WO2018107246A1 - Amélioration d'une radiothérapie interne sélective - Google Patents

Amélioration d'une radiothérapie interne sélective Download PDF

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WO2018107246A1
WO2018107246A1 PCT/AU2017/051404 AU2017051404W WO2018107246A1 WO 2018107246 A1 WO2018107246 A1 WO 2018107246A1 AU 2017051404 W AU2017051404 W AU 2017051404W WO 2018107246 A1 WO2018107246 A1 WO 2018107246A1
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dose
particulate material
patient
treatment
polymeric
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Ross Stephens
Gregory David Tredwell
Lee Andrew Philip
Karen Knox
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The Australian National University
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Publication of WO2018107246A1 publication Critical patent/WO2018107246A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1244—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
    • A61K51/1251—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles micro- or nanospheres, micro- or nanobeads, micro- or nanocapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention provides a particulate material, a therapeutic, a therapeutic device and a method of improving the treatment of cancer, in particular liver cancer in a patient in need thereof.
  • Cancer is one of the leading causes of death in the United States and in many other countries.
  • the disease is characterized by an abnormal proliferation of cell growth known as a neoplasm.
  • Malignant neoplasms in particular, can result in a serious disease state, which can threaten life.
  • colorectal cancer is one of the most common.
  • Metastatic carcinoma commonly occurs in the liver from primary carcinomas of, for example, the colonic mucosa.
  • the liver is a dominant site of metastatic spread of colorectal cancer as a result of the portal venous drainage of the gut.
  • Metastatic hepatic lesions are often multifocal and may occur on a background of hepatitis or liver cirrhosis. Hence, liver metastases are linked to poor prognosis - recurrence and death are common outcomes.
  • Single tumours may be resected with the expectation of achieving prolonged survival, but multifocal or diffuse metastases are generally not operable. Surgical resection of colorectal cancer liver metastases can result in a cure, but more often than not produces a 5-year survival of 27-39% to a 10-year survival of 12-36%, as opposed to median survival of approximately 9 months if untreated.
  • Effective anticancer agents include those that inhibit or control the rapid proliferation of cells associated with neoplasms, those that effect regression or remission of neoplasms, and those that generally prolong the survival of patients suffering from malignant neoplasia.
  • first-line chemotherapy is often used as first-line treatment in patients with non- resectable liver metastases, and in some cases, can sufficiently down-size the tumour burden in patients with previously inoperable liver metastases so that they may be converted to candidates for potentially curative resection.
  • Internationally accepted first- line chemotherapy regimens for patients with metastatic colorectal cancer include FOLFOX (combination of bolus and infusional 5-fluorouracil [5-FU], leucovorin [LV] and oxaliplatin) and FOLFIRI (combination of bolus and infusional 5-FU, LV and irinotecan). These regimens provide median survival times of 16-20 months.
  • microparticles in the selective delivery of therapeutic agents to a patient.
  • Such microparticles are usually bound or filled with chemotherapeutic agents or with radioactive isotopes, all of which are capable of killing neoplastic cells.
  • the challenge with such technologies has been to ensure that the microparticles are delivered specifically to a tumour to be treated without the particles being washed out of the tumour into the collecting vessels of the venous or lymphatic systems.
  • SIRT Selective Internal Radiation Therapy
  • SIRT is an effective alternative treatment or adjunctive treatment for liver tumours, using radioactively loaded polymer microparticles that are delivered via a trans-femoral hepatic artery catheter.
  • the use of microparticles to deliver SIRT has been a significant advance in the treatment of liver cancer. This treatment produces measurable tumour regression and has opened the possibility of prolonged survival. Accordingly, there is increasing interest in the use of microparticles for regional therapy of hepatic metastases.
  • a fundamental characteristic of nearly all microparticle technologies is that it is necessary to deliver these particles predominately to a tumour rather than to normal liver parenchyma.
  • microparticles need to be of an appropriate size to permit the microparticles to travel to a tumor once introduced into a patient. Usually this is achieved by either site specific delivery of microparticles to a tumour, which is ideal for single tumors but, becomes a challenge for multifocal or diffuse tumours.
  • a tumour which is ideal for single tumors but, becomes a challenge for multifocal or diffuse tumours.
  • microparticles are delivered to the liver via a trans-femoral hepatic artery catheter. The microparticles then use the hepatic arterial and capillary network to make their way to the tumour where they lodge at limiting diameters of the arterial vessels.
  • tumour blood vessels are heterogeneous with regard to organisation, function and structure.
  • tumour vasculature is unevenly distributed and chaotic. Tumour vessels often exhibit a serpentine course, branch irregularly and form arterio-venous shunts.
  • tumour blood vessels are more abundant at the tumour-host interface than in central regions, due to the angiogenesis induced by cytokines (e.g. VEGF) produced by tumour cells. Also, vascular density tends to decrease centrally as tumours . . grow, leading to inner zones of ischaemia and ultimately necrosis as tumours Outgrow their blood supply'. Finally, tumour blood vessels are structurally abnormal.
  • cytokines e.g. VEGF
  • microparticle size in that the microparticles must not be too small that they are washed out of the tumour into the collecting vessels of the venous or lymphatic systems, but must be large enough to travel in the hepatic arterial and precapillary network and in the tumour vasculature network so that they can lodge at limiting diameters or embolize in the finer angiogenic vessels that feed the tumour growth zone.
  • a second factor that influences distribution of microparticles in the liver is that the normal vessel divisions from the descending aorta to those ultimately supplying the liver have variations arising during embryological development.
  • the growth of a tumour in the liver and its associated angiogenesis can produce changes in the arterial network of the liver, sometimes resulting in significant hepatopulmonary or hepatogastric shunting.
  • T/L mean tumour to liver arterial perfusion ratio
  • 50 ⁇ microparticles did not preferentially lodge in malignant tissue.
  • they also assessed the homogeneity of distribution of microparticles embolizing in the normal liver tissue for each microparticle size. They discovered that as microparticle diameter increased from 15 to 50 ⁇ , microparticles lodged more evenly throughout the liver. For 15 ⁇ microparticles the coefficient of variation was 55.5% +/- 8.3 and 32.5 ⁇ microparticles distributed with a coefficient of 35% +/- 16.8 while 50 ⁇ spheres . .
  • 64(6):1031 -4 investigated the factors influencing the distribution of regionally injected microparticles.
  • a discreet tumour was induced in rats by subcapsular hepatic inoculations of HSN cells.
  • At 20 days 12.5 ⁇ , 25 ⁇ or 40 ⁇ diameter, radiolabelled albumin microparticles were administered, in various concentrations, via the gastroduodenal artery.
  • Tumour to normal liver microparticle distribution ratios were determined from tissue sampling and median values ranged from 0.1 (0.2 mg/ml 12.5 ⁇ microparticles) to 1 .8 (20 mg/ml 40 ⁇ microparticles).
  • Concentrated suspensions (20 mg/ml) of large microparticles (40 ⁇ ) produced the most favourable tumour to normal liver distribution ratios.
  • microparticle SIRT technologies have proceeded on the basis that microparticles of between 20 and 30 ⁇ are conventionally ideal for tumour treatments and that particles greater than 10 to 12 ⁇ (being the lower limit) are absolutely required for retention in capillary networks and to avoid venous drainage to the systemic circulation.
  • SIR-Spheres® microparticles for example, have a median diameter of 30 ⁇ and lodge at limiting diameters in the arterial vessels supplying a tumour, where their loading of Yttrium-90 radioisotope delivers cytotoxic beta radiation.
  • Experimental studies have shown that the increased density of the angiogenic network at the periphery of metastatic tumours growing in the liver can result in significantly higher . . dose delivery to the tumour tissue compared to the normal liver parenchyma [Campbell et al., (2001 ). Phys Med Biol, 46: 487-798].
  • a therapeutic product that improves the treatment of liver cancer will be of significant benefit to patients.
  • the present invention seeks to provide an improved or at least an alternative product and methods of use thereof for the treatment of cancer, and in particular, lung and or liver cancer.
  • the present invention provides an improved anticancer therapy that has utility, in cancer treatments generally but more specifically in the treatment of primary and secondary lung and or liver cancer.
  • polymeric particulate microparticles that have a size range of 6 to 12 ⁇ , preferably, 7 to 1 1 ⁇ , 8 to 10 ⁇ and most preferably 8 or 9 ⁇ , provide significant improvements in SIRT.
  • Particles of this size and polymeric form distribute more homogeneously in tumours compared to larger microparticles, lodge preferentially in tumour tissue sparing the normal tissue in patients and yet present surprisingly little washout of isotope from the tumour site to the systemic circulation.
  • the invention resides in a polymeric particulate material comprising: (a) polymeric matrix, having a diameter in the size range of 6 to 12 ⁇ or 7 to 1 1 ⁇ or 8 to 10 ⁇ and most preferably 8 or 9 ⁇ , and (b) a radionuclide stably incorporated therein.
  • the radionuclide is incorporated in the polymeric particulate material delivers a radiation dose of between about 10 and 800 Gy.
  • the radiation dose delivered by the radionuclide is between 10 and 200Gy. More preferably it is between 10 and 150Gy, 10 and 100Gy, 20 and 80Gy, 25 and 75Gy, 30 and 70Gy, 35 and 65Gy, 40 and 60Gy or 40 and 55Gy with approximately 50 Gy being optimal, at least in the treatment of liver metastases.
  • the invention resides in a process for the production of a polymeric particulate material having a diameter in the range of from of . .
  • said process comprising the step of: combining a polymeric matrix and a radionuclide for sufficient time and under conditions sufficient to stably incorporate the radionuclide in the matrix.
  • the invention provides a method for treating a patient in need of SIRT therapy, said method comprising the step of: administering to a cancerous tissue in a patient on need of SIRT therapy a polymeric particulate material as herein described.
  • the polymeric particulate material is administered to a patient at a therapeutic dose that delivers a radiation dose of between about 10 and 800 Gy to at least a tumour in the cancerous tissue.
  • the radiation dose delivered by the polymeric particulate material is between 10 and 200Gy. More preferably it is between 10 and 150Gy, 10 and 100Gy, 20 and 80Gy, 25 and 75Gy, 30 and 70Gy, 35 and 65Gy, 40 and 60Gy or 40 and 55Gy with approximately 50 Gy being optimal, at least in the treatment of liver metastases.
  • the method of treatment may be integrated into other regimens of treatment, such as chemotherapeutic treatments that are commonly applied to cancer patients.
  • the cancer is a metastatic carcinoma which, for example, may arise in the liver from primary carcinomas of, for example, the colonic mucosa.
  • the invention resides in the use of a polymeric particulate material as herein described, in internal radiation therapy of a patient.
  • the invention resides in the use of a polymeric particulate material as herein described, in the manufacture of medicament for the treatment of cancer in a patient.
  • the cancer is a metastatic carcinoma which, for example, may arise in the liver from primary carcinomas of, for example, the colonic mucosa.
  • Figure 1A is a graphical representation of FibrinLite nanoparticles (FL; US 8,778,300) pretreated with low microgram concentrations of protamine binding readily to polystyrene micro-wells.
  • Figure 1 B is a graph showing the results of the mean values for six separate microsphere binding experiments using FibrinLite nanoparticles pretreated with protamine.
  • Figure 1 C is a scanning electron micrograph showing islands of protamine treated FibrinLite bound on the surface of a microsphere.
  • Figure 1 D is a scanning electron micrograph showing plain microspheres for comparison with 1 C.
  • FIG. 2 shows the results from lung retention tests of radiolabeled microparticles after intravenous injection in rabbits.
  • the frames A - C show gamma camera images of anaesthetised normal rabbits taken 3 h after intravenous injection of a 5% dextrose suspension (5 imL) containing 15 mg (130 MBq) FL-MS30, FL-MS12, and FL-MS8 respectively, (where FL is Fibrinlite and MS refers to the median diameter ( ⁇ ) of the tested microspheres).
  • frame D shows a 3 h post-injection image of a rabbit injected with the lung diagnostic agent Tc99m-MAA (2.5 mg, 130 MBq); note activity in the lungs but also in the kidneys.
  • Figures 3A to 3D show the distribution of radiolabeled microparticles and MAA in normal rabbit livers after intra-arterial instillation.
  • Figures 3A to 3C show gamma camera images of excised livers removed from normal rabbits 1 h after intra-arterial instillation of a 5% dextrose suspension (8 imL) containing 40 mg (130 MBq) FL-MS30 (Figure 3A), FL-MS12 ( Figure 3B) and FL-MS8 ( Figure 3C) respectively.
  • Figure 3D shows an excised liver removed from a rabbit 1 h after intra-arterial instillation of Tc99m-MAA (2.5 mg, 130 MBq). . .
  • Figures 4A to 4D show the distribution of radiolabeled microparticles and MAA in rabbit livers hosting a VX2 tumour implant.
  • Figures 4A to 4C show gamma camera images of excised livers with tumours removed from rabbits 1 h after intra-arterial instillation of a 5% dextrose suspension (8 imL) containing 40 mg (130 MBq) FL-MS30 (Figure 4A), FL-MS12 ( Figure 4B) and FL-MS8 ( Figure 4C), respectively.
  • Figure 4D shows an excised liver with tumour removed from a rabbit 1 h after intra-arterial instillation of Tc99m-MAA (2.5 mg, 130 MBq).
  • FIG. 5 is VX2 tumour imaging in an intact rabbit with FL-MS8.
  • the frames A to C show the coronal, sagital and transaxial SPECT/CT views respectively of an anaesthetized rabbit with a liver implant of a VX2 tumour, 1 h after intra-arterial instillation of FL-MS8 (40 mg; 130 MBq).
  • microparticles in a size range of 6 to 12 ⁇ , preferably 7 to 1 1 ⁇ , 8 to 10 ⁇ and most preferably 8 or 9 ⁇ provides significant improvements in SIRT.
  • Particles of this size surprisingly distribute more homogeneously in tumours compared to larger microparticles and preferentially towards tumour tissue sparing normal tissue in patients without significant washout effects from a tumour.
  • the invention is described below by reference to certain identified embodiments, nonetheless the skilled reader will appreciate that the invention so identified herein presents a principal that has broad and general application. It provides a hitherto unknown and unexpected refocusing and refinement of SIRT technology with significant advantages to both the patient and the clinician in the treatment of patients with a tumour.
  • the invention described herein includes various values (for example, size, homogeneity etc.).
  • a range of values will be understood to include all values within the range, including the values defining the range, and values adjacent to the range that lead to the same or substantially the same outcome as the values immediately adjacent to that value which defines the boundary to the range.
  • a person skilled in the field will understand that a 10% variation in upper or lower limits of a range can be totally appropriate and is encompassed by the invention. More particularly, the variation in upper or lower limits of a range will be 5% or as is commonly recognised in the art, whichever is greater.
  • microparticle includes all particulate materials that meet the parameters of the present invention - - including microspheres preferably without sharp edges or points that could damage patients' arteries or catch in unintended locations. It is not limited to spheres. Nor should the term microparticle be limited to spheres. Preferably, the microparticle is substantially spherical or oval, but need not be regular or symmetrical in shape. The microparticles also need not be limited to any form or type of microparticles. Any microparticles may be used in the present invention provided the microparticles can receive a radionuclide such as through impregnation, absorbing, coating or more generally bonding the particles together.
  • a radionuclide such as through impregnation, absorbing, coating or more generally bonding the particles together.
  • treatment includes:
  • terapéuticaally effective amount includes within its meaning a non-toxic but sufficient amount of a polymeric particulate material as herein described for use in the invention to provide a desired therapeutic effect.
  • the exact amount of material required to treat a disease, disorder or condition will vary from subject to subject depending on factors such as the species being treated, the age, weight and general condition of the subject, co-morbidities, the severity of the disease, disorder or condition being treated, the specific characteristics of the polymeric particulate material being administered and the mode of administration.
  • an appropriate "effective amount" of a polymeric particulate material may be determined by one of ordinary skill in the art using only routine methods.
  • references herein to use of microparticles in a therapy will be understood to be equally applicable to human and non-human, such as veterinary, applications.
  • reference to a "patient”, “subject” or “individual” means a human or non-human species, such as an individual of any species of social, economic or research importance including but not limited to lagomorph, ovine, bovine, equine, porcine, feline, canine, primate and rodent species.
  • kit or “device” will be understood to include devices which may be used in therapy, including prevention and treatment of an actual condition or symptom, and those which may be used in diagnosis, including where the diagnosis is performed on or in the body of a patient and where the diagnosis is performed on or with a sample obtained from the body of a patient.
  • the present invention provides a polymeric particulate material that has utility in the treatment of various forms of cancers and tumours, particularly in the treatment of primary liver cancer and secondary liver cancer and, more specifically, in secondary liver cancer deriving from the gastrointestinal tract, such as secondary liver cancers deriving from colorectal cancer.
  • radioactive microparticles or other small particles When radioactive microparticles or other small particles are administered into the arterial blood supply of a target organ, it is desirable to have them of a size, shape and density that results in the optimal homogeneous distribution within a target organ. If radioactive microparticles or small particles do not distribute evenly as a function of the arterial blood flow, they can accumulate in excessive numbers in some areas and cause focal areas of excessive radiation. They also may not reach the arterial micro-vessels supplying a tumour. [0054] The inventors have discovered that, contrary to conventional wisdom, the ideal polymeric particulate material for injection into the blood stream within a target organ should have a very narrow size range of approximately 6 to 12 ⁇ , 7 to 1 1 ⁇ , 8 to 10 ⁇ and most preferably 8 or 9 ⁇ . This range of particle size it should be noted is comparable with the size of normal blood cells and therefore can be fully expected to reach the fine vessels of a tumour's angiogenic growth zone - -
  • the polymeric particulate material has a mass median diameter or d50 in the range of 6 to 12 ⁇ , preferably 7 to 1 1 ⁇ , more preferably 8 to 10 ⁇ and most preferably 8 or 9 ⁇ .
  • the polymeric particulate material also has a narrow particle size distribution.
  • the standard deviation of the sample is about 0.5 to 2 ⁇ .
  • the standard deviation will be 0.5, 0.6, 0.7, 0.8, 0.9, 1 , 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, 2.3, 2.4 or 2.5 ⁇ . More preferably, the standard deviation will be about 1 .0, 1 .1 , 1 .2, 1 .3, 1 .4 or 1 .5 ⁇
  • the d10 value of the particle size distribution is greater than about 1 ⁇ and more preferably greater than about 1 .5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6 or 6.5 ⁇ .
  • the d10 value for the material may vary depending on the mass median diameter of the polymeric particulate material. For example, if the median particle size is about 8 ⁇ and the standard deviation of the sample is about 1 ⁇ then the d10 will be about 6.5 ⁇ to 7 ⁇ , preferably 6.9 ⁇ . Alternatively, if the median particle size is 12.4 ⁇ and the standard deviation of the sample is 1 .5 ⁇ then the d10 will be about 10 ⁇ to 10.5 ⁇ , preferably 10.4 ⁇ .
  • an embodiment of the invention provides a polymeric particulate material, with a mass median diameter or d50 in the range of 6 to 12 ⁇ wherein at least 10% of the particles have a particle size of less than about 1 .5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 ⁇ wherein the d10 will be within 0.5 to 2.5 standard deviations (optionally, 0.5 0.6, 0.7, 0.8, 0.9, 1 , 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, 2.3, 2.4 or 2.5 standard deviations) from the d50 of the polymeric particulate material.
  • the d90 value of the particle size distribution is less than about 16 ⁇ and more preferably less than about 15.5, 15, 14.5, 14, 13.5, 13, 12.5, 12, 1 1 .5, 1 1 , 10.5 or 10 ⁇ .
  • the d90 value for the material may vary depending on the mass median diameter of the polymeric particulate material. For example, if the median particle size is 8.18 ⁇ and the standard deviation of the sample is 1 .06 ⁇ then the d90 will be about 9.5 ⁇ to 10 ⁇ , preferably 9.7 ⁇ . Alternatively, if the median particle size is 12.4 ⁇ and the standard deviation of the sample is 1 .52 ⁇ then the d90 will be about 14.5 ⁇ to 15 ⁇ , preferably 14.6 ⁇ . - -
  • an embodiment of the invention provides a polymeric particulate material, with a mass median diameter or d50 in the range of 6 to 12 ⁇ wherein at least 90% of the particles have a particle size of less than about 16 ⁇ and more preferably less than about 15.5, 15, 14.5, 14, 13.5, 13, 12.5, 12, 1 1 .5, 1 1 , 10.5 or 10 ⁇ wherein the d90 will be within 0.5 to 2.5 standard deviations (optionally, 0.5 0.6, 0.7, 0.8, 0.9, 1 , 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2.0, 2.1 , 2.2, 2.3, 2.4 or 2.5 standard deviations) from the d50 of the polymeric particulate material.
  • the particle size distribution of the polymeric particulate material will have: (i) a d10 value for the particle size distribution that is greater than about 4, 4.5, 5, 5.5, 6 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 ⁇ depending on the d50 of the polymeric particulate material, and (ii) a d90 value of the particle size distribution that is less than about 16 ⁇ , more preferably less than about 15.5, 15, 14.5, 14, 13.5, 13, 12.5, 12, 1 1 .5, 1 1 , 10.5, 10, 9.5, 9 ⁇ depending on the d50 of the polymeric particulate material.
  • the median particle size is about 8 ⁇ and the standard deviation of the sample is 1 .06 ⁇ then (i) the d10 will be about 6.5 ⁇ to 7 ⁇ , preferably 6.9 ⁇ and (ii) the d90 will be about 9.5 ⁇ to 10 ⁇ , preferably 9.7 ⁇ .
  • the median particle size is 12.4 ⁇ and the standard deviation of the sample is 1 .5 ⁇ then (i) the d10 will be about 10 ⁇ to 10.5 ⁇ , preferably 10.4 ⁇ and the d90 will be about 14.5 ⁇ to 15 ⁇ , preferably 14.6 ⁇ .
  • Methods of determining the size of particles are well known in the art. For example, the general method of U.S. Patent No. 4,605,517, incorporated herein by reference, could be employed. The following is a description of one non-limiting method.
  • microparticle size is characterized using an instrument adapted to measure equivalent spherical volume diameter, a Horiba LA910 Laser Scattering Particle Size Distribution Analyzer or a Malvern Mastersizer 3000 laser diffraction particle size analyzer or equivalent instrument.
  • Polymeric particulate material of such a size range and particle size distribution as presented above has been found to preferentially concentrate in neoplasia in a target organ with surprisingly little washout or shunting. Retention of radiolabeled material, as - - demonstrated by imaging, was shown to be highly favourable for achieving tumour irradiation with a therapeutic microsphere.
  • the particulate polymeric material is suitable for SIRT.
  • the preferred particulate polymeric material is in the form of microparticles with a level of radioactivity that is between about 0.01 to 0.4 GBq (activity per particle).
  • the activity per microparticles is 0.10, 0.1 1 , 0.12, 0.14, 0.15, 0.16, 0.17, 0.18, 0.20, 0.21 , 0.22, 0.23, 0.24, 0.26, 0.27, 0.28, 0.29, 0.30, 0.32, 0.33, 0.34, 0.35, 0.36, 0.38, 0.39, 0.40, GBq.
  • polymeric microparticles loaded with Yttrium 90 will deliver a level of radioactivity to a tumor of up to 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.3 or 3.4 GBq of tumor volume at the site of treatment.
  • the polymeric particulate material has a mass median diameter in the size range of 6 to 12 ⁇ , more preferably 7 to 1 1 ⁇ or 8 to 10 ⁇ and most preferably 8 or 9 ⁇ and comprises a polymeric matrix in which a radionuclide is stably incorporated, wherein the polymeric particulate material incorporating the radionuclide delivers a radiation dose of between about 10 and 800 Gy.
  • the radiation dose delivered by the polymeric particulate material is between 10 and 200Gy. More preferably it is between 10 and 150 Gy, 10 and 100 Gy, 20 and 80 Gy, 25 and 75 Gy, 30 and 70 Gy, 35 and 65 Gy, 40 and 60 Gy or 40 and 55 Gy with approximately 50 Gy being optimal, at least in the treatment of liver metastases.
  • SIRT treatment is most effective when the activity of microparticles loaded with Yttrium 90, delivers a radiation dose of between about 10 and 800 Gy.
  • a radiation dose of between about 10 and 800 Gy Generally, 1 GBq of Yttrium-90/kg of tissue provides 50 Gy of radiation dose.
  • the radiation dose delivered by the microparticles is between 10 and 200Gy. More preferably it is between 10 and 150 Gy, 10 and 100 Gy, - -
  • the invention is not limited to delivering the above doses of radiation. It can be used to deliver higher radiation doses. Such higher doses of radiation can be used to treat liver metastases or used to treat other forms of metastases, such as those commonly seen in the lung and kidneys. In such instances, the activity of the polymeric microparticles produced according to the invention delivers a radiation dose to a neoplasia of between about 10 and 800 Gy.
  • the radiation dose is 10, 20, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790 or 800 Gy.
  • the radiation dose delivered to a neoplasia is between about 10 and 200 Gy.
  • Illustrative radiation doses include: 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 1 10, 120, 130, 140, 150, 160, 170, 180, 190 or 200 Gy.
  • the radioactivity of the microparticles used in the SIRT can be calculated by determining the tumour volume and then adjusting the amount of the radioactive microparticles, having regard to tumour volume, to deliver to the neoplasia the desired radiation dose.
  • references to the radionuclide being stably incorporated into particulate material or polymeric matrix are to be understood as referring to incorporation of the radionuclide so that it does not substantially leach out of the particulate material under physiological conditions such as in a patient or in storage.
  • the radionuclide is incorporated by precipitation into a polymeric matrix forming the microparticle.
  • the radionuclide doped microparticles need not be limited to any particular form or type of microparticle. So, for example, the radionuclide doped microparticles suitable for use in the invention may comprise any additional material capable of receiving a radionuclide such as through impregnation, absorbing, coating or more generally - - bonding the radionuclide with the microparticle or material used to carry the radionuclide.
  • Yttrium-90 is a high-energy pure beta-emitting isotope with no primary gamma emission.
  • the maximum energy of the beta particles is 2.27 MeV, with a mean of 0.93 MeV.
  • the maximum range of emissions in tissue is 1 1 mm, with a mean of 2.5 mm.
  • the half-life of yttrium-90 is 64.1 hours. In use requiring the isotope to decay to infinity, 94% of the radiation is delivered in 1 1 days leaving only background radiation with no therapeutic value.
  • the microparticles themselves are a permanent implant and each device is for single patient use.
  • Alternate radionuclides that can be used in the production of these microparticles include for example, lutetium, holmium, samarium, iodine, phosphorous, iridium rhenium and terbium.
  • the radionuclide that is incorporated into the microparticle in accordance with the present invention is preferably yttrium-90, but may also be any other suitable radionuclide which can be precipitated in solution, of which the isotopes.
  • Variation to the activity of the microparticle used in the SIRT and the intended radiation dose to the neoplasia are two of the variable that must be accounted for in delivering a therapy. Relevantly, any variation of the radiation dose delivered to the neoplasia will cause a consequential variation to the activity of the microparticles used in the method and vice versa.
  • the radionuclide is stably incorporated into the particulate material or polymeric matrix such that the incorporated radionuclide does not substantially leach out of the particulate material under physiological conditions such as in the patient or in storage.
  • the leaching of radionuclides from the polymeric matrix can cause non-specific radiation damage to the patient and damage surrounding tissue.
  • a radionuclide will be stably incorporated into a particulate material if less than 5% of the radionuclide leaches from the particulate material, under physiological conditions, over the radioactive life of the particulate material. More - - preferably, a radionuclide will be stably incorporated into a particulate material if less than 4%, 3%, 2%, 1 % or 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1 % of the radionuclide leaches from the particulate material, under physiological conditions, over the radioactive life of the particulate material.
  • the radionuclide will be stably incorporated into a particulate material for at least 2 days, with, 3, 4,5, 6, 7, 8, 9, 10 or 1 1 days being more preferable. In therapeutic use, requiring the isotope to decay to infinity, 94% of the radiation is delivered in 1 1 days
  • the polymeric particulate material has a mass median diameter in the size range of 6 to 12 ⁇ more preferably 7 to 1 1 ⁇ or 8 to 10 ⁇ and most preferably 8 or 9 ⁇ and comprises a polymeric matrix in which a radionuclide is stably incorporated, wherein (i) the polymeric particulate material incorporating the radionuclide delivers a radiation dose of between about 10 and 800 Gy; and (ii) less than 5% (optionally less than 4%, 3%, 2%, 1 % or 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1 %) of the radionuclide leaches from the particulate material, under physiological conditions, over the radioactive life of the particulate material.
  • One method of assessing leaching is by adjusting a sample to pH 7.0 and agitating in a water bath at 37°C for 20 minutes. A 100 ⁇ sample is counted for beta emission in a Geiger-Muller counter. Another representative 100 ⁇ _ sample is filtered through a 0.22 ⁇ filter and the filtrate counted for beta emission in the Geiger-Muller counter. The per cent unbound radionuclide is calculated by:
  • the radionuclide can be stably incorporated into the polymeric matrix by precipitating it as an insoluble salt.
  • the radionuclide used is yttrium-90 the yttrium is preferably precipitated as a phosphate salt.
  • the present invention also extends to precipitation of the radionuclide as other insoluble salts including, for example, carbonate and bicarbonate salts.
  • the particulate polymeric material used in the invention are polymer based and separated by filtration or other means known in the art to obtain a cohort of microparticles of the defined specific size range that is preferred for a particular use in the herein described methods.
  • the invention provides a particulate polymeric material as described above in which the polymeric matrix is an ion exchange resin, particularly a cation exchange resin.
  • the ion exchange resin comprises a partially cross linked aromatic polymer, including polystyrene.
  • One particularly preferred cation exchange resin is the sulfonated styrene/divinylbenzene copolymer resin commercially available under the trade name Aminex 50W-X4 (Biorad, Hercules, CA). However, there are many other commercially available cation exchange resins which are suitable.
  • the polymer of the present invention can be any polymer having a surface that is biocompatible with blood (i.e. does not promote blood coagulation by the so-called intrinsic pathway, or thrombosis by promotion of platelet adhesion).
  • the polymer of the present invention is a cationic exchange resin comprising anionic substituent groups, such as sulfate, sulfonate, carboxylate and phosphate groups.
  • the polymer may be any blood biocompatible polymer known in the art, including but not limited to polystyrene, polystyrene sulfonate, polypropylene, polytetrafluorethylene (PTFE), expanded polytetraflouroethylene (EPTFE), polyurethane, polyvinyl chloride, polyamides, teflon, polyester, polyethylene terephthalate, poly(butylene terephthalate) (PBT), poly(ethylene oxide) (PEO), polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), poly(e- caprolactone), polydioxanone, trimethylene carbonate, polyanhydride, and poly[bis(p- carboxy
  • polytetrafluorethylene PTFE
  • expanded polytetraflouroethylene EPTFE
  • polyurethane polyvinyl chloride
  • polyamides polystyrene and teflon
  • the polymer microparticles used in the present invention includes those used in the manufacture of SIR-spheres® (SIR-spheres ® is a registered trademark of Sirtex SIR-Spheres Pty Ltd) microparticles, which are resin based microparticles comprised of polystyrene sulfonate. Density
  • the particulate polymeric material is preferably low density, more particularly a density below 3.0 g/cm 3 , even more preferably below 2.8 g/cm 3 , 2.5 g/cm 3 , 2.3 g/cm 3 , 2.2 g/cm 3 or 2.0 g/cm 3 .
  • the particulate material manufactured so that the suspending solution has a pH less than 9. If the pH is greater than 9 then this may result in irritation of the blood vessels when the suspension is injected into the artery or target organ.
  • the pH is less than 8.5 or 8.0 and more preferably less than 7.5.
  • the present invention particularly provides a method for the production of a radioactive particulate material comprising a polymeric matrix as described above, characterised by the steps of:
  • Alternate sources of yttrium-90 may be used in the production of these microparticles.
  • a highly pure source of yttrium-90 may be obtained by extracting yttrium-90 from a parent nuclide and using this extracted yttrium-90 as the source of the soluble yttrium salt that is then incorporated into the polymeric matrix of the microparticles.
  • the microparticles may be washed to remove any un-precipitated or loosely adherent radionuclide.
  • the present invention provides a suspension of the required pH by precipitating the yttrium with a tri-sodium phosphate solution at a concentration containing at least a three-fold excess of phosphate ion, but not exceeding a 30-fold excess of phosphate ion, and then washing the microparticles with de-ionised water.
  • Another approach which ensures that the pH of the microparticle suspension is in the desired range is to wash the resin with a phosphate buffer solution of the desired pH.
  • the present invention also provides a method of radiation therapy of a human or other mammalian patient that comprises administration to the patient of particulate material as described above.
  • the present invention provides a method of treating liver or lung neoplasia in a subject in need of treatment, by subjecting the patient to SIRT.
  • the amount of microparticles used in the method and which will be required to provide effective treatment of a neoplastic growth will depend on the radionuclide used in the preparation of the microparticles.
  • an amount of yttrium-90 activity that will result in an inferred radiation dose to the normal liver of approximately 10 to 200 Gy may be delivered. Because the radiation from SIRT is delivered as a series of discrete point sources, the dose of 10 Gy to 200 Gy is an average dose with many normal liver parenchymal cells receiving much less than this dose. Alternate doses of radiation may be delivered depending on the disease state and the physician's treatment needs. Such variation of radiation doses obtained by altering the amount of microparticles used will be something that a skilled artisan will know how to determine.
  • the radiation dose delivered by the polymeric particulate material is between 10 and 200Gy. More preferably it is between 10 and 150 Gy, 10 and 100 Gy, 20 and 80 Gy, 25 and 75 Gy, . -
  • the radiation is delivered preferentially to the cancer within the target organ.
  • the radiation is slowly and continually delivered as the radionuclide decays.
  • the arterial blood supply with vasoactive substances, it is possible to enhance the percentage of radioactive particles that go to the cancerous part of the organ, as opposed to the healthy normal tissues. This has the effect of preferentially increasing the radiation dose to the cancer while maintaining the radiation dose to the normal tissues at a lower level.
  • SIRT which may also be known as radio-embolization or microparticle brachytherapy involves two procedural components:
  • Embolization injection into the arterial tumour feeding vessels of permanently embolic microparticles which act as the delivery vehicle for the therapeutic moiety, and
  • Irradiation embolization of microparticles in the distal microvasculature of the tumour delivers high dose irradiation to the tumour microvascular plexus and to tumour cells themselves.
  • direct irradiation of tissue and microvascular bed destruction, rather than pure embolization is responsible for the tissue destructive effects of SIRT therapy.
  • radioactive microparticles do not exhibit pharmacodynamics in the classic sense, but induce cell damage by emitting radiation. Once implanted, radioactive microparticles remain within the vasculature of tumours. They are not phagocytised nor do they dissolve or degrade after implantation. High radiation emitted from the radioactive microparticles is preferably cytocidal to cells within the range of the radiation. After the radioactive microparticle has decayed, the non-radioactive microparticles remain intact and are not removed from the body. [00102] Intrinsic to the concept of SIRT is the preferential placement of the radioactive microparticles selectively into the distal microvascular supply of tumours. . -
  • radionuclide doped microparticles may be by any suitable means, but preferably by delivery via the relevant artery.
  • administration is preferably by insertion of a catheter into the hepatic artery.
  • Pre or co-administration of another agent may prepare the tumour for receipt of the particulate material, for example a vasoactive substance, such as angiotension-2 to redirect arterial blood flow into the tumour. Delivery of the particulate matter may be by single or multiple doses, until the desired level of radiation is reached.
  • a vasoactive substance such as angiotension-2
  • SIRT therapy can also be effective in causing regression and prolonged survival for patients with primary hepatocellular cancer (Lau W, et al (1994) Brit J Cancer 70, 994-999; Lau W, et al. (1998) Int J Rad Oncol Biol Phvs. 40, 583-592).
  • microparticles of the invention are allowed to have an additive effect with other cytotoxic agents and are typically administered for the treatment of neoplasm.
  • microparticles of the invention are delivered to a patient concomitantly with either systemic or loco-regional chemotherapeutic agents . - such as oxiplatin, 5-Fluorouracil or Leucovorin.
  • systemic or loco-regional chemotherapeutic agents . - such as oxiplatin, 5-Fluorouracil or Leucovorin.
  • This interaction may be exploited to the benefit of the patient, in that there can be an additive toxicity on tumour cells, which can enhance the tumour cell kill rate. This interaction can also lead to additive toxicity on non-tumourous cells.
  • the invention may also include an effective treatment with immunomodulators and other agents as part of therapy.
  • immunomodulators suitable for use with the invention are alpha interferon, beta interferon, gamma interferon, interleukin-2, interleukin-3, tumour necrosis factor, granulocyte-macrophage colony stimulating factors and the like.
  • the present invention further provides a synergistic combination of antineoplastic agents and an amount of radionuclide-doped microparticles suitable for use in SIRT for treatment of a neoplastic growth.
  • an amount of 5-FU and LV that is "effective to treat the neoplasia" is an amount that is effective to ameliorate or minimize the clinical impairment or symptoms of the neoplasia, in either a single or multiple dose of 5-FU and LV when combined with SIRT.
  • the clinical impairment or symptoms of the neoplasia may be ameliorated or minimized by diminishing any pain or discomfort suffered by the subject; by extending the survival of the subject beyond that which would otherwise be expected in the absence of such treatment; by inhibiting or preventing the development or spread of the neoplasm; or by limiting, suspending, terminating, or otherwise controlling the maturation and proliferation of cells in the neoplasm.
  • the amounts of 5-FU and LV effective to treat neoplasia in a subject in need of treatment will vary depending on the type of SIRT used, as well as the particular factors of each case, including the type of neoplasm, the stage of neoplasia, . - the subject's weight, the severity of the subject's condition, and the method of administration. These amounts can be readily determined by the skilled artisan.
  • doses of 5-FU administered intraperitoneal ⁇ may be between 100 and 600mg/m 2 /day, or between 200 mg/m 2 /day and 500 mg/m 2 /day. More preferably doses of 5-fluorouracil administered intraperitoneal ⁇ will be between 300 and 480 mg/m 2 /day, or between 400 mg/m 2 /day and 450 mg/m 2 /day. An example being 425 mg/m 2 /day. Doses of LV administered intraperitoneal ⁇ will usually be about one twentieth of the dose of 5-FU. So, for example if the dose of 5-FU is 425 mg/m 2 /day then the dose of LV will be about 20 mg/m 2 /day. A skilled artisan will recognise appropriate levels of LV.
  • 5-FU and LV treatment according to the present invention may be administered to a subject by known procedures, including, but not limited to, oral administration, parenteral administration (e.g., intramuscular, intraperitoneal, intravascular, intravenous, or subcutaneous administration), and transdermal administration.
  • parenteral administration e.g., intramuscular, intraperitoneal, intravascular, intravenous, or subcutaneous administration
  • transdermal administration e.g., transdermal administration.
  • the 5-FU and LV agents are administered parenterally.
  • the formulations of 5-FU and LV may be combined with a sterile aqueous solution that is preferably isotonic with the blood of the subject.
  • a sterile aqueous solution that is preferably isotonic with the blood of the subject.
  • Such formulations may be prepared by dissolving a solid active ingredient in water containing physiologically-compatible substances, such as sodium chloride, glycine, and the like, and having a buffered pH compatible with physiological conditions, so as to produce an aqueous solution, then rendering said solution sterile.
  • the formulations may be presented in unit or multi-dose containers, such as sealed ampoules or vials. Moreover, the formulations may be delivered by any mode of injection, including, without limitation, epifascial, intracapsular, intracutaneous, intramuscular, intraorbital, intraperitoneal (particularly in the case of localized regional therapies), intraspinal, intrasternal, intravascular, intravenous, parenchymatous, or subcutaneous.
  • the method includes a step of treating the patient with one or more biological anticancer agents. Desirably that step is included at either cycle 1 or cycle 4 of the treatment regime.
  • the biological anticancer - - agent is an antibody or antibody fragment or antibody like molecule that is targeted against cells or the blood vessels supplying the cancer cells.
  • the agent may be an antibody or fragment thereof that targets EGF and VEGF, may also be used.
  • the anticancer agent is bevacizumab.
  • the present invention provides a method of treating neoplasia in a subject in need of treatment, by administering to the subject an amount of a combination of 5-fluorouracil and leucovorin effective to treat a neoplasia, in combination with SIRT using the microparticles of the invention, wherein a synergistic antineoplastic effect results.
  • the invention further relates to a kit for killing neoplastic cells in a subject having neoplastic cells.
  • the kit comprises an effective antineoplastic amount of 5-FU and LV and an amount of radionuclide-doped microparticles suitable for use in SIRT for treatment of a neoplastic growth.
  • the kit may further comprise an instructional material.
  • the kit is prepared for use in treating a patient with colorectal liver metastases.
  • the invention still further relates to use of an effective antineoplastic amount of 5-FU and LV and an amount of radionuclide-doped microparticles suitable for use in SIRT using the microparticles of the invention, for manufacture of a medicament for killing neoplastic cells in a subject having neoplastic cells.
  • the medicament is prepared for use in treating a patient with colorectal liver metastases.
  • the invention yet further relates to the use of an effective antineoplastic amount of 5-FU and LV and an amount of radionuclide-doped microparticles suitable for use in SIRT using the microparticles of the invention, for manufacture of a kit for killing neoplastic cells in a subject having neoplastic cells.
  • the 5-FU and LV and radionuclide-doped microparticles are manufactured for use in a kit for treating a patient with colorectal liver metastases.
  • 5-FU and LV is administered to a subject in combination SIRT using the microparticles of the invention, such that a synergistic antineoplastic effect is produced.
  • a "synergistic antineoplastic effect” refers to a greater-than-additive antineoplastic effect that is produced by a combination of chemotherapeutic drugs and SIRT, which exceeds that which would otherwise result - - from individual therapy associated with either therapy alone.
  • Treatment with 5-FU and LV in combination with SIRT unexpectedly results in a synergistic antineoplastic effect by providing greater efficacy than would result from use of either of the antineoplastic agents alone.
  • administration of 5-FU and LV "in combination with" SIRT using the microparticles of the invention refers to coadministration of the two antineoplastic treatments. Co-administration may occur concurrently, sequentially, or alternately. Concurrent co-administration refers to administration of both 5-FU and LV and SIRT at essentially the same time. For concurrent co-administration, the courses of treatment with 5-FU and LV and with SIRT may also be run simultaneously. For example, a single, combined formulation of 5-FU and LV, in physical association with SIRT, may be administered to the subject.
  • 5-FU and LV therapy and SIRT also may be administered in separate, individual treatments that are spaced out over a period of time, so as to obtain the maximum efficacy of the combination.
  • administration of 5-FU and LV is preferably given to a patient for a period of time such as 1 to 10 days, but more preferably about 3 to 5 days following which SIRT is applied. This cycle may be repeated as manner times as necessary and as long as the subject is capable of receiving said treatment.
  • a method of treating neoplasia in a subject in need of treatment by administering to the subject an amount of a combination of 5-FU, LV and OXA effective to treat a neoplasia, in combination with SIRT using the microparticles of the invention, wherein a synergistic antineoplastic effect results.
  • the amount of 5-FU, LV and OXA that is effective to treat the cancer is an amount that at least ameliorates cancer.
  • a method for treatment of a neoplasia patient in need of such treatment which comprises the steps of: (i) delivering to said patient on day one of a treatment regime:
  • step (ii) delivering SIRT using the microparticles of the invention to said patient on day 3 or 4 following the commencement of step (i);
  • step (iii) repeating step (i) for three cycles at an interval of one to three weeks between treatment cycles;
  • step (iv) following about two weeks from the final treatment delivered in step (iii) delivering to said patient the following treatment:
  • step (v) repeating step (iv) every 2 to 3 weeks, until the cancer is treated.
  • step (v) in the method of the invention is repeated until either liver hepatotoxicity becomes a problem or peripheral neuropathy becomes an issue for the patient. Hepatotoxicity of tissues peripheral to neoplasia tissue may become apparent as a result of excessive chemotherapy in a subject.
  • liver toxicity is a rather complex process particularly when using chemotherapeutic agents.
  • the current methods usually comprise clinical investigations (e.g. ultrasonography), pathological and histo-pathological investigations as well as a biochemical analysis.
  • a state-of the-art evaluation of the drug-induced liver toxicity is described in the CDER/CBER Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 as well as in the EMEA (CHMP) Reflection paper on non-clinical evaluation of drug-induced liver injury (DILI), 24 Jun. 201 0 (Doc Ref EMEA/CHMP/SWP ⁇ 501 15/2006).
  • the doses of OXA administered to a patient in the initial three cycles of the invention will be less than the dose of OXA administered in the fourth and subsequent cycles of drug administration.
  • the primary safety concern is that the OXA in the chemotherapy regimen is a radio-sensitising agent, which when . - used in combination with SIRT using the microparticles of the invention results in toxicity at doses greater than initially delivered.
  • OXA doses in the fourth and subsequent cycles should be more than the first three cycles but minimized as much as possible to maximise the time that patients can receive protocol chemotherapy before peripheral neuropathy becomes an issue (which necessitates the removal of OXA).
  • the method contemplates either a single or multiple doses of 5-FU, LV and OXA delivered according to the treatment regime to impair the symptoms of the cancer being treated.
  • impairment of symptoms of the cancer may be ameliorated by diminishing pain or discomfort suffered by the patient; by extending the survival of the patient beyond that which would otherwise be expected in the absence of such treatment; by inhibiting or preventing the development or spread of the cancer; or by limiting, suspending, terminating, or otherwise controlling the maturation and proliferation of cells in the cancer.
  • the amounts of 5-FU, LV and OXA effective to treat neoplasia in a patient in need of treatment will vary depending on the type of SIRT used, as well as the particular factors of each case, including the type of cancer, the stage of the cancer, the patient's weight, the severity of the patient's condition, and the method of administration. These amounts can be readily determined by the skilled artisan.
  • OXA is delivered to the patient in the initial three treatment cycles at a dose of about 60 to 80 mg/m 2 .
  • a dose of OXA at 54, 55, 56, 57, 58 or 59 mg/m 2 can appropriately be used in the treatment regime and such doses should be considered within the scope of the present invention.
  • doses of OXA at 81 , 82, 83, 84, 85, 86, 87, or 88 mg/m 2 can also appropriately be used in the first treatment cycle.
  • the dose will reside within the range of 60 to 80 mg/m 2 .
  • the dose of OXA will be closer towards the lower end of the stipulated range.
  • Such doses of OXA include 60, 61 , 62, 62, 64, 64, 66, 67, 68, 69, 70 mg/m 2 . . .
  • the dose of OXA is increased to at least about 80 to 100 mg/m 2 .
  • Reference to the use of the term "about” in this statement seeks to import a level of variability into the treatment regime that is consistent with the manner in which a doctor might vary the OXA regime depending on the needs of a patient.
  • a dose of OXA at 77, 78 or 79, 80, 81 , 82, 83 or 84 mg/m 2 can appropriately be used in the treatment regime and such doses should be considered within the scope of the present invention.
  • doses of OXA at 101 , 102, 103, 104, 105, 106, 107, or 108, 109 or 1 10 mg/m 2 can also appropriately be used in the first treatment cycle.
  • the dose will reside within the range of 80 to 100 mg/m 2 .
  • the dose of OXA will be closer towards the lower end of the stipulated range.
  • Such doses of OXA include 80, 81 , 82, 82, 84, 84, 85, 86, 87, 88, 89, 90 mg/m 2 .
  • the dose of OXA administered in the initial three cycles of the invention is about 60 mg/m 2 while the dose administered in the fourth cycle is 85 mg/m 2 .
  • OXA is delivered at a dose of 60 mg/m 2 for the first three cycles of chemotherapy, and in subsequent cycles is increased to a dose of 85 mg/m 2 .
  • the primary safety concern is that the OXA in the chemotherapy regimen is a radio-sensitising agent, which when used in combination with the present invention results in toxicity at doses >60 mg/m 2 .
  • OXA doses in the fourth and subsequent cycles should be 85 mg/m 2 rather than the dose of 100 mg/m 2 , this will maximise the time that patients can receive protocol chemotherapy before peripheral neuropathy becomes an issue (which necessitates the removal of OXA).
  • the dose of LV delivered to the patient in the initial three treatment cycles and in the fourth cycle is at a dose of about 100 to 400 mg/m 2 .
  • Reference to the use of the term "about” in this statement seeks to import a level of variability into the treatment regime that is consistent with the manner in which a doctor might vary the LV regime depending on the needs of a patient.
  • a dose of LV at 90, 91 , 92, 93, 94, 95, 96, 97, 98 or 99 mg/m 2 can appropriately be used in the treatment regime and such doses should be considered within the scope of the present invention.
  • doses of LV at 401 , 402, 403, 404, 405, 406, 407, up to 428 mg/m 2 inclusive can also appropriately be used in the first treatment cycle.
  • the dose will reside within the range of 100 and 400 mg/m 2 .
  • the dose of LV will be closer towards the lower end of the stipulated range, eg 100 to 200 mg/m 2 .
  • doses of LV include 100, 1 10, 120, 130, 140, 150, 160, 170, 180 and 190 mg/m 2 as well as every dose in between these specified doses.
  • the bolus of 5-FU delivered to the patient in the initial three treatment cycles and in the fourth cycle is at a dose of about 300 to 500 mg/m 2 .
  • Reference to the use of the term "about” in this statement seeks to import a level of variability into the treatment regime that is consistent with the manner in which a doctor might vary the LV regime depending on the needs of a patient.
  • a dose of 5-FU in the bolus can be at 250, 260, 270, 280, 290 mg/m 2 can appropriately be used in the treatment regime and such doses should be considered within the scope of the present invention.
  • doses of 5-FU in the order of 510, 520, 530, 540 and 550 mg/m 2 inclusive can also appropriately be used in the first treatment cycle.
  • the dose will reside within the range of 300 and 500 mg/m 2 .
  • the dose of 5-FU in the bolus will be about 400 mg/m 2 .
  • the continuous infusion of 5-FU that is delivered to the patient in the initial three treatment cycles and in the fourth cycle is at a dose of about 2.0 to 2.6 g/m 2 .
  • Reference to the use of the term "about” in this statement seeks to import a level of variability into the treatment regime that is consistent with the manner in which a doctor might vary the LV regime depending on the needs of a patient.
  • a dose of 5-FU in the continuous infusion can be at 1 .5, 1 .6, 1 .7, 1 .8, 1 .9 or 2.0 g/m 2 can appropriately be used in the treatment regime and such doses should be considered within the scope of the present invention.
  • doses of 5-FU in the continuous infusion in the order of 2.6, 2.7, 2.8 or 2.9 g/m 2 inclusive can also appropriately be used in the first treatment cycle.
  • the dose will reside within the range of 2.0 to 2.6 g/m 2 .
  • the dose of 5-FU in the bolus will be about 2.4 g/m 2 .
  • the time period over which the continuous infusion of 5-FU is delivered to the patient may vary from about 40 to 50 hours.
  • a physician period will preferably determine the delivery time.
  • the delivery time is selected from the group consisting of 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49 or 50 hours. Most preferably the infusion is for 46 hours. . .
  • the dose of chemotherapeutic agent delivered to the patient according to the above treatment regime may vary within the various dose ranges specified.
  • the dose of chemotherapeutic agent delivered to a patient may vary between treatment cycles.
  • variation of the dose of drug delivered accommodates for hepatotoxicity.
  • the dose of drug delivered in a treatment cycle should seek to keep to a minimum the hepatotoxicity in that treatment cycle.
  • a method of treatment of a neoplasia patient in need of such treatment which comprises the steps of:
  • step (iii) repeating step (i) three times at an interval of one to three weeks between treatment cycles; then
  • step (iv) following about two weeks from the final treatment delivered in step (iii) delivering to said patient the following treatment:
  • step (v) repeating step (iv) every 2 to 3 weeks, until the neoplasia is treated.
  • Chemotherapeutic agents used in the treatment according to the present invention may be administered to a patient by known procedures, including, but not limited to, oral administration, parenteral administration (e.g., intramuscular, intraperitoneal, intravascular, intravenous, or subcutaneous administration), and transdermal administration.
  • parenteral administration e.g., intramuscular, intraperitoneal, intravascular, intravenous, or subcutaneous administration
  • transdermal administration e.g., the 5-FU, LV and OXA agents are administered parenterally. . .
  • the method may also include a step of treating the patient with one or more biological anticancer agents such as antibodies, fragments thereof or antibody like molecules targeted against a variety of cancer cells or the blood vessels supplying the cancer cells.
  • biological anticancer agents such as antibodies, fragments thereof or antibody like molecules targeted against a variety of cancer cells or the blood vessels supplying the cancer cells.
  • antibodies, fragments thereof or antibody like molecules target EGF or VEGF.
  • the anticancer agent is bevacizumab.
  • a method for treatment of a neoplasia patient in need of treatment which comprises the steps of:
  • step (iii) repeating step (i) for three cycles at an interval of one to three weeks between treatment cycles;
  • step (iv) two weeks after the final treatment delivered in step (iii) delivering to said patient the following treatment:
  • step (v) repeating step (iv) every 2 to 3 weeks, until the neoplasia is treated.
  • the biological anticancer agent(s) may be administered at any dose that is recommended for treating patients with cancer.
  • the biological anticancer agent is bevacizumab preferably a dose of about 5 to 10 mg/kg is delivered to said patient.
  • the time over which the agent is delivered to a patient will be varied depending on the patient and severity of treatment required.
  • the agent treatment time is 30 to 60 minutes.
  • Bevacizumab therapy may be delivered at any one or more of the various cycles of treatment. Desirably, bevacizumab therapy is delivered with the first cycle of therapy or in the last cycle. In a highly preferred form of the invention bevacizumab therapy is delivered in the last cycle of therapy immediately after OXA therapy.
  • the invention resides in a method for treatment of a neoplasia patient in need of treatment, which comprises the steps of:
  • step (ii) delivering SIRT to said patient on day 3 or 4 following the commencement of step (i);
  • step (iii) repeating step (i) for three cycles at an interval of one to three weeks between treatment cycles;
  • step (iv) two weeks after the final treatment delivered in step (iii) delivering to said patient the following treatment:
  • step (c) followed by a bolus of 5-FU at a dose of about 400 mg/m 2 and a 30 to 60 minute infusion of bevacizumab at about 5 to 10 mg/kg, followed by an infusion of 5-FU at a dose of about 2.4 g/m 2 for about 46 hours; and (v) repeating step (iv) every 2 to 3 weeks, until the neoplasia is treated.
  • the invention resides in the use of a polymeric particulate material as herein described, in internal radiation therapy of a patient.
  • the invention resides in the use of a polymeric particulate material as herein described, in the manufacture of medicament for the treatment of neoplasia in a patient.
  • the neoplasia is a metastatic . . carcinoma which, for example, may arise in the liver from primary carcinomas of, for example, the colonic mucosa.
  • FL nanoparticles are highly stable, and integrity of the isotope encapsulation is preserved under standard autoclave conditions of 20 min at 120 Q C.
  • the inventors have previously shown using a membrane filtration model and micro-well binding assays that polycations such as polylysine bind to the surface of FL with high affinity [Lobov et al., (2013). Biomate als: 34: 1732-1738]. Binding of these polycations to FL is also stable under in vivo conditions.
  • the inventors have previously proposed [see Freeman CG, et al. (2013). Biomatehals; 34:5670-5676] that binding is mediated by multi-site pi-cation interactions between the positively charged amino groups of the amino acid side-chains and the pi-electrons of the planar carbon rings of the graphite surface.
  • the protamine family of proteins are also polycations due to a high content of arginine and lysine residues.
  • PS protamine sulfate
  • FL 5 MBq was added to serial dilutions of PS (20 to 0 ⁇ g/mL) in 0.5 mM Tris acetate buffer (pH 7.2) and allowed to stand for 1 h at 20 Q C.
  • Freshly prepared FL (260 MBq in 6 mL) was first treated with PS (20 ⁇ g/mL) for 30 min before addition to the final centrifuged pellet of washed MS.
  • the PS treated FL was then allowed to bind to the MS with gentle mixing for 30 min at 20 Q C, . . during which the colour of MS changed from pale yellow to dark grey and the supernatant cleared.
  • FL-MS30 prepared by the method above was prepared for SEM using sputter coating with gold and imaged using a Jeol model 840 SEM instrument at the Westmead Centre for Oral Health, Sydney. Unlabelled and labelled microparticles were scanned for direct comparison of their surface features.
  • Imaging of the anaesthetised rabbits and their excised organs after 3 h was performed with a GE Hawkeye Infinia SPECT-CT camera.
  • suspensions of FL-MS30, FL12 and FL-MS8 (1 10-170 MBq on 15 mg MS in 5 imL 5% dextrose) were injected intravenously into an ear vein, so that the MS were mechanically arrested at limiting diameters in the arterial network of the lungs.
  • FL is coated with PS the coated nanoparticles are not retained in the lungs by binding to the heparan sulphate in the vascular glycocalyx [Freemann et al., (2013) Biomaterials: 34: 5670-5676].
  • the lungs and liver were then excised after tying off blood vessels to prevent leakage of isotope, and the excised organs and blood sample were imaged separately using a 5 min acquisition on a 1024 x 1024 matrix, and utilising the camera's zoom function (4x).
  • Counts registered in the acquisitions were corrected for the background activity of the corresponding field, and the corrected counts were used for calculation of the percentage activity in the lungs, liver, blood and carcass.
  • the total blood volume and radioactivity were calculated assuming 60 imL of blood per kg of rabbit body weight. Activity levels in the images shown in the Figures were assigned false colours using the Xeleris XT21 Brainl colour map.
  • Table 1 shows the biodistribution of radioactivity in rabbits 3 h after intravenous (ear vein) injection of suspensions of FL radiolabeled microparticles and the particulate imaging agent, Tc99m-MAA.
  • the polymer microparticles (15 mg) had median diameters of 30 ⁇ (FL-MS30), 12 ⁇ (FL-MS12) and 8 ⁇ (FL-MS8) and each 5 imL injection contained 130-170 MBq Tc99m.
  • the clinical diagnostic imaging agent Tc99m-MAA (2.5 mg; 1 10-170 MBq) was also injected intravenously for comparison.
  • a blood sample (5 imL) was taken prior to dissection for calculation of the total blood radioactivity, assuming a blood volume of 60 imL per kg body weight.
  • the carcass values shown are corrected for the total blood activity. Images for measurement of radioactivity in the excised liver, lungs, blood sample and carcasses were acquired using a GE Hawkeye Infinia gamma camera. The results shown are the means and SEM of triplicate experiments for each type of MS/particle. All radioactivity measurements were corrected for background in the corresponding acquisition field. Note transit of some FL-MS8 to the liver and label from Tc99m-MAA in the blood and carcass. - -
  • the mean lung proportion at dissection for 3 animals was 92.9 +/- 1 .5% of the total body activity and only 4.3% was in the excised liver and 0.84% in the total blood volume.
  • the mean lung proportion was 87.6 +/- 2.5%, while 9.8% was in the liver and 0.66% in the total blood volume.
  • the same test with FL-MS8 showed that 72.8 +/- 1 .9% of activity had been retained in the lungs after 3 h, while 23.1 % had been taken up the liver, and 1 .1 % was in the total blood volume (Table 1 ).
  • Imaging of intact rabbits 1 h after arterial instillation of FL-MS30 in the liver showed virtually complete retention of radiolabel in the organ. Imaging of two dissected animals showed a mean retention of 99.9% of the total radioactivity in the excised liver, while barely detectable levels in the excised lungs and a blood sample verified that escape of radiolabel to other organs was negligible (Table 2).
  • Imaging of the excised livers also revealed a pronounced, coarsely segmented distribution of the radiolabel within the organ (Fig 3A), which was markedly different from the previously reported uniform liver uptake of radiolabelled FL nanoparticles by the reticuloendothelial system following intravenous or intra-arterial administration. Distribution of label did not extend throughout all areas of the organ and was highly variable between different livers. The appearance was of restricted distribution in which dispersal of FL-MS30 by the blood flow had been arrested at limiting diameters of the arterial network extending from the main feeder vessels, so that MS distribution was incomplete and clearly could not transit to the venous side.
  • a blood sample (5 imL) was taken prior to dissection for calculation of the total blood radioactivity, assuming a blood volume of 60 imL per kg body weight.
  • the carcass values shown are corrected for the total blood activity. Images for measurement of radioactivity in the excised liver, lungs, blood sample and carcass were acquired using a GE Hawkeye Infinia gamma camera. The results shown are the means of duplicate experiments for each type of MS/particle (16 experiments altogether). All radioactivity measurements were corrected for background in the corresponding acquisition field. Note high rates of retention in the liver 1 h post-instillation, for normal and tumour livers.
  • tumours typically appeared as a single oblate ellipsoid of up to 2 cm diameter, thickening but still contained within the liver lobe and not involving the body wall or other organs. On sectioning, they usually had a white necrotic centre, surrounded by a prominently vascularised peripheral zone.
  • Hepatic artery instillation of FL-MS30 in 2 rabbits hosting such liver VX2 tumours resulted in 99.2% retention of radiolabel in the liver after 1 h (Table 2); it was not noticeably less than the retention by a normal liver. Accordingly, leakage to the systemic circulation in these tumour rabbits was still very low, as shown in Table 2.
  • the imaging of excised livers showed coarsely segmented features within the organ as in normal livers but the lobe hosting the tumour had accumulated noticeably more radiolabel than the rest of the liver (Fig 4A).
  • the accumulation of label in the lobes hosting VX2 tumours in 6 different VX2 host rabbits represented an average 33.1 % (range 23.6 to 50.8%) of the total liver uptake, but the respective host lobes represented on average just 15.8% (range 1 1 .9 to 24.4%) of the liver weight.
  • the tumour lobe received - - approximately double the radioactivity of FL-MS30 per gram of tissue compared to the rest of the liver.
  • Accumulation of label at the tumour site featured prominently, and assumed the form of a bright, complete annulus at the angiogenic growth margin of the tumour, surrounding a lower intensity (necrotic) centre (Fig 4C).
  • Fig 5 clearer definition of the tumour site in the whole animal
  • Fig 4C was considerably facilitated by use of the smaller MS, and without degradation of the liver retention.
  • Hepatic artery instillation of FL-MS30 into the rabbit liver showed very efficient retention of this preparation at limiting diameters of the liver arterial network, producing a coarse segmented distribution in imaging, consistent with the distributing arterioles within the organ.
  • Arterial instillation of the smaller microparticles produced a noticeably different distribution of label, with finer features extending out to fill more of each liver lobe.
  • the diameter of the microparticles was clearly an important property determining distribution in the arterial network of the organ. While the larger microparticles reached a relatively proximal limiting diameter in the arterial supply, the smaller microparticles were carried further on to more distal limits, producing a finer featured distribution image.
  • retention of even the smallest microparticles in the liver was surprisingly efficient; transit of label from the liver to other organs was very low.
  • Tc99m-MAA while nominally of similar particle size to FL-MS30, and well retained in the liver after arterial instillation, nevertheless produced an image showing more extensive dispersal of label within the liver than that obtained with FL-MS30. This could suggest that the particle integrity of Tc99m-MAA was not maintained under blood flow conditions in the liver and that it was disaggregated by shear forces to produce smaller particles.
  • the isotope-microsphere complex was made according to the following methods. Protamine-FibrinLite-Microsphere Tc label
  • T VX2 tumour in liver
  • D5W 5% dextrose in water
  • Mean excluding 150127 091 T ** Carcass includes bl activity
  • microspheres were prepared by the method of PCT/AU2013/001510
  • liver VX2 rabbit models were investigated using Ga67-TA-MS8 (i.e. 8 micron microspheres).
  • rabbits 167, 169, 166 and 168 were observed to show poor tumour growth, with a size range of 148-1000 mm 3 .

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Abstract

La présente invention concerne un matériau particulaire, un agent thérapeutique, un dispositif thérapeutique et une méthode d'amélioration du traitement du cancer, en particulier du cancer du foie chez un patient en ayant besoin.
PCT/AU2017/051404 2016-12-16 2017-12-15 Amélioration d'une radiothérapie interne sélective WO2018107246A1 (fr)

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Citations (5)

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Publication number Priority date Publication date Assignee Title
WO2002034300A1 (fr) * 2000-10-25 2002-05-02 Sirtex Medical Limited Radionuclide a base de polymere contenant une matiere particulaire
US20040220135A1 (en) * 2003-04-30 2004-11-04 Sirtex Medical Limited Combination therapy for treatment of neoplasia
WO2005061009A2 (fr) * 2003-06-20 2005-07-07 University Of Maryland, Baltimore Microparticules pour imagerie et radiotherapie de micro-arteres
WO2014040143A1 (fr) * 2012-09-17 2014-03-20 Gray Bruce N Procédé de traitement du cancer
WO2015109367A1 (fr) * 2014-01-24 2015-07-30 Sirtex Medical Limited Traitement d'une néoplasie

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
WO2002034300A1 (fr) * 2000-10-25 2002-05-02 Sirtex Medical Limited Radionuclide a base de polymere contenant une matiere particulaire
US20040220135A1 (en) * 2003-04-30 2004-11-04 Sirtex Medical Limited Combination therapy for treatment of neoplasia
WO2005061009A2 (fr) * 2003-06-20 2005-07-07 University Of Maryland, Baltimore Microparticules pour imagerie et radiotherapie de micro-arteres
WO2014040143A1 (fr) * 2012-09-17 2014-03-20 Gray Bruce N Procédé de traitement du cancer
WO2015109367A1 (fr) * 2014-01-24 2015-07-30 Sirtex Medical Limited Traitement d'une néoplasie

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BILBAO, J.I. ET AL.: "Liver Radioembolization with 90Y Microspheres", MEDICAL RADIOLOGY, DIAGNOSTIC IMAGING, 2014, ISBN: 978-3-642-36472-3 *
HASHIKIN, N.A.A. ET AL.: "Neutron Activated Samarium- 153 Microparticles for Transarterial Radioembolization of Liver Tumour with Post-Procedure Imaging Capabilities", PLOS ONE, vol. 10, no. 9, 2015, pages 1/17 - 17/17, XP055493400 *
VAN HAZEL, G.A. ET AL.: "SIRFLOX: Randomized Phase III Trial Comparing First-Line mFOLFOX6 (Plus or Minus Bevacizumab) Versus mFOLFOX6 (Plus or Minus Bevacizumab) Plus Selective Internal Radiation Therapy in Patients With Metastatic Colorectal Cancer", JOURNAL OF CLINICAL ONCOLOGY, vol. 34, no. 15, 2016, pages 1723 - 1731, XP055393598 *
WESTCOTT, M.A. ET AL.: "Critical Review: '' The development, commercialization, and clinical context of yttrium-90 radiolabeled resin and glass microspheres", ADVANCES IN RADIATION ONCOLOGY, vol. 1, 2016, pages 351 - 364, XP055493405 *

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