WO2006002488A1 - Thérapie associée pour le traitement de la néoplasie - Google Patents
Thérapie associée pour le traitement de la néoplasie Download PDFInfo
- Publication number
- WO2006002488A1 WO2006002488A1 PCT/AU2005/000988 AU2005000988W WO2006002488A1 WO 2006002488 A1 WO2006002488 A1 WO 2006002488A1 AU 2005000988 W AU2005000988 W AU 2005000988W WO 2006002488 A1 WO2006002488 A1 WO 2006002488A1
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- cancer
- patient
- dose
- irinotecan
- agents
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Classifications
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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
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention provides an improved method for treating cancer.
- the method arose from the identification of an unexpected synergistic combination of known cancer therapies. It also relates to a therapeutic combination, which produces an unexpectedly greater treatment efficacy than each cancer therapy when used in the absence of the other therapy.
- the invention also relates to the use of the therapeutic combination described herein in the preparation of a medicament for the treatment of cancer.
- Cancer is now the second leading cause of death in the United States and is a disease characterized by an abnormal proliferation of cell growth known as a neoplasm.
- Malignant cancers in particular, can result in a serious disease state, which may threaten life.
- Significant research efforts and resources have been directed toward the elucidation of anticancer measures, including chemotherapeutic and radiotherapeutic agents, which are effective in treating patients suffering from cancer.
- 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 neoplasia.
- neoplasia, malignant neoplasia, neoplastic growth and cancer are used interchangeably throughout this document.
- colorectal cancer is one of the most common.
- the liver is a dominant site of metastatic spread of colorectal cancer as a result of the portal venous drainage of the gut and is the main cause of death in these patients.
- Treatment of such disease states is usually achieved with one or a combination of four therapies: surgery, chemotherapy, radiotherapy and immunotherapy.
- Chemotherapy may involve the use of one or more anticancer drugs either with or without other cancer agents such as biologic modifying agents of which antibodies targeting the epidermal growth factor (EGF) or vascular endothelial growth factor (VEGF) are examples.
- chemotherapy means any combination of these agents.
- the major classes of anticancer drugs include alkylating agents, antimetabolites and antagonists, and a variety of miscellaneous agents (see Haskell, C. M., ed., (1995) and Dorr, R. T. and Von Hoff, D. D., eds. (1994)).
- the classic alkylating agents are highly reactive compounds that have the ability to substitute alkyl groups for the hydrogen atoms of certain organic compounds. The damage they cause interferes with DNA replication and RNA transcription.
- the classic alkylating agents include mechlorethamine, chlorambucil, melphalan, cyclophosphamide, ifosfamide, thiotepa and busulfan.
- methotrexate 5-fluorouracil (5-FU)
- floxuridine floxuridine
- cytarabine 6-mercaptopurine
- 6-thioguanine deoxycoformycin
- fludarabine 2-chlorodeoxyadenosine
- hydroxyurea hydroxyurea.
- the compound 5-FU is possibly the most widely used anticancer drug in the world.
- 5-FU has been used clinically in the treatment of malignant tumours and cancer, including, for example, carcinomas, sarcomas, skin cancer, cancer of the digestive organs and liver, and breast cancer.
- 5-FU causes serious adverse reactions such as nausea, alopecia, diarrhoea, stomatitis, leukocytic thrombocytopenia, anorexia, pigmentation, and edema.
- 5- FU is highly toxic, it is sometimes impossible to administer the compound over a prolonged period of time and therefore to achieve the desired curing effect.
- LV Leucovorin
- lrinotecan is a semi-synthetic derivative of camptothecin (a cytotoxic alkaloid). Irinotecan inhibits the activity of the DNA replication enzyme topoisomerase I by binding to the topoisomerase I-DNA complex and preventing the DNA strands from religating (Kuhn, J. G., "Pharmacology of Irinotecan” Oncology (1998), 12 supp. 6, 39-42.). The outcome is breakage of double-strand DNA and eventual cell death.
- the primary use of irinotecan is in treatment of colorectal cancer, as well as cervical cancer, gastric cancer, lung cancer and pancreatic cancer.
- irinotecan in patients with prior radiation treatment appears to increase the risk of toxicity (LDN S et al., (1999), Journal Clinical Oncology, 17 (10):3136-42).
- use of irinotecan in patients with pre- existing hepatic dysfunction and pulmonary diseases may result in increased toxicity of the drug.
- chemotherapeutic agent may also be severely limited by the emergence of malignant cells resistant to that drug.
- resistance to one drug may confer resistance to other biochemically distinct drugs.
- amplification of the gene encoding thymidylate synthase is related to resistance to treatment with 5-fluoropyrimidines.
- Radiotherapy has been used as an alternative to chemotherapy and usually relies on treatment through external beam technologies or through locally administering radioactive materials to patients with cancer in a technique known as brachytherapy.
- brachytherapy are where the radioactive materials have been incorporated into small particles, seeds, wires and similar related configurations that can be directly implanted into the cancer.
- SIRT Selective Internal Radiation Therapy
- the main form of application of SIRT has been its use to treat cancers in the liver. Liver cancer is particularly suited to treatment with SIRT due to the dual blood supply of the liver, which allows targeting of the radioactive particles to cancers within the liver when the radioactive particles are administered into the hepatic artery.
- 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 (Burton, M.A. et al. (1988) Europ. J. Cancer Clin. Oncol. 24(8), 1373-1376).
- microparticles or other small particles When 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 distribution within the target organ.
- the radiation emitted should be of high energy and short range. This ensures that the energy emitted will be deposited into the tissues immediately around the particulate material and not into tissues that are not the target of the radiation treatment. In this treatment mode, it is desirable to have high energy but short penetration beta-radiation, which will confine the radiation effects to the immediate vicinity of the particulate material.
- radionuclides that can be incorporated into microparticles that can be used for SIRT. Of particular suitability for use in this form of treatment is the unstable isotope of yttrium (Y-90). Yttrium-90 decays with a half-life of 64 hours by emitting high energy pure beta radiation.
- Y-90 yttrium
- Yttrium-90 decays with a half-life of 64 hours by emitting high energy pure beta radiation.
- other radionuclides may also be used in place of Y-90 of which isotopes of holmium, samarium, iodine,
- SIRT The technique of SIRT has been previously reported (see, for example, Chamberlain M, et al (1983) Brit. J. Surg.. 70: 596-598; Burton MA, et al (1989) Europ. J. Cancer Clin. Oncol., 25, 1487-1491; Fox RA, et al (1991) Int. J. Rad. Oncol. Biol. Phvs. 21, 463-467; Ho S et al (1996) Europ J Nuclear Med. 23, 947- 952; Yorke E, et a/ (1999) Clinical Cancer Res. 5 (Suppl), 3024-3030; Gray BN, et al. (1990) Int. J. Rad. Oncol. Biol. Phvs, 18, 619-623).
- 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) lnt J Rad Oncol Biol Phvs. 40, 583-592). Although SIRT is effective in controlling the liver disease, it has no effect on extra-hepatic disease.
- Combination therapies now being tested use agents with dissimilar mechanisms of action, based on the rationale that targeting two independent pathways will result in enhanced cytotoxicity, whether additive or synergistic.
- the results of these experiments are entirely unpredictable as the use of two entirely different therapies usually means that each therapy works independently of the other and thus would not be expected to interact to improve the other.
- the present invention arose from the discovery of an unexpected synergistic effect from the combination of known anticancer therapies.
- the inventor has discovered that when irinotecan is administered to a patient at or about the same time that the patient is undergoing SIRT, the result obtained from the combination of these therapies is greatly improved compared to each therapy alone.
- SIRT is used to generally describe selective internal radiation therapy.
- therapy is carried out using radioactive particles or materials, including without limitation, radiolabeled microparticles, capsules or other particulate material, target directed antibodies labeled with a therapeutic radioactive material or any other radioactively labelled carrier molecules.
- the invention provides a method of treating cancer in a patient, said method comprising the steps of: (a) administering to the patient in need of cancer therapy a therapeutically effective amount of irinotecan; and (b) treating the patient with SIRT.
- the invention provides a method for inhibiting cell proliferation and or causing cell death in a tumour in a patient, said method comprising the steps of: (a) administering to the patient in need of cancer therapy a therapeutically effective amount of irinotecan; and (b) treating the patient with SIRT.
- the above methods also include the step of: administering to the patient a therapeutically effective amount of at least another therapeutic agent, which aids in the treatment of cancer in the patient and or provides a secondary therapeutic benefit to the patient.
- the additional therapeutic agent is 5'-FU and LV.
- the invention provides a therapeutic composition for treating cancer comprising: a therapeutically effective amount of irinotecan and a therapeutically effective amount of radionuclide-doped agents suitable for SIRT.
- the invention relates to the use of a therapeutically effective amount of irinotecan and an amount of radionuclide-doped particles suitable for use in SIRT, in the manufacture of a medicament for treating cancer in a cancer patient.
- the medicament is prepared for use in treating a patient with primary liver cancer, secondary liver cancer, secondary liver cancer deriving from the gastrointestinal tract, or more specifically secondary liver cancer deriving from colorectal cancer.
- the medicament also includes a therapeutically effective amount of another therapeutic agent which either aids in the treatment of cancer in the patient or provides a secondary therapeutic benefit to the patient.
- Said secondary therapeutic benefit may be to treat a condition caused by the cancer or may be to treat a side effect of the treatment which the patient is undergoing or to treat another condition which a patient may suffer while undergoing such treatment.
- agents will include one or more alternate chemotherapeutic agents, anti-angiogenesis agents or other anti-cancer agents.
- agents will include but will not be limited to 5- FU, LV 1 oxaliplatin, capecitabine and antibodies directed against EGF and VEGF.
- the invention in a fifth aspect relates to a kit for treating cancer in a patient.
- the kit comprises a therapeutically effective amount of irinotecan and an amount of radionuclide-doped microparticles suitable for use in SIRT for treatment of a cancer.
- the kit may further comprise an instructional material.
- the kit is prepared for use in treating a patient with primary liver cancer, secondary liver cancer, secondary liver cancer deriving from the gastrointestinal tract, or more specifically secondary liver cancer deriving from colorectal cancer.
- the invention described herein may include one or more range of values (eg size, concentration 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 which lead to the same or substantially the same outcome as the values immediately adjacent to that value which defines the boundary to the range.
- the term 'patient' includes, without limitation, a vertebrate, preferably a mammal, but more preferably a human. Mammals include, but are not limited to, humans, sport animals and pets, such as dogs and horses.
- the terms 'treat', 'treatment' or 'treating' describe prophylactic, therapeutic or curative treatments of cancerous pathologies to which the present invention is directed.
- these terms include: (i) preventing a disease, disorder or condition from occurring in a patient who may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; (ii) relieving the disease, disorder or condition or (iii) inhibiting the disease, disorder or condition, i.e., arresting its development.
- the phrase "therapeutically effective amount” refers to an amount of therapeutic agent either as an individual compound or in combination with other compounds that is sufficient to induce a therapeutic effect on an ailment which the compound is applied to treat. This phrase should not be understood to mean that the dose must completely eradicate the ailment. So, for example, a therapeutic effect would be induced by the clinical impairment of symptoms of cancer. Such impairment might arise by diminishing any 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.
- What constitutes a therapeutically effective amount will vary depending on, inter alia, the biopharmacological properties of the compound used in the methodology, the condition being treated, the frequency of administration, the mode of delivery, characteristics of the individual to be treated, the severity of the disease and the response of the patient. These are the types of factors that a skilled pharmaceutical chemist will be aware of and will be able to account for when preparing formulations for a treatment as herein described. Supporting guidance for the preparation of such formulations can be found in Goodman and Gilman's "The Pharmacologic Basis of Therapeutics" (Gilman et al. Eds., 8 th Edition, Pergamon Press, 1990), which is expressly incorporated by reference herein.
- the invention provides a method of treating cancer in a patient, said method comprising the steps of: (a) administering to the patient in need of cancer therapy a therapeutically effective amount of irinotecan; and (b) treating the patient with SIRT.
- the invention provides a method for inhibiting cell proliferation or causing cell death in a tumour in a patient, said method comprising the steps of: (a) administering to the patient in need of cancer therapy a therapeutically effective amount of irinotecan; and (b) treating the patient with SIRT.
- the methods of the invention have utility in the treatment of various forms of cancer and tumours, including for example, liver cancer, colorectal cancer, cancer of the brain, cancer of the kidney, cancer in other soft tissues (eg breast tissue), and bone sarcomas.
- the cancer to be treated is primary and/or secondary liver cancer and, more specifically, secondary liver cancer deriving from the gastrointestinal tract such as secondary liver cancer deriving from colorectal cancer.
- the method is used for treating a patient with colorectal liver metastases.
- irinotecan therapy can be co-administered with SIRT or it can be administered prior to or after this therapy.
- the method will be performed where there is a synergistic effect between irinotecan therapy and SIRT.
- a "synergistic effect” refers to a greater-than- additive anticancer effect that is produced by a combination of irinotecan therapy and SIRT as compared to each of irinotecan therapy and SlRT alone.
- irinotecan therapy and SIRT are carried out within a few months of each other.
- radioactive particles or material for SIRT are implanted into the patient within a few months more desirably within a few weeks and even more desirably within days of irinotecan therapy.
- irinotecan will be repeatedly administered to the patient.
- SIRT will also be provided to the patient but not necessarily at the same time as the irinotecan therapy.
- Irinotecan therapy may be carried out for a few days to many months or possibly even a year or years depending on the severity of the cancer. According to the invention the method will be performed where there is a synergistic effect between irinotecan therapy and SIRT. That effect need not be the result of the two therapies being applied together but may result from the administration of SIRT or Irinotecan therapy being applied to the other therapy some time later (ie within days, weeks or months of the first therapy).
- irinotecan therapy will be provided to the patient in a cyclic manner where the patient receives irinotecan treatment for a period of about 1 to 20 days, but more preferably about 3 to 14 days.
- the patient is then given a rest period of a few weeks (preferably 3 weeks) and then the cycle is repeated. This cycle may be repeated as many times as necessary and as long as the patient is capable of receiving said treatment.
- SIRT therapy may be administered at any time during the course of the irinotecan therapy or during a rest period. Typically the patient will receive 1 to 5 doses of SIRT, although usually the patient will only receive about 1 or 2 doses of SIRT.
- Irinotecan 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., transdermal administration.
- the irinotecan is administered parenterally.
- irinotecan may be combined with a sterile aqueous solution that is preferably isotonic with the blood of the patient.
- a sterile aqueous solution that is preferably isotonic with the blood of the patient.
- 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.
- physiologically-compatible substances such as sodium chloride, glycine, and the like
- the formulations may be presented in unit or multi-dose containers, such as sealed ampoules or vials.
- 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.
- irinotecan is given parenterally it may be delivered by any form of injection to the patient.
- it is infused into a patient at a dose of about 10 mg/m 2 to about 250 mg/m 2 . More preferably, it is infused at a dose of about 20 mg/m 2 to about 150 mg/m 2 , while doses in the range of about 50 mg/m 2 to about 100 mg/m 2 are highly preferred.
- a dose that would fall within that range which is exemplified herein is 75 mg/m 2 .
- irinotecan is ingested orally it can be provided in, for example, a tablet or capsule or as an ingestible liquid form, like a tablespoon of syrup.
- the dose of irinotecan administered by this method is about 20 to about 250 mg of irinotecan, more preferably from about 20 to about 40 mg of irinotecan.
- irinotecan is initially given to the patient at a relatively low dose (eg 25 to 75 mg/m 2 ) and then that dose is increased to a higher maintenance dose (eg around 100 mg/m 2 ) as the patient's body learns to accommodate the therapy.
- a relatively low dose eg 25 to 75 mg/m 2
- a higher maintenance dose eg around 100 mg/m 2
- the above methods also include the step of: administering to the patient a therapeutically effective amount of at least another therapeutic agent, wherein the agent aids in the treatment of cancer in the patient and or provides a secondary therapeutic benefit to the patient.
- the additional therapeutic agent will "aid in the treatment of cancer” if it either directly causes a chemotherapeutic effect (i.e. is a chemotherapeutic agent it self), or it indirectly achieves a chemotherapeutic benefit by assisting, improving or potentiating the chemotherapeutic effect of one or more of the chemotherapeutic agents or therapies used in the method of the invention.
- the additional therapeutic agent will provide a secondary therapeutic benefit where the agent treats a condition caused by the cancer or treats a side effect of the treatment which the patient is undergoing or treats another condition which a patient may suffer while undergoing such treatment (eg pain, nausea, vomiting, diarrhoea, impairment of immunity, depletion of blood cell counts etc).
- the additional therapeutic agent can be co-administered with either the irinotecan chemotherapy and/or the SIRT or it can be administered prior to or after one or both of these therapies. Further, the additional therapeutic agent 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., transdermal administration.
- the additional therapeutic agent is delivered by the same route as the irinotecan therapy or SIRT, this is not essential.
- the invention also contemplates that the additional therapeutic agent is delivered by a route unrelated to the modes of delivery of irinotecan or SIRT.
- the other therapeutic agent is at least an agent that aids in the treatment of cancer.
- the method of the invention also includes the step of: (a) administering to the patient a therapeutically effective amount of an agent that aids in the treatment of cancer.
- irinotecan chemotherapy is combined with an agent that aids in the treatment of cancer and or is a second chemotherapeutic agent, the combined therapy is collectively referred to herein as 'irinotecan based therapy', or IBT.
- the second chemotherapeutic agent may comprise a plurality of agents which can be of like form or activity, or of different form but the same activity, or of different activity. Any agent that has a chemotherapeutic effect on cancer tissue may be employed in this step of the method, the proviso being that it does not impair the effect of either irinotecan of SIRT.
- the chemotherapeutic agent can include: 5-FU, etoposide, paclitaxel, doxorubicin, vincristine, oxaliplatin, capecitabine, carboplatin, thiotepa, bleomycin sulfate, mitomycin, dactinomycin, streptozotocin, carmustine, methotrexate, floxuridine, cytarabine, 6-mercaptopurine, 6- thioguanine, deoxycoformycin, fludarabine, 2-chlorodeoxyadenosine, cyclophosphamide, ifosfamide, and hydroxyurea.
- agents that aid in chemotherapy are not limited to those that have a direct chemotherapeutic effect, but also include compounds that assist, improve or potentiate the chemotherapeutic effect of one or more of the chemotherapeutic agents or therapies used in the method of the invention.
- Such a compound that has a substantial therapeutic benefit, when combined with a chemotherapeutic agent would be LV.
- irinotecan or IBT is administered to a patient in combination with SIRT, such that a synergistic effect is produced.
- “synergistic effect” refers to a greater-than-additive anticancer effect that is produced by a combination of chemotherapeutic drugs and SIRT.
- irinotecan, 5-FU and LV in combination with SIRT unexpectedly results in a synergistic anticancer effect by providing a greater effect than would result from use of each of the anticancer agents alone.
- administration of irinotecan or IBT "in combination with" SIRT refers to co-administration of the anticancer treatments. Co ⁇ administration may occur concurrently, sequentially, or alternately. Concurrent co-administration refers to administration of irinotecan or IBT and SIRT at or about the same time. For concurrent co-administration, the courses of treatment with irinotecan or IBT and with SIRT may also be run simultaneously. For example, a single, combined formulation of irinotecan or IBT 1 in physical association with SIRT, may be administered to the patient.
- irinotecan chemotherapy is preferably combined with either 5-
- FU chemotherapy or LV chemotherapy More preferably, irinotecan chemotherapy is combined both 5-FU chemotherapy and LV chemotherapy.
- the invention provides a method for treating cancer or a tumour in a patient, said method comprising the step of: (a) administering to the patient a therapeutically effective amount of each of 5-FU, LV and irinotecan; and (b) subjecting the cancerous tissue in the patient to SIRT to treat the cancer or tumour.
- irinotecan treatment and or 5-FU and LV treatment can be co-administered with SIRT or these treatments administered prior to or after each therapy.
- irinotecan, 5-FU and LV therapy and SIRT are carried out within a few months of each other.
- radioactive particles or material for SIRT are implanted into the patient within a few months more desirably within a few weeks and even more desirably within days of irinotecan , 5-FU and LV therapy. Over the course of treatment, irinotecan and or 5-FU and LV will be repeatedly administered to the patient. SIRT will also be provided to the patient but not necessarily at the same time as the irinotecan therapy.
- Irinotecan , 5-FU and LV therapy may be carried out for a few days to many months or possibly even a year or years depending on the severity of the cancer.
- the method will be performed where there is a synergistic effect between irinotecan , 5-FU and LV therapy and SIRT. That effect need not be the result of the two therapies being applied together but may result from the administration of SIRT or Irinotecan , 5-FU and LV therapy being applied to the other therapy some time later (ie within days, weeks or months of the first therapy).
- irinotecan, 5-FU and LV therapy will be provided to the patient in a cyclic manner where the patient receives irinotecan, 5-FU and LV therapy.
- SIRT therapy may be administered at any time during the course of the irinotecan, 5-FU and LV therapy or during a rest period. Typically the patient will receive 1 to 5 doses of SIRT, although usually the patient will only receive about 1 or 2 doses of SIRT.
- irinotecan is administered by any of the routes herein described and at any of the dose described herein.
- 5-FU and LV treatment 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.
- Doses of 5-FU administered intraperitoneally may be between 100 and 600mg/m 2 , or between 200mg/m 2 and 500mg/m 2 . More preferably doses of 5-FU administered intraperitoneally will be between 300 and 480mg/m 2 , or between
- Doses of LV administered intraperitoneally will usually be about one twentieth of the does of 5-
- FU for example if the dose of 5-FU is 425mg/m 2 then the dose of LV will be about 20mg/m 2 . A skilled artisan will recognise appropriate levels of LV.
- the therapeutically effective amounts of 5-FU, LV and irinotecan needed to treat cancer in a patient 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. The precise amounts can be readily determined by the skilled artisan.
- the other therapeutic agent provides a secondary therapeutic benefit to the patient.
- the method of the invention also includes the step of: (a) administering to the patient a therapeutically effective amount of a therapeutic agent that provides a secondary therapeutic benefit to the patient.
- This additional step may be included with any of the methods described herein including for example the method which incorporates a second chemotherapeutic agent.
- the secondary therapeutic benefit treated by this step in the method includes, without limitation, treating a condition caused by the cancer or treating a side effect of the cancer treatment which the patient is undergoing or treats another condition which a patient may suffer while undergoing such treatment (eg pain, nausea, vomiting, diarrhoea, impairment of immunity, depletion of blood cell counts etc).
- the agent may comprise a plurality of agents which can be of like form or activity, or of different form but the same activity, or of different activity.
- the active agent employed in this step of the method can be any compound or agent that provides a secondary therapeutic benefit to the patient.
- the active agent may be selected from the group comprising: anti-angiogenesis factors to effect blood supply to cancers; anticancer agents such as antibodies targeted against a variety of cancer cells or the blood vessels supplying the cancer cells, for example antibodies targeting VEGF or EGF, may also be used; anti-inflammatory agents; non-steroidal anti-inflammatory drugs; antineoplastic agents; gastrointestinal therapeutic agents; parasympathomimetic agents; psychotherapeutic agents; major tranquilizers; minor tranquilizers; sedative- hypnotics; steroids; anti-migraine agents; antispasmodics; fluid and electrolyte replacements; ergotalkaloids; alkaloids; analgesics; narcotics; narcotic antagonists; non-narcotics; anti-cancer agents; anti-convulsants; immunomodulators; drugs to promote or to stimulate bone marrow production and or drugs to suppress bone m
- Anti-angiogenesis factors that may be used in the method will include those selected from the list comprising: antibodies to or aptamers of Vascular Endothelial Growth Factor (VEGF) or a related family member such as (VEGF B, C, D; PDGF) such as AVASTI N ® (bevacizumab) and LUCENTIS ® (rhuFAb V2; ranibizumab) (Genentech), and other anti-VEGF compounds such as MACUGEN; EGF; Pigment Epithelium-Derived Factor(s) (PEDF); CELEBREX ® ; VIOXX ® ; interferon alpha; interleukin-12 (IL-12); thalidomide and derivatives such as REVIMIDTM (CC-5013) (Celgene Corporation); squalamine; endostatin; angiostatin; the ribozyme inhibitor ANGIOZYME ® (Sirna Therapeutics); multifunctional anti-angiogenic agents such as NE
- the anti-angiogenesis factor is selected from the group consisting of: (a) Lucentis ® (Genentech); or (b) Macugen ® (Eyetech Pharmaceuticals).
- Lucentis ® and Macugen ® are potent anti-angiogenic compounds.
- Lucentis ® (ranibizumab), formerly known as rhuFab V2 or AMD-Fab is a humanized, therapeutic anti-VEGF (vascular endothelial growth factor) antibody fragment developed at Genentech to bind and inhibit VEGF, a protein that plays a critical role in angiogenesis (the formation of new blood vessels).
- Lucentis is designed to block new blood vessel growth and reduce leakage, which are thought to lead to wet AMD disease progression.
- Lucentis should be provided in either about 300 or about
- Macugen ® pegaptanib sodium, anti-VEGF aptamer or EYE001
- Eyetech Pharmaceuticals consists of a synthetic fragment of genetic material that specifically binds to the VEGF molecule and blocks it from stimulating the receptor on the surface of endothelial cells.
- Macugen ® should be provided in a dose ranging from either about 0.3 mg to about 3.0 mg every four or six weeks.
- anti-inflammatory agents such as anti-inflammatory agent is preferably selected from the group comprising: colchicine, ANAPROX® and ANAPROX DS® (naproxen sodium) (Roche); ANSAID® (flurbiprofen) (Pharmacia Pfizer); ARTHROTEC® (diclofenac sodium and misoprostil) (Searle Monsanto); BEXTRA® (valdecoxib) (Pfizer); CATAFLAM®
- anti-inflammatory agent is preferably selected from the group comprising: colchicine, ANAPROX® and ANAPROX DS® (naproxen sodium) (Roche); ANSAID® (flurbiprofen) (Pharmacia Pfizer); ARTHROTEC® (diclofenac sodium and misoprostil) (Searle Monsanto); BEXTRA® (valdecoxib) (Pfizer); CATAFLAM®
- non-steroidal anti-inflammatory drugs such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as celecoxib and rofecoxib, analgesics and intraarticular therapies such as corticosteroids and hyaluronic acids such as hyalgan and synvisc; (c) Gastrointestinal therapeutic agents such as aluminium hydroxide, calcium carbonate, magnesium carbonate, sodium carbonate and the like;
- Major tranquilizers such as chlorpromazine HCI, clozapine, mesoridazine, metiapine, reserpine, thioridazine and the like;
- Narcotic antagonists such as naltrexone and naloxone and the like
- Non-narcotics such as salicylates, aspirin, acetaminophen, d- propoxyphene and the like
- Anti-convulsants such as mephenytoin, phenobarbital, trimethadione
- Anti-emetics such as thiethylperazine; antihistamines such as chlorophinazine, dimenhydrinate, diphenhydramine, perphenazine, tripelennamine and the like;
- Anti-inflammatory agents such as hydrocortisone, prednisolone, prednisone, non-hormonal agents, allopurinol, aspirin, indomethacin, phenylbutazone and the like;
- immunomodulators such as alpha interferon, beta interferon, gamma interferon, interleukin-2, interIeukin-3, tumour necrosis factor, and the like;
- Cytokines such as G-CSF, GM-CSF, EPO, IL, interferon, etc.
- the agent providing a secondary therapeutic benefit can be co-administered with either irinotecan, IBT, SIRT or a second chemotherapeutic agent of it can be administered, as a separate formulation. If prepared as a separate formulation it will be administered at or about the same time as either SIRT or the irinotecan, IBT, or second chemotherapeutic therapy.
- SIRT may be applied by any of a range of different methods, some of which are described in US patents 4789501 , 5011677, 5302369, 6296831 , 6379648, or WO applications 200045826, 200234298 or 200234300 (incorporated herein by reference).
- administration of radionuclide doped particles or materials 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 radioactive particles or materials, for example a vasoactive substance, such as angiotension-2 to redirect arterial blood flow into the tumour. Delivery of the radioactive particles or materials may be by single or multiple doses, until the desired level of radiation is reached.
- a vasoactive substance such as angiotension-2
- the radioactive particles or materials need not be limited to any particular form or type of microparticle.
- the radionuclide doped microparticles suitable for use in the invention may comprise any 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.
- the radioactive particles or materials are prepared as polymeric particles.
- the microparticles are prepared as ceramic particles (including glass).
- they are prepared from chitosan.
- they are formed of yttria.
- they are formed substantially from silicon.
- they are formed from proteins.
- they are formed from antibodies.
- radioactive particles or materials are prepared as a polymeric matrix they will preferably have a stably incorporated radionuclide. More preferably the radionuclide will be incorporated by precipitation of the radionuclide as a salt.
- a d ⁇ scription of such particles including methods for their production and formulation as well as their use is provided in co-owned European application number 200234300, of which the teachings therein are expressly incorporated herein by reference.
- the radionuclide will preferably be stably incorporated into the silicon matrix or within the pores or micropores of the matrix or coated onto the matrix.
- the radionuclide will preferably be stably incorporated into the yttria matrix or coated onto the surface.
- radioactive particles or materials are ceramic particles (including glass)
- the selected particles will usually possess the following properties.
- They will generally be biocompatible, such as calcium phosphate-based biomedical ceramics or glass, or aluminium-boro silicate glass, or silicate based glass.
- Radionuclides that preferably emits radiation of sufficiently high energy and with an appropriate penetration distance in tissue, which are capable of releasing their energy complement within the tumour tissue to effectively kill the cancer cells and to minimize damage to adjacent normal cells or to attending medical personnel.
- the level of radiation activity of the ceramic or glass will be selected and fixed based upon the need for therapy given the particular cancer involved and its level of advancement.
- the ideal half-life of the radionuclides is somewhere between days and months. On the one hand, it is impractical to treat tumours with radionuclides having too short a half-life, this characteristic limiting therapy efficiency. On the other hand, in radiotherapy it is generally difficult to trace and control radionuclides having a long half-life.
- the size of the particles for treatment depends upon such variables as the selected method of introduction into the tumour. There are many processes for producing small granular ceramic or glass particles. One of these involves the introduction of small amounts of the ceramic particles passing through a high-temperature melting region. Ceramic spherules are yielded by surface tension during melting. After the solidification, condensation, collection and sorting processes, ceramic spherules of various sizes can be obtained. The particle size of ceramic spheroids can be controlled by the mass of granules introduced into the high-temperature melting region or can be controlled by collecting spheroids of various sizes through the selection of sedimentation time during liquid-sedimentation.
- the ceramic or glass materials for preparing those particles can be obtained commercially or from ultra-pure ceramic raw materials if the commercial products do not meet specifications for one reason or another.
- the ceramic or glass particles for radiation exposure in this invention can be yielded by traditional ceramic processes, which are well known by those skilled in this art.
- the ceramic processes such as solid-state reaction, chemical co-precipitation, sol-gel, hydrothermal synthesis, glass melting, granulation, and spray pyrolysis can be applied in this invention for the production of specific particles.
- the radioactive particles or materials of the invention be they polymer, ceramic, glass or silicon based or other can be separated by filtration or other means known in the art to obtain a population of microparticles of a particular size range that is preferred for a particular use.
- the radionuclide which is incorporated into the microparticles in accordance with the present invention is preferably yttrium-90, but may also be any other suitable radionuclide of which holmium, samarium, iodine, phosphorous, iridium and rhenium are some examples.
- the amount of radioactive particles or materials 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 80 Gy may be delivered. Because the radiation from SIRT is delivered as a series of discrete point sources, the dose of 80 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.
- microparticle is used in this specification as an example of a particulate material, it is not intended to limit the invention to microparticles of any particular shape or configuration and includes radiolabeled microparticles, capsules or other particulate material, target directed antibodies labeled with a therapeutic radioactive material or any other radioactively labelled carrier molecules.
- shape of the particulate material will preferably be substantially spherical, but need not be regular or symmetrical in shape and could be of any shape or size.
- the invention provides a therapeutic composition for treating cancer comprising: a therapeutically effective amount of irinotecan and a therapeutically effective amount of radionuclide-doped agents suitable for SIRT.
- the therapeutic composition is prepared for use in treating a patient with primary liver cancer, secondary liver cancer, secondary liver cancer deriving from the gastrointestinal tract, and more specifically secondary liver cancer deriving from colorectal cancer.
- the therapeutic composition also includes another therapeutic agent which either aids in the treatment of cancer in the patient or provides a secondary therapeutic benefit to the patient.
- Said secondary therapeutic benefit may be to treat a condition caused by the cancer or to treat a side effect of the treatment which the patient is undergoing or to treat another condition which a patient may suffer while undergoing such treatment.
- agents will include one or more alternate chemotherapeutic agents, anti-angiogenesis agents or other anti-cancer agents.
- agents will include but will not be limited to 5-FU, LV, oxaliplatin, capecitabine and antibodies directed against EGF and VEGF.
- the invention relates to the use of a therapeutically effective amount of irinotecan and an amount of radionuclide-doped particles suitable for use in SIRT, in the manufacture of a medicament for treating cancer in a cancer patient.
- the medicament is prepared for use in treating a patient with primary liver cancer, secondary liver cancer, secondary liver cancer deriving from the gastrointestinal tract, or more specifically secondary liver cancer deriving from colorectal cancer.
- the medicament also includes a therapeutically effective amount of another therapeutic agent which either aids in the treatment of cancer in the patient or provides a secondary therapeutic benefit to the patient.
- Said secondary therapeutic benefit may be to treat a condition caused by the cancer or may be to treat a side effect of the treatment which the patient is undergoing or to treat another condition which a patient may suffer while undergoing such treatment.
- agents will include one or more alternate chemotherapeutic agents, anti-angiogenesis agents or other anti-cancer agents.
- agents will include but will not be limited to 5- FU, LV, oxaliplatin, capecitabine and antibodies directed against EGF and VEGF.
- the invention in a fifth aspect relates to a kit for treating cancer in a patient.
- the kit comprises a therapeutically effective amount of irinotecan and an amount of radionuclide-doped microparticles suitable for use in SIRT for treatment of a cancer.
- the kit may further comprise an instructional material.
- the kit is prepared for use in treating a patient with primary liver cancer, secondary liver cancer, secondary liver cancer deriving from the gastrointestinal tract, or more specifically secondary liver cancer deriving from colorectal cancer.
- the primary objective of the study was to evaluate the toxicity and response rate resulting from a combination of SIRT plus systemic chemotherapy using either irinotecan alone, or irinotecan combined with other chemotherapy agents, in patients with advanced colorectal metastases involving the liver. Further objectives of this study where to evaluate the time to progressive disease, site of progressive disease and patient survival.
- the SIR-Spheres ® was administered into the hepatic artery via a trans-femoral catheter that was placed under local anaesthetic. Patients treated with SIRT received a standard dose of between 0.75 to 2.44GBq of yttrium-90 activity. SIR-Spheres ® dose was determined from the patient size and amount of tumour within the liver and according to the standard published dose calculation formula.
- RECIST criteria Therasse P et al (2000) J Natl Cancer Inst 92, 205-216.
- the RECIST criteria were developed with particular application for reporting the results of phase 2 trials and result in very similar response outcomes as the conventional WHO method.
- Toxicity was recorded on all patients using standard UICC recommendations for grading of acute and subacute toxicity criteria.
- protocol treatment ceased, further cancer specific treatment, including non-protocol chemotherapy, was allowed to best manage patient care. All non-protocol cancer specific treatment was recorded in all patients. Other supportive, but not cancer specific treatment was allowed for patient management.
- Experiment 1 The first experiment comprised treating a series of 25 patients with advanced liver metastases from a primary adenocarcinoma of the colorectum and who had already progressed following treatment with at least one previous fluorouracil based chemotherapy regimen. Twelve of these patients also had cancer at extra-hepatic sites. This patient population is generally regarded as refractory to treatment with a response rate of approximately 5-11% to irinotecan alone [see van Cutsem et al., (1999), Seminars in Oncology, 26:13; Michael et al., (2002), Clinical Colorectal Cancer, 2:93; and Schoemaker et a/., (2004), British
- the patients in our experiment were treated with a combination of SIRT plus irinotecan as the sole chemotherapy agent.
- the first six patients received irinotecan at a dose of 50mg/m 2 of body surface area infused over a 90 minute period weekly for 2 weeks and repeated every 3 weeks. From cycle three onwards, the irinotecan dose was increased up to a maintenance dose of 100mg/m 2 IV for 2 weeks every 3 weeks, provided the toxicity profile allowed until progression of their disease.
- SIR-Spheres ® (at the calculated patient dose) was implanted one day after the first day of administration of chemotherapy in Cycle one.
- the next 13 patients were treated with a similar chemotherapy regimen, except that the dose of irinotecan was increased to 75mg/m 2 of body surface area.
- a final group of six patients was treated with the same chemotherapy regimen except that the dose of irinotecan was increased to dose of 100mg/m 2 of body surface area.
- CEA serum carcinoembryonic antigen
- CEA carcinoembryonic antigen
- Figure 1 depicts the median serum CEA levels detected in the 22 patients with data that could be evaluated.
- Serum CEA has a range in normal people of 1-10 ng/ml. Eight patients actually had serum CEA levels drop to within the normal range following treatment with the combined therapy. The median fall in CEA was 88.4% for all patients. In 5 of 10 patients in whom there was no extra-hepatic cancer at the time of treatment, the CEA level fell into the normal range.
- the median time to disease progression has also provided extremely beneficial outcomes.
- Phase III trial data for a comparative patient population treated with irinotecan alone yields a median time to progression of 2.7 to 4.2 months with the first site of disease progression being the liver (van Cutsem et al, 1999, Seminars in Oncology 26:13; Michael et al, 2002 Clinical Colorectal cancer 2:93; Schoemaker et al, 2004, British Journal of Cancer 91:1434).
- the median time to disease progression is currently 6.1 months anywhere in the body or 8.25 months in the liver.
- Experiment 2 The second experiment comprised treating a series of 11 patients with advanced colorectal liver metastases and who had not previously been treated with any sort of chemotherapy. These patients were treated with a combination of SIRT plus a chemotherapy regimen consisting of irinotecan, fluorouracil (FU) and leucovorin (LV). The first 6 patients were treated with 5FU (500mg/m 2 IV bolus) plus LV (20mg/m 2 body surface area IV bolus) plus irinotecan 25mg/m 2 IV infused over a 90 minute period weekly for 2 weeks and repeated every 3 weeks.
- 5FU 500mg/m 2 IV bolus
- LV 20mg/m 2 body surface area IV bolus
- irinotecan 25mg/m 2 IV infused over a 90 minute period weekly for 2 weeks and repeated every 3 weeks.
- the irinotecan dose may be increased up to a maintenance dose of 100mg/m 2 IV for 2 weeks every 3 weeks, provided the toxicity profile allowed.
- SIR-Spheres ® at the calculated patient dose
- the next three patients were treated with a similar chemotherapy regimen, except that the dose of irinotecan was increased to 50mg/m 2 of body surface area.
- the final three patients were treated with a similar chemotherapy regimen except that the dose of irinotecan was increased to 75mg/m 2 of body surface area. This study is ongoing.
- SlRT is a form of localised brachytherapy. Brachytherapy is not used in combination with systemic chemotherapy as the brachytherapy is expected to adequately deal with localised disease. Furthermore there is no evidence that systemic chemotherapy using irinotecan-based chemotherapy can enhance the local effect of any form of brachytherapy, including SIRT. Therefore the outcome from treating patients with a combination of a local therapy such as SIRT together with a systemic chemotherapy regimen is unknown.
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Abstract
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