeds 204 upon radioactive decay due to recoil from the decay. The percentage of daughter radionuclides that leave the support upon decay is called the desorption probability. Binding of the radiotherapy atoms to the seeds is achieved, in some embodiments, by a heat treatment. Alternatively, or in addition, a coating covers the seeds and atoms to prevent release of the radionuclide atoms upon radioactive decay and / or to regulate the rate of release of the daughter radionuclides. The daughter radionuclide may pass through the coating and out of the seed 204 due to recoil, or recoil may carry the daughter radionuclide to the coating from where it may be released by diffusion.

[0035] Seed 204, in some embodiments, includes a seed for complete implantation within a patient's tumor and may have any suitable shape, such as a rod or plate. Instead of being completely implanted, seed 204 may be only partially implanted within the patient and may be part of a needle, wire, the tip of an endoscope, the tip of a laparoscope, or any other suitable probe. In some embodiments, the seeds 204 are cylindrical and have a length of at least 1 millimeter, at least 2 millimeters, or even at least 5 millimeters. The seeds 204 may have a length between 5 and 60 mm (millimeters). The seeds 204 may have a diameter of 0.7 to 1 mm, although in some cases larger or smaller diameter sources are used. For small spacing treatment designs in particular, the seeds 204 may have a diameter of less than 0.7 mm, less than 0.5 mm, less than 0.4 mm, or even 0.3 mm or less.

[0036] experiment FIG. 3 shows the results of an experiment conducted by the applicant to test the method of FIG. 1. In this experiment, the efficacy of DaRT with systemic administration of BEV in glioblastoma multiforme (GBM) xerographs was examined. Athymic nude mice were injected with a total of 5·10 BEVs per mouse into the flank. 6 U87 cells were inoculated intradermally at 100 μl of cells per well (volume 100 μl). Tumors were allowed to grow for 9 days to an average size of 5-6 mm (longest diameter) and either a single DaRT or inactive (non-radioactive control) seed was inserted into the center of each tumor. Five days after seed insertion, each mouse received an ip (intraperitoneal) administration of either IgG (control antibody) or BEV. This administration included three doses (5 mg / kg each) per week for three consecutive weeks (total of nine doses). Mice were divided into four treatment groups as follows: a. Inactive + control IgG (untreated control); b. Inactive + BEV (Bev as monotherapy); c. DaRT + control IgG (DaRT as monotherapy); d.DaRT+BEV (multidisciplinary therapy)

[0037] Tumor volume was monitored three times a week along with radioactivity measurements using a Geiger counter to ensure that DaRT seeds were present in the tumor. As can be seen in Figure 3, the tumors in the inactive + IgG group grew rapidly and had to be eliminated after 23 days of treatment due to exceeding the acceptable tumor volume. BEV as a single treatment provided a moderate but significant attenuation of tumor growth compared to the control (inactive + IgG) group. Furthermore, DaRT-treated tumors were significantly smaller compared to the control and BEV-treated groups, and two of the seven tumors were completely eradicated. Notably, a significant effect on tumor growth was observed in the combination therapy group compared to all other treatment groups. Similarly, two of the six tumors in the combination group were completely eradicated and did not recur for a period of just over four months, and were therefore declared to be completely cured. This experiment was repeated with similar results.

[0038] Figure 4 shows the results of an experiment conducted by applicant to test the method of Figure 1. In the experiment, the efficacy of DaRT was tested with systemic administration of BEV under the same conditions as in Figure 3, except for the timing of the initiation of BEV treatment, which was 4 days before DaRT insertion, and tumor size was larger with DaRT insertion. 5A and 5B show the results of an experiment conducted by the applicant to test the method of FIG. 1. In the experiment, autoradiography experiments were performed to calculate the effective diameter (i.e., the distance from the DaRT seed where the dose is greater than 10 Gy) of U87 tumors treated with DaRT and BEV and compared with the effective diameter of tumors treated with DaRT and IgG control (same treatment regimen as mentioned in FIG. 4). Tumors were harvested 4-5 days after DaRT insertion. Analysis of covariance for effective diameter showed significant differences between DaRT and BEV compared to DaRT and IgG in the effect on effective diameter (FIG. 5A) and leakage of radioactive atoms from tumors to external organs (FIG. 5B), with similar slopes but different intercepts. Effective diameter was significantly negatively correlated with leakage from tumors in both groups. This may suggest that BEV increased the efficacy of DaRT by preventing leakage of radioactive atoms from tumors, thereby promoting the effective diameter in tumors.

[0039] conclusion It will be appreciated that the methods and apparatus described above are to be construed to include apparatus for performing the methods and methods for using the apparatus. It should be understood that features and / or steps described with respect to one embodiment may be used with other embodiments, and that not all embodiments of the invention will have all of the features and / or steps shown in a particular figure or described with respect to one of the particular embodiments. Tasks do not necessarily have to be performed in the exact order described. It should be noted that some of the above-described embodiments may include details of structures, acts, or structures and acts that may not be essential to the present invention and are described as examples. The structures and acts described herein may be replaced with equivalents that perform the same function, even if the structures or acts are different, as is known in the art. The above-described embodiments are cited as examples, and the present invention is not limited to those specifically shown and described above. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described above, as well as variations and modifications thereof that may occur to a person skilled in the art upon reading the above description and that are not disclosed in the prior art. Thus, the scope of the present invention is limited only by the elements and limitations as used in the claims, and the terms "comprise", "include", "have" and variations thereof, when used in the claims, shall mean "including, but not necessarily limited to".

Claims

1. An angiogenesis inhibitor for use as a medicament for treating a patient's tumor, wherein the administration pattern of the medicament comprises administering a therapeutically effective amount of the angiogenesis inhibitor to the patient in one or more sessions, and implanting seeds carrying radium-224 into the tumor for alpha-radiation therapy of the tumor, and the time between administering the angiogenesis inhibitor and implanting the seeds is less than 6 weeks.

2. The angiogenesis inhibitor according to claim 1, wherein the time between administering the angiogenesis inhibitor and implanting the seeds is less than 2 weeks.

3. The angiogenesis inhibitor according to claim 1, wherein the administration pattern of the medicament comprises initiating administration of the angiogenesis inhibitor within less than 5 days after implantation of the seeds.

4. The angiogenesis inhibitor according to claim 1, wherein the administration pattern of the medicament comprises initiating administration of the angiogenesis inhibitor after implantation of the seeds.

5. The angiogenesis inhibitor according to claim 4, wherein the administration pattern of the medicament comprises initiating administration of the angiogenesis inhibitor at least 12 hours after implantation of the seeds.

6. The angiogenesis inhibitor according to claim 5, wherein the administration pattern of the medicament comprises initiating administration of the angiogenesis inhibitor at least 72 hours after implantation of the seeds.

7. The angiogenesis inhibitor according to claim 1, wherein the administration pattern of the medicament comprises initiating administration of the angiogenesis inhibitor at least 12 hours before implantation of the seeds.

8. The angiogenesis inhibitor according to claim 7, wherein the administration pattern of the medicament comprises initiating administration of the angiogenesis inhibitor at least 72 hours before implantation of the seeds.

9. The angiogenesis inhibitor according to any one of claims 1 to 8, comprising an anti-angiogenic agent.

10. The angiogenesis inhibitor according to claim 9, wherein the anti-angiogenic agent comprises a vascular endothelial growth factor (VEGF) blocker.

11. The angiogenesis inhibitor according to claim 10, wherein the VEGF blocker comprises an antibody against vascular endothelial growth factor (VEGF).

12. The angiogenesis inhibitor according to claim 11, wherein the antibody against VEGF comprises bevacizumab.

13. The angiogenesis inhibitor according to claim 10, wherein the VEGF blocker comprises a vascular endothelial growth factor (VEGF) decoy receptor.

14. The angiogenesis inhibitor according to claim 10, wherein the VEGF blocker comprises an antibody against a VEGF receptor.

15. The angiogenesis inhibitor according to claim 9, wherein the anti-angiogenic agent comprises a kinase inhibitor.

16. The angiogenesis inhibitor according to claim 15, wherein the kinase inhibitor comprises at least one of sorafenib, sunitinib, regorafenib, and lenvatinib.

17. The angiogenesis inhibitor according to claim 9, wherein the anti-angiogenic agent comprises an immunomodulatory imide drug (IMiD).

18. The angiogenesis inhibitor according to claim 17, wherein the immunomodulatory imide drug (IMiD) comprises at least one of thalidomide, pomalidomide, and lenalidomide.

19. The angiogenesis inhibitor according to claim 9, wherein the anti-angiogenic agent comprises an anti-angiogenic microRNA or an endothelin receptor blocker.

20. The angiogenesis inhibitor according to claim 9, wherein the anti-angiogenic agent comprises bosentan, an mTOR inhibitor, rapamycin, a fibroblast growth factor inhibitor, or brivanib.

21. The angiogenesis inhibitor according to claim 9, wherein the anti-angiogenic agent comprises an angiopoietin inhibitor.

22. The angiogenesis inhibitor according to claim 9, wherein the anti-angiogenic agent comprises a platelet-derived growth factor inhibitor, endostatin, ponatinib, or a hepatocyte growth factor (HGF) / c-MET inhibitor.

23. The angiogenesis inhibitor according to claim 9, wherein the anti-angiogenic agent comprises a natural anti-angiogenic factor, or a derivative or mimetic of a natural anti-angiogenic factor.

24. The angiogenesis inhibitor according to claim 10, wherein the anti-angiogenic agent comprises one or more β-adrenergic agonists.

25. The angiogenesis inhibitor according to claim 10, wherein the anti-angiogenic agent comprises an angiogenesis inhibitor, propranolol, a cannabinoid, a matrix metalloprotease inhibitor, or an inhibitor of the angiogenesis-promoting activity of integrin.

26. The angiogenesis inhibitor according to any one of claims 1 to 8, comprising a vascular disrupting agent.

27. The seed is: a support having a length of at least 1 millimeter; and radium-224 atoms bound to the support such that when the seed is implanted into a tumor, less than 20% of the radium-224 atoms decay without disintegration and exit the support to the tumor within 24 hours, and at least 5% of the daughter radionuclides of the radium-224 atoms exit the support upon disintegration. The angiogenesis inhibitor according to any one of claims 1 to 8, comprising the above.

28. An alpha-emitting device designed for use in intratumoral alpha-emitting radiotherapy treatment of a patient's tumor, wherein the intratumoral alpha-emitting radiotherapy treatment pattern comprises implanting an intratumoral alpha-emitting device into the tumor and administering a therapeutically effective amount of an angiogenesis inhibitor in one or more sessions within 6 weeks before or after the start of the intratumoral alpha-emitting radiotherapy.

29. A support having a length of at least 1 millimeter; and Radon-224 atoms bonded to the support such that when the device is implanted into the tumor, less than 20% of the radon-224 atoms decay without decay out of the support into the tumor within 24 hours, but at least 5% of the daughter radionuclides of the radon-224 atoms decay out of the support upon decay. The device according to claim 28, comprising.

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