WO2006002488A1 - Combination therapy for treatment of neoplasia - Google Patents

Abstract

A method of treating cancer in a patient comprising administering to the patient an effective amount of irinotecan in combination with SIRT, wherein a synergistic anticancer effect results.

Description

"Combination Therapy for Treatment of Neoplasia"

This application claims benefit of Australian Provisional Patent Application No. 2004903682 filed 6 July 2004.

The foregoing application, and all documents cited therein, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention.

Field of the Invention

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.

Background Art

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. The terms neoplasia, malignant neoplasia, neoplastic growth and cancer are used interchangeably throughout this document.

Of the vast forms of malignant neoplasms 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.

Surgery involves the bulk removal of diseased tissue. When tumour growth is recognized, excision of the tumour mass by surgery is regarded as the therapy of choice. In a minority of patients with liver metastases some form of local ablation, such as cryotherapy or radiofrequency ablation, can also offer the potential for long-term cure. However, these approaches, while producing satisfactory results as a general measure, are effective only for patients with tumours at an early stage of development. They cannot be used in the liver, for example, where the vast majority of the liver is covered with multiple primary or secondary cancers.

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. For the purposes of this document "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. Among the many antimetabolites that have been developed and clinically tested are methotrexate, 5-fluorouracil (5-FU), floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, deoxycoformycin, fludarabine, 2-chlorodeoxyadenosine, and 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, however, causes serious adverse reactions such as nausea, alopecia, diarrhoea, stomatitis, leukocytic thrombocytopenia, anorexia, pigmentation, and edema. Further, as 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.

Leucovorin (LV) addition to 5-FU approximately doubles the response rates in patients with gastrointestinal neoplasms. LV addition to 5-FU therapy is currently very commonly used in the United States.

lrinotecan (irinotecan) 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. The use of irinotecan in patients with prior radiation treatment appears to increase the risk of toxicity (Lhomme C et al., (1999), Journal Clinical Oncology, 17 (10):3136-42). In addition, use of irinotecan in patients with pre- existing hepatic dysfunction and pulmonary diseases may result in increased toxicity of the drug.

The clinical usefulness of a chemotherapeutic agent may also be severely limited by the emergence of malignant cells resistant to that drug. In some cases, resistance to one drug may confer resistance to other biochemically distinct drugs. In this respect amplification of the gene encoding thymidylate synthase is related to resistance to treatment with 5-fluoropyrimidines. - A -

In summary, chemotherapy has not made a dramatic impact on the treatment of cancer.

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. Examples of 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. When radioactive particles are administered into the blood supply of the target organ the technique has become known as Selective Internal Radiation Therapy (SIRT). Generally, 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.

There are many potential advantages of SIRT over conventional, external beam radiotherapy. Firstly, the radiation is delivered preferentially to the cancer within the target organ. Secondly, the radiation is slowly and continually delivered as the radionuclide decays. Thirdly, by manipulating 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).

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.

For radioactive particulate material to be used successfully for the treatment of neoplastic growth, 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. There are many 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. However, other radionuclides may also be used in place of Y-90 of which isotopes of holmium, samarium, iodine, iridium, phosphorus, rhenium are some examples.

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). Treatment with SIRT has been shown to result in high response rates for patients with neoplastic growth in particular with colorectal liver metastases (Gray B.N. et al (1989) Surg. Oncol, 42, 192-196; Gray B, et al. (1992) Aust NZ J Surgery, 62, 105-110; Gray B N et al. (2000) Gl Cancer, 3(4), 249-257; Stubbs R, et al (1998) Hepato-gastroenterology Suppl II, LXXVII). Other studies have shown that 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.

Recently, clinicians have tried to improve the effectiveness of cancer treatment by combining two or more anticancer therapies into a single therapeutic regimen. One example of such combination therapy is demonstrated by the randomised clinical trial carried out by Gray et al where they compared treatment of cancer by floxuridine either with or without the addition of a single dose of radioactive microparticles (Gray et al (2001) Annals of Oncology 12: 1711-1720). This study has shown that the addition of radioactive microparticles increased the response rate from 17.6% to 44% and the time to disease progression from 9.7 months to 15.9 months. An important finding from this trial was that although most patients eventually succumbed to their disease, the liver metastases were not the primary cause of death for most patients treated with SIRT.

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.

It would be advantageous to show that combining chemotherapy with other forms of cancer therapy, such as brachytherapy using SIRT, resulted in an improved outcome for cancer patients. It is well recognised that the outcome measure of 'response' is a measure of the ability of the treatment to cause regression of a cancer and that prolongation of the time a cancer is held in remission, known as 'time to disease progression', is a measure of particular benefit. There is described herein a process which provides such advantages.

Summary of the Invention

The present invention arose from the discovery of an unexpected synergistic effect from the combination of known anticancer therapies. In particular 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.

Throughout this specification SIRT is used to generally describe selective internal radiation therapy. Preferably such 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. In one aspect, 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.

In a second aspect, 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.

In a preferred form, 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. In a highly preferred form of the invention the additional therapeutic agent is 5'-FU and LV.

In a third aspect, 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.

In a fourth aspect, 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. Preferably, 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. In a highly preferred form of the invention 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. Preferably such agents will include one or more alternate chemotherapeutic agents, anti-angiogenesis agents or other anti-cancer agents. Such agents will include but will not be limited to 5- FU, LV₁ oxaliplatin, capecitabine and antibodies directed against EGF and VEGF.

In a fifth aspect the invention 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. Preferably, 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.

Other objects, features, and advantages of the instant invention, will be comprehended from the following description when considered in light of the appended claims.

Brief Description of the Drawings

Comprehension of the invention is facilitated by reading the following detailed description, in conjunction with the annexed drawings.

Figure 1 Serum CEA level following SIR-Spheres implantation and commencement of protocol chemotherapy

Detailed Disclosure of the Invention

General

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. The invention includes all such variations and modifications. The invention also includes all of the steps, features, formulations and compounds referred to or indicated in the specification, individually or collectively and any and all combinations or any two or more of the steps or features.

Each document, reference, patent application or patent cited in this text is expressly incorporated herein in their entirety by reference, which means that it should be read and considered by the reader as part of this text. That the document, reference, patent application or patent cited in this text is not repeated in this text is merely for reasons of conciseness.

The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, formulations and methods are clearly within the scope of the invention as described herein.

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.

Throughout this specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. It is also noted that in this disclosure and particularly in the claims and/or paragraphs, terms such as "comprises", "comprised", "comprising" and the like can have the meaning attributed to it in U.S. Patent law; e.g., they can mean "includes", "included", "including", and the like; and that terms such as "consisting essentially of and "consists essentially of have the meaning ascribed to them in U.S. Patent law, e.g., they allow for elements not explicitly recited, but exclude elements that are found in the prior art or that affect a basic or novel characteristic of the invention.

As used herein 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.

As used herein the terms 'treat', 'treatment' or 'treating' describe prophylactic, therapeutic or curative treatments of cancerous pathologies to which the present invention is directed. In particular 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.

As used herein 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.

Other definitions for selected terms used herein may be found within the description of the invention and apply throughout. Unless otherwise defined, all other scientific and technical terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the invention belongs. Description of Preferred Embodiments

Surprisingly, applicant has found that the co-administration of systemic chemotherapy and SIRT to a patient with liver cancer, potentiates the effect of the radiation from SIRT on the liver cancer, and also has a beneficial effect on extra- hepatic disease.

In one aspect, 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.

In a second aspect, 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. In a preferred form of the invention 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. In a highly preferred form the method is used for treating a patient with colorectal liver metastases.

According to the invention, irinotecan therapy can be co-administered with SIRT or it can be administered prior to or after this therapy. According to the invention 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.

Preferably irinotecan therapy and SIRT are carried out within a few months of each other. In a particularly preferred form of the invention, 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. Over the course of treatment, 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).

In a highly preferred form of the invention 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. Preferably, the irinotecan is administered parenterally.

For parenteral administration, irinotecan may be combined with 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. 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.

Where irinotecan is given parenterally it may be delivered by any form of injection to the patient. Preferably it is infused into a patient at a dose of about 10 mg/m² to about 250 mg/m². More preferably, it is infused at a dose of about 20 mg/m² to about 150 mg/m², while doses in the range of about 50 mg/m² to about 100 mg/m² are highly preferred. A dose that would fall within that range which is exemplified herein is 75 mg/m².

Where 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. Preferably, 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.

Preferably, irinotecan is initially given to the patient at a relatively low dose (eg 25 to 75 mg/m²) and then that dose is increased to a higher maintenance dose (eg around 100 mg/m²) as the patient's body learns to accommodate the therapy.

Addition of a second therapeutic agent

In a preferred form, 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.

While it is preferable that the additional therapeutic agent is delivered by the same route as the irinotecan therapy or SIRT, this is not essential. Thus, the invention also contemplates that the additional therapeutic agent is delivered by a route unrelated to the modes of delivery of irinotecan or SIRT.

(0 Addition of an agent that aids in the treatment of cancer

In one embodiment of the preferred form of the method, the other therapeutic agent is at least an agent that aids in the treatment of cancer. Thus, according to this first embodiment, 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. When 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.

As used herein a reference to a singular second chemotherapeutic agent must be read in its singular form and in its plural form. Thus, 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. For example, 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. What constitutes a therapeutically effective amount for these agents can be determined using routine pharmacological testing of the nature disclosed in Goodman and Gilman's "The Pharmacologic Basis of Therapeutics" (Gilman et al. Eds., 8^th Edition, Pergamon Press, 1990, Chapter 52), which is expressly incorporated by reference herein.

As mentioned above 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.

In the method of the present invention, irinotecan or IBT is administered to a patient in combination with SIRT, such that a synergistic effect is produced. A

"synergistic effect" refers to a greater-than-additive anticancer effect that is produced by a combination of chemotherapeutic drugs and SIRT. For example treatment with 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.

In the method of the invention, 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 IBT₁ in physical association with SIRT, may be administered to the patient.

By way of example, 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.

Thus, according to this exemplified form 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.

According to the invention, 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. Preferably irinotecan, 5-FU and LV therapy and SIRT are carried out within a few months of each other. In a particularly preferred form of the invention, 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. According to the invention 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).

In a highly preferred form of the invention, 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 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 2 to 4 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, 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.

According to this method 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. Preferably, the 5-FU and LV agents are administered parenterally.

Doses of 5-FU administered intraperitoneally may be between 100 and 600mg/m², or between 200mg/m² and 500mg/m². More preferably doses of 5-FU administered intraperitoneally will be between 300 and 480mg/m², or between

400mg/m² and 450mg/m². An example being 425mg/m². Doses of LV administered intraperitoneally will usually be about one twentieth of the does of 5-

FU. So, for example if the dose of 5-FU is 425mg/m² then the dose of LV will be about 20mg/m². A skilled artisan will recognise appropriate levels of LV.

Notably, 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.

(ii) Addition of agents which provide secondary therapeutic effect.

In a second embodiment of the preferred form of the method the other therapeutic agent provides a secondary therapeutic benefit to the patient. Thus, according to this second embodiment, 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).

As used herein a reference to a singular agent providing a secondary therapeutic benefit must be read in its singular form and in its plural form. Thus, 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. For example, 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 marrow production; cytokines; vitamins; or health supplements.

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 REVIMID™ (CC-5013) (Celgene Corporation); squalamine; endostatin; angiostatin; the ribozyme inhibitor ANGIOZYME^® (Sirna Therapeutics); multifunctional anti-angiogenic agents such as NEOVASTAT^® (AE-941) (Aeterna Laboratories, Quebec City, Canada); etc., as known to one skilled in the art.

In a preferred form, 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. When administered in accordance with the method of the invention Lucentis should be provided in either about 300 or about

500 microgram doses for four doses.

Macugen^® (pegaptanib sodium, anti-VEGF aptamer or EYE001) made by 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. When administered in accordance with the method of the invention Macugen^® should be provided in a dose ranging from either about 0.3 mg to about 3.0 mg every four or six weeks.

Illustrative compounds that are included within the scope of the above classes of compounds include: (a) 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®

(diclofenac potassium) (Novartis); CELEBREX® (celecoxib) (Searle Monsanto); CLINORIL® (sulindac) (Merck); DAYPRO® (oxaprozin) (Pharmacia Pfizer); DISALCID® (salsalate) (3M); DOLOBID® (salicylate) (Merck); EC NAPROSYN® (naproxen sodium) (Roche); FELDENE® 20 (piroxicam) (Pfizer); INDOCIN® (indomethacin) (Merck); LODINE®

(etodolac) (Wyeth); MOBIC® (meloxicam) (Boehringer Ingelheim); MOTRIN® (ibuprofen) (Pharmacia Pfizer); NAPRELAN® (naproxen)(Elan); NAPROSYN® (naproxen) (Roche); ORUDIS® (ketoprofen) (Wyeth); ORUVAIL® (ketoprofen) Wyeth; RELAFEN® (nabumetone) (SmithKline); TOLECTIN® (tolmetin sodium) (McNeil); TRILISATE® (choline magnesium trisalicylate) (Purdue Fredrick); and VIOXX® (rofecoxib) (Merck);

(b) 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;

(d) Parasympathomimetic agents;

(e) Psychotherapeutic agents;

(f) Major tranquilizers such as chlorpromazine HCI, clozapine, mesoridazine, metiapine, reserpine, thioridazine and the like;

(g) Minor tranquilizers such as chlordiazepoxide, diazepam, meprobamate, temazepam and the like; (h) Sedative-hypnotics such as codeine, phenobarbital, sodium pentobarbital, sodium secobarbital and the like; (i) Steroids such as testosterone and testosterone propionate; sulfonamides; sympathomimetic agents; (j) Vitamins and nutrients such as the essential amino acids;

(k) Anti-migraine agents such as mazindol, phentermine and the like; (I) Antispasmodics such as atropine, methscopolamine bromide and the like; (m) Electrolyte replacements such as potassium chloride; (n) Ergotalkaloids such as ergotamine with and without caffeine, hydrogenated ergot alkaloids, dihydroergocristine methanesulfate, dihydroergocornine methanesulfonate, dihydroergokroyptine methanesulfate and combinations thereof; (o) Alkaloids such as atropine sulfite, Belladonna, hyoscine hydrobromide and the like; (p) Analgesics; narcotics such as codeine, dihydrocodienone, hydromorphine, meperidine, morphine and the like;

(q) Narcotic antagonists such as naltrexone and naloxone and the like; (r) Non-narcotics such as salicylates, aspirin, acetaminophen, d- propoxyphene and the like; (s) Anti-convulsants such as mephenytoin, phenobarbital, trimethadione;

(t) Anti-emetics such as thiethylperazine; antihistamines such as chlorophinazine, dimenhydrinate, diphenhydramine, perphenazine, tripelennamine and the like;

(u) Anti-inflammatory agents such as hydrocortisone, prednisolone, prednisone, non-hormonal agents, allopurinol, aspirin, indomethacin, phenylbutazone and the like; (v) immunomodulators such as alpha interferon, beta interferon, gamma interferon, interleukin-2, interIeukin-3, tumour necrosis factor, and the like; and (w) 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 Therapy

According to the invention the person skilled in the art will appreciate that 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). Accordingly, administration of radionuclide doped particles or materials may be by any suitable means, but preferably by delivery via the relevant artery. For example, in treating liver cancer, 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.

The radioactive particles or materials 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 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.

In one particular form of the invention the radioactive particles or materials are prepared as polymeric particles. In another form of the invention the microparticles are prepared as ceramic particles (including glass). In another, they are prepared from chitosan. In another they are formed of yttria. In another they are formed substantially from silicon. In another they are formed from proteins. In another they are formed from antibodies.

Where the 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 dθscription 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.

Where the radioactive particles or materials are based on silicon 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.

Where the radioactive particles or materials are based on yttria, the radionuclide will preferably be stably incorporated into the yttria matrix or coated onto the surface.

Where the radioactive particles or materials are ceramic particles (including glass) the selected particles will usually possess the following properties.

(1) They will generally be biocompatible, such as calcium phosphate-based biomedical ceramics or glass, or aluminium-boro silicate glass, or silicate based glass.

(2) They will generally comprise a radionuclide 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.

(3) Third, they must be of a suitable size. 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. By way of example, 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.

The term 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. A person skilled in the art will, however, appreciate that the 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.

In a third aspect, 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. Preferably, 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. In a highly preferred form of the invention 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. Preferably such agents will include one or more alternate chemotherapeutic agents, anti-angiogenesis agents or other anti-cancer agents. Such agents will include but will not be limited to 5-FU, LV, oxaliplatin, capecitabine and antibodies directed against EGF and VEGF.

In a fourth aspect, 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. Preferably, 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. In a highly preferred form of the invention 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. Preferably such agents will include one or more alternate chemotherapeutic agents, anti-angiogenesis agents or other anti-cancer agents. Such agents will include but will not be limited to 5- FU, LV, oxaliplatin, capecitabine and antibodies directed against EGF and VEGF.

In a fifth aspect the invention 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. Preferably, 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.

EXAMPLES

Further features of the present invention are more fully described in the following non-limiting example. It is to be understood, however, that this detailed description is included solely for the purposes of exemplifying the present invention. It should not be understood in any way as a restriction on the broad description of the invention as set out above.

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.

In this demonstration of the unexpected and synergistic effect of SIRT plus irinotecan, two different experiments were performed in patients with advanced colorectal liver metastases. All patients underwent a pre-treatment CT scan of the whole abdomen and either a CT scan of the chest or chest X-ray and blood tests to assess haematologic, renal and liver function and serum CEA. Patients treated with SIRT underwent a trans-femoral hepatic angiogram to assess the arterial anatomy of the liver and to plan the subsequent administration of SIR-Spheres^®. In both experiments patients received SIR-Spheres^® (at the calculated patient dose) implanted one day after the first day of administration of chemotherapy in cycle one. 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.

Patients were followed with three monthly clinical evaluation, three-monthly CT scans of the abdomen and either a plain X-ray or CT scan of the chest and monthly serologic tests of haematologic, liver and renal function and CEA. Patients found to have obtained a complete (CR) or partial (PR) response on CT scan had a second confirmatory CT scan at not less than 4 weeks after the initial scan that showed the response.

Response was determined using 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. Once 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

Journal of Cancer, 91 :1434].

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/m² 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/m² 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/m² 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/m² of body surface area.

Results: The initial follow up of patients was limited but there was sufficient early evidence to show that an unusually large percentage of patients were responding to treatment with this combination. The toxicity profile was low with one patient experiencing a grade 3 and two patients experiencing a grade 4 toxicity event. This toxicity profile is low in comparison with other chemotherapy regimens. The following table 1 shows that 15 of the patients had an elevated serum carcinoembryonic antigen (CEA) level before treatment and had at least one post-treatment CEA level performed. CEA is a tumour antigen and is widely used to determine response to treatment in cancer patients with an increasing CEA level signalling tumour growth and a falling CEA level signally tumour regression.

* patients had known extra-hepatic cancer at time of treatment

Table 1

All 15 patients with an elevated serum CEA level before treatment and in whom follow-up CEA levels were available had a substantial fall in serum CEA levels following treatment with SIRT plus irinotecan. The median fall was 87% for all patients. In 5 of 8 patients in whom there was no extra-hepatic cancer at the time of treatment, the CEA level fell into the normal range. These results are extra¬ ordinarily positive and far greater than recorded for similar patients treated with second or third line chemotherapy and also far greater than for patents treated with SIRT alone. The results are even more remarkable because the dose of irinotecan was suboptimal for the great majority of patients.

Once follow up of the patients was complete, the results showed that an unusually large percentage of patients responded to treatment with this combination. The toxicity profile was comparable to that of irinotecan alone as can be seen with the trial summary and the irinotecan registration trial summary. Table 2 below compares the comparative toxicity of this dose escalation study with the toxicity values from the company product sheet.

Table 2

Outcomes from treatment also met with unusually favourable outcomes. The RECIST response from this dose escalation trial resulted in 48% of patients recording a 'partial response' (a reduction in tumour length of 30% and no tumour growth elsewhere in the body). 39% of patients experienced 'stable disease' while only 13% experienced progressive disease. This RECIST response level is well above the standard outcomes expected from this form of chemotherapy treatment alone, where a RECIST response of 5 - 11% has been reported in a phase III clinical trial setting.

Response to treatment can also be shown by an analysis of the cancer marker known as carcinoembryonic antigen (CEA). CEA is a tumour antigen and is widely used to determine response to treatment in cancer patients with an increasing CEA level signalling tumour growth and a falling CEA level signally tumour regression. 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. These results are extra-ordinarily positive and show far greater reductions in CEA levels than are normally recorded for similar patients treated with second or third line chemotherapy and also far greater than for patents treated with SIRT alone. The results are even more remarkable because the dose of irinotecan was suboptimal for the great majority of patients.

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). In this study, the median time to disease progression is currently 6.1 months anywhere in the body or 8.25 months in the liver.

Median survival has also been noticeably influenced for patients with this treatment modality. Contemporary phase III trial survival data yields a median survival of 6.4 - 9.4 months for this body of patients (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). Median survival for those receiving SIR-Spheres and irinotecan is currently 13.6 months. With just under half of the patients still alive, this median value cannot shrink but will continue to grow, with a theoretical maximum of 17.3 months which is a level of survival normally reserved for 1^st line patients with best possible treatment options.

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/m² IV bolus) plus LV (20mg/m² body surface area IV bolus) plus irinotecan 25mg/m² IV infused over a 90 minute period weekly for 2 weeks and repeated every 3 weeks. From cycle three onwards, the irinotecan dose may be increased up to a maintenance dose of 100mg/m² IV for 2 weeks every 3 weeks, provided the toxicity profile allowed. SIR-Spheres^® (at the calculated patient dose) were implanted 1 day after the first day of administration of chemotherapy in Cycle one. The next three patients were treated with a similar chemotherapy regimen, except that the dose of irinotecan was increased to 50mg/m² 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/m² of body surface area. This study is ongoing.

Results: Follow up of patients is limited at this time but there is sufficient early evidence to show that an unusually large percentage of patients are responding to treatment with this combination. As with patients in Experiment 1 , the toxicity profile is moderate with only three patients experiencing grade 3 toxicity. The following table 3 shows that 8 of the 11 patients had an elevated serum carcinoembryonic antigen (CEA) level before treatment and all least one post- treatment CEA level performed. All 8 patients had at least a 50% fall in serum CEA levels following treatment with a median fall in CEA of 78%.

patients had known extra-hepatic cancer at time of treatment.

Table 3

DISCUSSION: 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.

Until now there has been no evidence that combining a local therapy such as SIRT with a systemic chemotherapy regimen would result in any advantage over using either treatment alone. However it is well known that not all patients respond to treatment with SIRT and it would be of benefit for patients if the combination resulted in a enhanced rate of tumour regression that would translate into patient benefit.

The experiments described above have shown for the first time that by combining a local treatment (SIRT) with a systemic chemotherapy regimen does greatly improve the response rate of patients who are otherwise considered to be very difficult to treat. The fact that 48% of patients who had already proved refractory to previous chemotherapy responded positively (with a reductionin excess of 30% of the baseline tumour length) to treatment with the combination of SIRT plus irinotecan is extraordinary and unexpected.

Having thus described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification and examples. It is intended that the specification, including the examples, is considered exemplary only, with the scope and spirit of the invention being indicated by the claims which follow.

Claims

The claims defining the invention are as follows

1. 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.

2. 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.

3. The method according to either claim 1 or 2 wherein the cancer is liver cancer, colorectal cancer, cancer of the brain, cancer of the kidney, cancer in other soft tissues, or bone sarcomas.

4. The method according to either claim 3 wherein the cancer is selected from the group comprising: primary liver cancer, secondary liver cancer, secondary liver cancer deriving from the gastrointestinal tract, secondary liver cancer deriving from colorectal cancer.

5. A method according to anyone of the preceding claims wherein irinotecan therapy is co-administered with SIRT.

6. A method according to anyone of the preceding claims wherein irinotecan therapy is given parenterally at a dose of about 10 mg/m² to about 250 mg/m².

7. A method according to anyone of the preceding claims wherein irinotecan therapy is given parenterally at a dose of about 20 mg/m² to about 150 mg/m².

8. A method according to anyone of the preceding claims wherein irinotecan therapy is given parenterally at a dose of about 50 mg/m² to about 100 mg/m².

9. A method according to anyone of the preceding claims wherein irinotecan therapy is initially given to the patient at a relatively low dose and then that dose is increased to a higher maintenance dose as the patient's body learns to accommodate the therapy.

10. A method according to anyone of the preceding claims wherein said method includes 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.

11. A method according to anyone of the preceding claims wherein said method includes the step of: (a) administering to the patient a therapeutically effective amount of an agent that aids in the treatment of cancer.

12. A method according to claim 11 wherein agent is LV.

13. A method according to claim 11 wherein the agent is selected from the group comprising: 5-FU, etoposide, paclitaxel, doxorubicin, vincristine, etoposide, 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.

14. 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.

15. A method according to claim 14 wherein irinotecan therapy is given parenterally at a dose of about 10 mg/m² to about 250 mg/m².

16. A method according to claim 14 wherein irinotecan therapy is given parenterally at a dose of about 20 mg/m² to about 150 mg/m².

17. A method according to claim 14 wherein irinotecan therapy is given parenterally at a dose of about 50 mg/m² to about 100 mg/m².

18. A method according to claim 14 wherein 5-FU is administered intraperitoneally at a dose of 100 and 600mg/m².

19. A method according to claim 14 wherein 5-FU is administered intraperitoneal^ at a dose of between 200mg/m² and 500mg/m².

20. A method according to claim 14 wherein 5-FU is administered intraperitoneal^ at a dose of between 300 and 480mg/m².

21. A method according to claim 14 wherein 5-FU is administered intraperitoneal^ at a dose of between 400mg/m² and 450mg/m².

22. A method according to claim 14 wherein LV is administered intraperitoneal^ at a dose of about one twentieth of the dose of 5-FU.

23. A method according to any one of the preceding claims wherein said method includes the step of: (a) administering to the patient a therapeutically effective amount of an agent that provides a secondary therapeutic benefit to the patient.

24. A method according to claim 23 wherein the agent is 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; electrolyte replacements; ergotalkaloids; alkaloids; analgesics; narcotics; narcotic antagonists; non-narcotics; anti¬ cancer agents; anti-convulsants; vitamins; health supplements; immunomodulators; drugs to promote or to stimulate bone marrow production and or drugs to suppress bone marrow production; cytokines; vitamins; or health supplements.

25. A therapeutic composition for use in anticancer treatments comprising: a therapeutically effectively amount of irinotecan and an amount of radionuclide- doped agents suitable for SIRT to effectively treat cancer.

26. A therapeutic composition according to claim 25 wherein the composition includes irinotecan at a dose of about 10 mg/m² to about 250 mg/m².

27. A therapeutic composition according to claim 25 wherein the composition includes irinotecan at a dose of about 20 mg/m² to about 150 mg/m².

28. A therapeutic composition according to claim 25 wherein the composition includes irinotecan at a dose of about 50 mg/m² to about 100 mg/m².

29. A therapeutic composition according to any one of claims 25 to 28 wherein the composition includes 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.

30. A therapeutic composition according to claim 29 wherein the agent is LV.

31. A therapeutic composition according to claim 30 wherein the composition also includes a chemotherapeutic agent.

32. A therapeutic composition according to claim 30 wherein the chemotherapeutic agent is selected from the group comprising: 5-FU, etoposide, paclitaxel, doxorubicin, vincristine, etoposide, 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.

33. A therapeutic composition for treating cancer or a tumour in a patient, said composition comprising: (a) a therapeutically effective amount of each of 5- FU, LV and irinotecan; and (b) an amount of radionuclide-doped agents suitable for SIRT to effectively treat cancer.

34. A composition according to claim 33 wherein irinotecan is present at a dose of about 10 mg/m² to about 250 mg/m².

35. A composition according to claim 33 wherein irinotecan is present at a dose of about 20 mg/m² to about 150 mg/m².

36. A composition according to claim 33 wherein irinotecan is present at a dose of about 50 mg/m² to about 100 mg/m².

37. A composition according to claim 33 wherein 5-FU is present at a dose of 100 and 600mg/m².

38. A composition according to claim 33 wherein 5-FU is present at a dose of between 200mg/m² and 500mg/m².

39. A composition according to claim 33 wherein 5-FU is present at a dose of between 300 and 480mg/m².

40. A composition according to claim 33 wherein 5-FU is present at a dose of between 400mg/m² and 450mg/m².

41. A composition according to claim 33 wherein LV is present at a dose of about one twentieth of the dose of 5-FU.

42. A therapeutic composition according to any one of claims 29 to 41 wherein the composition includes an agent that provides a secondary therapeutic benefit to the patient.

43. A therapeutic composition according to claim 42 wherein the agent is 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; electrolyte replacements; ergotalkaloids; alkaloids; analgesics; narcotics; narcotic antagonists; non-narcotics; anti-cancer agents; anti-convulsants; vitamins; health supplements; immunomodulators; drugs to promote or to stimulate bone marrow production and or drugs to suppress bone marrow production; cytokines; vitamins; or health supplements.

44. 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.

45. A kit for treating cancer in a patient, said kit comprising a therapeutically effective amount of irinotecan and an amount of radionuclide-doped microparticles suitable for use in SIRT for treatment of a cancer.

46. The kit according to claim 45 which further comprises instructional material for using the kit.

47. A method according to any one of claims 1 to 24 and as hereinbefore described in the description on the specification.

48. A composition according to any one of claims 25 to 43 and as hereinbefore described in the description on the specification.