TWI307628B - Use of zd0473 in combination with a non-platinum based anti-cancer agent - Google Patents

Description

1307628

The present invention relates to a therapeutic combination product and a kit comprising a sterically hindered platinum coordination compound and a non-platinum anticancer combination, and a sterically hindered platinum coordination compound, a non-platinum based A pharmaceutical composition in combination with an anticancer agent and a pharmaceutically acceptable carrier or diluent. The present invention also relates to a method of inhibiting the growth of human tumor cells that are afflicted with tumors, comprising administering to such persons an effective amount of a therapeutic combination of the invention and a pharmaceutical composition for inhibiting tumor cell growth. The invention also relates to the use of a combination of a sterically hindered platinum coordination compound and a non-platinum-based anticancer agent for the manufacture of a medicament for inhibiting the growth of human tumor cells that are afflicted with tumors. Cisplatin, also known as cis-dichloro-diamine platinum (11), has been used as a chemotherapeutic agent for the treatment of malignant tumors in humans for many years and has a very broad spectrum of activity. Although cisplatin has been reported to have antitumor activity in the treatment of some tumors such as sputum malaria and ovarian cancer, the strong side effects such as renal damage, and nausea & vomiting are unacceptable at an early stage. These side effects have been reduced to a certain extent (for example, when nephrotoxicity is used for hyperhydration with isotonic saline, a Category 3 serotonin (5-HT3) antagonist is used first for nausea & vomiting), but There is a significant synthetic drive for the development of a platinum analog with a more acceptable toxic form. Recently, the initial analogs such as carb〇platin (cis-diamine-1,1_cyclobutanedicarboxylic acid platinum (II)) have been shown to be useful as a chemotherapeutic agent in the treatment of various human solid malignancies. Its efficacy. Although carboxyplatinum has lower neurotoxicity and lower nephrotoxicity than cisplatin, it is significantly more spinally toxic than cisplatin. However, although platinum-based agents like cisplatin and carboxyplatin have been widely used -4

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1307628 A7 _____B7 V. Invention description (2) Applied to human body as a chemotherapeutic agent, but it is not effective for all patients, and it cannot inhibit all Type of solid tumor. In addition, the tolerance and resistance of tumors to cisplatin represents a major resistance to successful treatment. This resistance is often considered to be intrinsic (ie, produced at the onset of treatment (ie, in the course of chemotherapy). A typical example of a tumor that exhibits intrinsic resistance to chloramphenicol is colon cancer and Non-small cell lung cancer is often observed in patients with Indian and small cell lung cancer. As mentioned earlier, a key goal for the development of modified cisplatin/carboxyplatin is to overcome drug resistance. The observation that an agent made by substituting an amine ligand with a diaminocyclohexane (DACH) group is active against a cisplatin-resistant cell line results in the development of a range of such agents. Among them, Oxley (oxaliplatin) alone or in combination with 5 _fluorouracil (5 _ F u ) shows activity against advanced colorectal cancer. However, oxaliplatin causes a peculiar neurotoxic pattern, including exposure Facial sensation induced by hypothermia. Peripheral sensory neuropathy may also occur. In addition to neurotoxicity, the drug does not cause significant nephrotoxicity, and oxaliplatin is treated in the late stage of treatment. There is also some progress in cancer. Therefore, although some progress has been made in overcoming cisplatin resistance and reducing toxic side effects, there is still a lack of a clinically important cancer showing antitumor activity in the field of platinum anticancer drugs. And has an acceptable toxic form of the drug" and, currently, the results of chemotherapy treatment for cancer patients are not satisfactory. There are many practices to overcome cisplatin resistance, and platinum-related toxicity Prevention also attracts significant interest. Ship-based chemotherapy is often used in the treatment of various cancers - this paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1307628 A7 B7 V. Description of invention (3) One or more drugs. For example, for most patients with SCLC, cisplatin and etoposide are the preferred choices for combination chemotherapy. Carboplatin can replace cisplatin without loss of efficacy. Sexually transmitted diseases, the addition of radiation therapy to standard chemotherapy to improve survival is very limited, and for extensive disease, radiation Treatment does not improve survival, but it has an extremely important role in alleviating the condition. Another useful combination is cisplatin plus paclitaxel, which is used in the treatment of advanced ovarian cancer. It can improve the efficacy, but the unacceptable toxicity patterns and other difficulties caused by previous platinum-containing anticancer agents, such as the order of various treatments, and the need for infusion, make the combination therapy less satisfactory. It is necessary to increase the activity of known chemical combination therapies using platinum compounds to inhibit tumor cell growth and/or to provide a means to reduce the dose of chemical drugs to reduce adverse effects on patients or potentially toxic side effects. . Although ideal synergists are rare in the treatment of cancer treatments. The invention of the light combination therapy product, the use of the drug compound and the method of the method are very necessary. (SP-4-3)-cis-amine dichloro-[2-methylpyridinium]platinum (π), hereinafter referred to as ZD0473, is a novel hindered platinum complex that was developed to overcome intrinsic or The later-produced resistance to cisplatin [ZD0473] is described in US 5,665,771, which states: "The complex of the invention can be used alone or in combination with other chemotherapeutic agents such as cisplatin, monotherapy , or staged treatment, or as part of a combination therapy with other drugs, used to inhibit or eliminate various side effects 'toward bioavailability, can also be combined with other treatments -6 - This paper scale applies to Chinese National Standards (CNS) A4 size (210 X 297 mm) 1307628 A7 ______B7 V. Description of the invention (4) The method is used in combination with laser treatment, etc. In this US 5,665,771, there is no mention of the binding of any complex of the present invention to other therapies. Can produce amazingly beneficial effects. The 35th American S() eiety of Clinical Oncologists meeting held in Atlanta in May 1999 mentioned the results of the first phase of the experiment on ZD0473 alone, indicating the dose-limiting toxicity of ZD〇473 For bone marrow suppression 'but no signs of kidney or neurotoxicity. For ZD0473, neutropenia and thrombocytopenia can be observed' but patients who recover quickly and who have not received prior treatment for heavy doses can receive three Mondays Secondary treatment. For the study of perennial anemia and thrombocytopenia, there is no clinically relevant evidence of peripheral neurotoxicity, ototoxicity or nephrotoxicity. Ototoxicity may be a problem, especially when using cisplatin. Because it is often irreversible. The recommended dose and schedule for the second phase is initially 12 mg/m2 every three weeks. Patients who have taken a large amount of cytotoxic agents that can destroy bone marrow stem cells are likely to need to reduce their dosage and cannot The drug is tolerated every three weeks. However, some patients are able to receive larger doses, such as 15 mg/m2 (see recommended dosage) or higher. For various comorbidities. Patients including small cell & non-small cell lung cancer, nasopharyngeal carcinoma, head and neck, breast cancer and ovarian cancer have observed anti-tumor Evidence of activity. ZD〇473 is being studied to determine the maximum level of drug that can be safely administered to patients, to explore how the drug is disposed of by the body, and to determine the nature of dose-limiting toxicity. We are now surprised and surprised to find this. A special compound Ζ〇〇473 is used in combination with a non-platinum-based anticancer agent. Zd〇473 is used alone. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1307628 A7 ___B7_ V. Description of invention (5)

A significantly better anticancer effect (anti-cell proliferation) with or without an anti-cancer agent based on the initial. It is understood that those who are also covered by the definition of the special compound ZD0473 are prodrugs capable of producing the ZD0473 species in vivo (e.g., Pt(IV) tri-alkyl, monochloro, monoamine prodrug of ZD0473). A preferred embodiment of the invention relates to a hindered platinum coordination compound (S p _ 4 _ 3 ) _ (cis-amine digas _ [ 2 _methylpyridine] starting (II). We believe ZD0473 (and similar The sterically hindered platinum (Pt(II) & Pt(IV)) is a mis-synthesis in which the 2-methylpyridine ligand of zd〇473 is substituted by another amine as described in US 5,665,771. US 5,665,771 The relevant definitions and examples are incorporated herein by reference) to have a highly desirable activity and side effect profile that is lacking in current platinum-cytotoxic combination regimens, making them particularly suitable for combination with non-platinum-based anticancer agents. A particularly useful combination is a combination of ZD0473 with a favorable myelosuppressive state but no significant neurotoxicity and nephrotoxicity.

For example, it has now been found that when a sterically hindered platinum coordination compound such as ZD 〇 473 is used in combination with other non-platinum chemotherapeutic agents, it has therapeutic benefit, thereby potentially increasing tumor suppression compared to the individual use of each component. Cell growth activity. At the same time, it has been observed that these benefits may result in the need to use less or less of the platinum-based anti-cancer agent and/or other non-platinum-based anticancer agents relative to each component. In some cases, when the combination confers a protective effect on normal (non-tumor) cells, it may result in a higher tolerance agent. The FP may be administered at a higher dose of each component or both components. ZD〇473 has a special pro-toxic form (including favorable neurotoxicity and nephrotoxicity) that allows it to be effectively combined with other non-initial-based anticancer agents, which are not platinum-based Cancer agent due to its own toxicity -8 - I paper scale 逋 ϋ 家 S fresh (CNS) A4 specifications (21G X 297 mm) --------- _ 1307628 A7 ___B7 V, invention description (6 The ~) ~ type limits the potential of the combination (for example: Taxol (Tax〇l) is dose-limited due to its neurogenicity and its combination with earlier platinum agents). The benefits of the invention may be demonstrated by appropriate in-vitro experiments or improved in vivo performance (e. g., evidence of improved toxicity or thrombocytopenic effect compared to monotherapy or combination with prior to difficult). As mentioned above, drugs such as cisplatin and carboplatin have been widely used in the treatment of refractory tumors such as lung cancer, ovarian cancer, and testicular cancer. Many of these tumor cells are initially reflected in platinum-based therapies, but in most cases tumor cells become resistant and relapse. ZD0473 θ is to overcome this resistance to the drug, and thus to produce an extended range of anticancer activity. In vivo studies of human tumor xenografts have demonstrated that the activity of ZD0473 is at least comparable to that of cisplatin and, in some cases, to cisplatin. It is also active against cisplatin-resistant CH1 ovarian tumor xenografts that progress even in cisplatin treatment. When the drug is administered orally, the ADJ/PC6eisR tumor is acquired in an anti-mouse tumor with anti-animal activity and is completely resistant to other drugs, and some activities can also be seen. A human tumor cell line showing a range of sensitivities and a corresponding cell line that develops resistance after administration of cisplatin has been subjected to ZD0473 and confirmed to overcome cisplatin resistance from different mechanisms. Also, good activity was observed in cell lines that were treated to have relatively high levels of glutathione or metallothioneins. Interestingly, in addition to the reduced sensitivity to glutathione inhibition, ZD0473 has also been shown to be resistant to cisplatin due to reduced uptake -9 - this paper scale applies to Chinese national standards ( CNS) A4 size (210X297 mm) 1307628 A7 !_-__B7 V. The 41MCisR ovary cell line of the invention (7) has the ability to overcome this resistance. Studies of the nature of ZD0473 and DNA interactions have found that the sequence specificity of the formation of DNA adducts differs from the presence of unique ZD〇473 binding sites. Therefore, another benefit of the present invention is a sterically hindered platinum. Coordination compounds such as ZD0473 can be combined with other non-platinum chemicals to produce therapeutically effective tumor cell growth in tumors and cell lines that are resistant or insensitive to other platinum (non-sterically) coordination compounds. Inhibition activity. Combination therapy involving potentially ineffective platinum-based coordination compounds can now be used in conjunction with sterically hindered platinum coordination = for example ZD0473. Thus, second-line treatment of patients who may previously be considered to be likely to benefit from combination therapy with platinum-based coordination compounds can now be treated with combination therapy with a sterically hindered platinum compound such as ZD0473. Accordingly, the present invention provides a combination therapeutic product comprising a sterically hindered coordination compound and a non-initial-based anticancer agent suitable for simultaneous, sequential or separate use. Preferably, the components of the composition are used simultaneously and/or separately so that the drug can be delivered simultaneously (i.e., simultaneously exposed) to the drug. The standard techniques can be used to readily determine whether the components are present in the body simultaneously. a further aspect of the invention provides a kit comprising a hindered platinum coordination compound of the invention and a non-platinum-based anticancer agent. According to another aspect of the invention, a kit is provided comprising: a) a sterically hindered platinum coordination compound in a first unit dosage form; b) in the second unit dosage form - the species mentioned herein are not -10-. The paper scale applies to the Chinese national standard ( CNS) A4 specification (21〇x 297 DON) 1307628 A7

1307628

A further combination of a sterically hindered platinum coordination compound and a non-platinum-based anticancer agent. According to another aspect of the invention, there is provided a method of producing an anti-cancer effect in a warm-blooded animal, such as a human, comprising administering a therapeutic combination or a pharmaceutical composition as defined herein. In the various aspects of the invention described above, a preferred sterically hindered coordination compound is ZD0473. According to another aspect of the invention, a combination therapy is provided which comprises administering to a warm-blooded animal, such as a human, in need of such treatment. An effective amount of ZD 〇 473 is administered as needed with a pharmaceutically acceptable excipient and carrier, and at the same time, a non-platinum-based anticancer agent as defined herein is administered sequentially and separately. According to another aspect of the invention, the utility of the method of treatment of the invention is expected to occur at least in combination with the utility of the various components used alone in the treatment, i.e., ZD0473 and the preferred non-platinum-based anticancer drug described herein. The sum of the effects is equal. "When the combination contains both drugs for the same stage of the same tumor cell and / or cell cycle, this addition is even more surprisingly beneficial. According to another aspect of the present invention, the therapeutic effect of the present invention is expected to be greater than the sum of the effects obtained by using the various components used alone in the treatment, i.e., the individual effects of ZD0473 and the preferred non-platinum-based anticancer drugs described herein. Sum. This synergy is even more surprising when the MTD level is lower than using each drug separately. When normal cells can tolerate higher doses of either or both components than tumor cells (ie, show greater antagonisticity) -12- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Binding

K- 1307628 A7 _____B7 n Explain (10) ' ~ , you can observe this benefit. Combination therapies as defined herein may be used as mono-therapies, and may include surgery and/or ionizing radiation therapy in addition to the combination therapies of the invention. Surgery can include partial or total tumor resection before, during, or after the combination therapy described herein. The combination therapy of the present invention is expected to be useful for the prevention and treatment of a wide variety of disease states such as lung cancer (SCLC or NSCLC), mesothelioma, ovarian cancer, breast cancer, uterine cancer, bladder cancer, prostate cancer, testicular cancer, pancreatic cancer, head and neck Cancer and liver cancer, Kaposi's sarcoma, lymphoma (NHL), leukemia, and other cell proliferative diseases such as psoriasis, arthritis, and fibrosis (such as the lungs), the combination therapy of the present invention is expected to be usefully Slowing the growth of primary and regenerative tumors such as, but not limited to, GI/stomach, colon, rectum, breast, prostate, lung, testicle, skin, bone, sarcoma, and kidney cancer. The ion radiation employed in a particular embodiment of the invention may be xenon, r, or stone. The dose of ionizing radiation is a known amount in clinical radiation therapy. The radiation treatment employed includes r-rays, x-rays, and/or radiation directly from the radiation isotope. The invention also encompasses forms of DNA destructive factors such as microwaves and light shots. These factors are likely to contribute to a wide range of damage to DNA, DNA precursors, DNA replication and repair, and chromosome assembly and maintenance. For example, the dose of X-ray per sputum is 18_2 〇 Gy, and the course of treatment is 5-6 weeks, 5 days a week. Usually a complete divided dose is in the range of c Gy. A single larger dose, such as 5_1 〇 Gy, can be administered as part of the radiation therapy process. A single dose can be administered during surgery. Highly separable radiation therapy can be used, whereby small doses can be applied regularly over a period of time. • 13- This paper scale applies to China National Standard 4 (21〇χ297 mm) Ϊ307628

The line 'e, for example, in a few days per hour (U Gy. The range of doses of radioisotopes varies widely depends on the half-life of the isotope, the intensity and type of radiation emitted, and the uptake rate of the cells. " sterically hindered platinum coordination The term "compound" means any of the tumor cell growth inhibiting sterically hindered platinum coordination compounds described and encompassed in us 5,665 77 (the compounds of this patent, and their preparation, which are incorporated herein by reference) The preferred sterically hindered platinum coordination compound is ZD0473 » "non-platinum-based anticancer agent." We mean a platinum-free compound with anticancer and/or antiproliferative activity, especially A compound or drug selected from the following classes: 1 _ camptothecin analog compound' is any tumor cell growth inhibitory compound that is structurally similar to camptothecin and inhibits topoisomerase I; Or a podophyllotoxin analog compound that inhibits valence isomerase 或 or an analog compound that inhibits smectin I and 11. Suitable camptothecin analogs Including, but not limited to, pure topoisomerase I inhibitors such as Topotecan 'Irinotecan', 9-aminocamptothecin, Rubitecan and Ike Exatecan (DX-8951f); mixed valence isomerase I and topoisomerase inhibitors such as XR-5000 and XR·11576; and appropriate pure valence isomerase inhibitors The podophyllin analog compounds include, but are not limited to, Etoposide and Teniposide. Such compounds also include, but are not limited to, referenced in WO 9393782 and the references mentioned herein. Any tumor cell growth inhibitory camptothecin analog disclosed or described in the literature. Applicable to Chinese Painter Standard (CNS) A4 Specification (210X297) in US Patent-14- This paper scale

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Line 13076 Correction 9G112G94 Patent Application Chinese Manual Replacement Page (May 96)

A7 B7 V. Description of the invention (12) 5,0,4,758 and European Patent Application Publication No. 321,122 for Topotecan (including its pharmaceutically acceptable salts, hydrates and solvates) The preparation and oral or parenteral pharmaceutical compositions containing Topotecan and an inert pharmaceutical acceptable carrier or diluent are described in detail. 2. Taxanes, such as taxol (paclitaxel) or Taxotere (docetaxel) ° 3 · Growth factor receptor inhibitors such as proteins - Kinase inhibitors, such as steroidal tyrosine kinase inhibitors, such as Iressa (ZD1839), and growth factor function inhibitors (such growth factors include platelet-derived growth factor and hepatocyte growth factor and such inhibitors include growth factors Antibodies, growth factor receptor antibodies and serine/threonine kinase inhibitors). Cell cycle kinase inhibitors such as CDK-2, CDK-4 and CDK-6 are also included. 4. Antimetabolites such as 5-FU, SI, UFT, Capecitabine; thymidine synthetase inhibitors such as Tomudex or ZD933 1 ' or LY23 15 14 (MTA, Pemei Pemetrexed) or Gemcitabine ' or anti-folate such as Methotrexate. 5. Vinca alkaloids such as vinorelbine (Nifebine), Vinclilbine (Navelbine), Vincent (Vincristine), Vinblastine (Vinblastine) or Vindesine (Vindesine). An anti-angiogenic compound, as mentioned in International Patent Application Publication No. WO 97/22596, WO 97/30035, WO 97/32856, WO 98/13354, WO 00/21955 and WO 00/47212. 70972-960507.DOC -15- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1307628 A7 B7 V. Description of invention (13) 7. Alkylation agent such as Melphalan , cyclophosphamide, Ifophamide or nitrosamine, such as Carmustine or Lomustine. 8 · Anthracyclin such as Doxorubicin, pirimibin (£1^1^丨(^11), idabisin (1 (1&1:111) to 11) or Doxil hydrochloride. 9. Anti-HER-neu compounds, such as Herceptin 10. Cell growth inhibitors such as antiestrogens (eg tamoxifen 'toremifen ( Toremifene), raloxifene, droloxifene 'iodoxyfene', progesterone (eg megestrol acetate), aromatase inhibitor (eg Anastazole, letrazole, vorazole, exemestane, antiprogestin, antiandrogen (eg, Hutamide, Nie Nilutamide, bicalutamide, cyproterone acetate, LHRH agonist and antagonist (eg goserelin acetate, lupo ray) (luprolide)), 睪_5<2-dihydroreductase inhibitors (such as non-naminamide) and anti-invasive agents (eg metal eggs) Metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activator receptor function. 11 · Natural or synthetic anti-mitotic agents 12. Interleukin and Interleukins such as TNF 13. Vaccine 14. Ingestion/outflow modulator such as mdr2 -16- This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1307628 A7 B7 V. Description of invention ( 14 ) 15 · Rescue agent 16. C a antagonist. To understand, other platinum agents with different modes of action or available forms (eg BBR3464 or oxliplatin can also be used with ZD0473). The various non-platinum anticancer agents listed above are commercially available and/or can be made by conventional techniques, including those mentioned in the above references. Other formulations such as the above non-platinum-based anticancer agents Poly-proline polymers (made of biodegradable polymers with cytotoxins) and liposome formulations are also included. Preferred non-platinum-based anticancer agents are listed above. Class 1, 2, 3, 4, 5, 6 and 8 It is of the 2, 3, 5 and 8. The above non-platinum-based anticancer agents are particularly suitable for use in the present invention as taxol, topotecan, and gemcitabine. , Navelbine, 'Doxil hydrochloride and 5 - FU. Thus preferred ingredients which can be used in various embodiments of the invention are the sterically hindered platinum coordination compound ZD0473 and are selected from the group consisting of taxol or Topotecan or Gemcitabine or Navelbine. Or a non-platinum-based anticancer agent of doxorubicin hydrochloride (Doxil) or 5-FU. Also preferred are ZD0473 and Taxotere. Another feature of the invention is the proposed triplet combination in which agents having different modes of action are employed (for example, ZD0473 with taxol plus Iressa or Gemcitabine; or ZD0473 plus anthracycline plus avidin) Pharmacy). Another feature of the present invention is to propose a sequence type dual body combination, wherein -17- the paper size is 中国 Chinese National Standard (CNS) A4 specification (210X297 public) 1307628 A7 ______B7 V. Invention Description (15) ~ ~ ~ ~ Different second agents (having different modes of action) are used later (for example, ZD0473 plus yew, followed by zd〇473 plus Gemcitabine) ^If the toxicity of the agents in the combination Where possible, a sequence-type double-body combination is also possible. The term "anti-cancer utility" includes inhibiting tumor cell growth and/or cytotoxicity of tumor cells that are sensitive to the combination products, compositions and treatments of the present invention. Kill. The term "inhibiting tumor cell growth" as used herein refers to inhibiting the growth of tumor cells that are sensitive to the methods of the invention. The anti-cancer effects produced by the use and method of the present invention include, but are not limited to, inhibition of tumor growth, tumor growth retardation, tumor regression, tumor contraction, increased tumor regrowth at the time of treatment, and slowing of disease progression. . When the therapeutic use and method of the present invention is administered to a warm-blooded animal, such as a human, in need of treatment for a cancer, including a solid tumor, the therapeutic use and method will produce a certain treatment & for example, via, for example, one or more of the following The measured person; the degree of anti-tumor effect, the rate of response, the time to progression of the condition, and the survival rate. Preferably, such treatment also results in a decline in tumor growth, i.e., a decrease in tumor size measured. Best of all, this treatment can lead to a complete decline in the tumor. The invention is useful, for example, in elderly, pediatric or kidney or liver damaged patients. The "effective inhibition of tumor cell growth dosage" "effective amount" as referred to herein means that the treatment process can effectively inhibit the growth of tumor cells sensitive to the therapy in cancer patients. Preferably, the treatment process The sterically hindered platinum coordination compound and/or the non-platinum-based anticancer agent may be administered at a lower dose than that required for the administration of the compound as the sole chemical agent. Preferably, the treatment The process can lead to sterically hindered platinum coordination compounds and/or non-platinum-based -18- paper scales applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1307628

The anti-cancer agent's ability to inhibit tumor cell growth is enhanced when these compounds are administered as the sole chemical agent. Particularly preferred is a typical synergistic effect in which the combined utility of the two compounds is greater/optimal than that expected by the two drugs (i.e., greater than the additive effect). It is to be understood that the actual preferred treatment is based on, among other things, the manner in which the compound is administered, the particular formulation of the compound employed, the mode of administration, the particular tumor cell to be treated, and the particular host to be treated, and the like. The optimal course of treatment for a group of conditions can be determined by the use of traditional treatments and trials and readings. β The pharmaceutical composition of the present invention comprises a sterically hindered coordination compound and a non-pin-based anticancer agent as defined herein, and a pharmaceutically acceptable carrier or dilution, to be used in the composition of the present invention. The pharmaceutically acceptable carrier or diluent is well known to those skilled in the art of formulating the compound into a pharmaceutical composition. The present invention is in a form suitable for parenteral or oral administration. These compositions can be formulated with various pharmaceutically acceptable carriers such as physiological saline for intravenous injection or for various injection methods well known to those skilled in the art. Preferably, such pharmaceutical compositions are in the form of a lyophilized mixture of two active ingredients in the unit dosages which may be prepared by conventional techniques, and which may be reconstituted with water or other suitable infusion liquid when administered. It will be appreciated by those skilled in the art that the amount of active ingredient in the pharmaceutical compositions of the present invention will vary widely depending on a number of factors, for example, the desired dosage and the pharmaceutically acceptable carrier employed. For administration, in the pharmaceutical composition of the present invention and other aspects, the ratio of the sterically hindered (tetra) compound to the m-based anticancer agent is 10:1 to 1:1 by weight. Preferably, the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm). Five invention descriptions (17 The combination products and pharmaceutical compositions of the invention contain each of the anti-slip coordination compounds' and each dosage form 5_5,_m == Anticancer agent. Mannitol and, or chlorine, are preferred; the physiological impact of the = or the pharmaceutical composition is established via a buffer known in the art of pharmaceutical formulation. The combination products and compositions may be in a form suitable for oral administration, a medicament or a capsule (suitable enteric shell), such as in the form of a powder or solution, for parenteral injection (including intravenous, subcutaneous, Intramuscular, intraperitoneal, intraperitoneal injection or infusion, such as sterile solution, suspension or milk, for topical use such as ointment or cream, for rectal administration such as test, or route of administration It can be directly injected into the tumor or the zoned or the local delivery. In another embodiment of the invention, the combination therapy can be performed by endoscopy, intratracheal, transluminal, transdermal, intravenous, subcutaneous, peritoneal. Inside or inside the tumor Formal Delivery, In summary, the compounds of the present invention can be prepared in a conventional manner using conventional excipients. The compositions of the present invention are advantageously presented in unit dosage form. The dosage of the treatment required for the therapeutic and prophylactic treatment of a particular disease state will certainly be Depending on the host treated, the route of administration and the severity of the condition to be treated, the optimal dose may be determined by the physician treating any particular patient. For example, it may be necessary or desirable to reduce the Dosage of certain ingredients to reduce toxicity. "administering" or, "administered" as used herein, includes parenteral and/or oral administration. " means intravenous, subcutaneous, intramuscular, or intraperitoneal or infusion. To understand, the actual better -20- This paper scale applies to the Chinese National Standard (CNS) A4 specifications _ (2l 〇 X297 mm 1307628 A7 — B7 V. The method and sequence of the invention (18) will be based on, among other things, the particular formulation used, the particular tumor cells to be treated, and The particular method of administration and the order of mutating for a particular host, etc., can be determined by the skilled artisan using conventional techniques and reading the information set forth herein. In the method of the invention, the steric hindrance Platinum coordination compounds can be administered in the same manner as in previous clinical practice. More specifically, slow intravenous infusion is a commonly used method of ZD0473. In order to improve diuretic's better carrier when using zD0473 It is a glucose/salt solution to which mannitol is added. The draft may also include pre-hydration using a glucose/salt solution to the patient. In the method of the present invention, the dose duration of the sterically hindered platinum complex may be in the course of each course of treatment per square meter. The surface area is based on from about 25 to about 500 mg, for example, for humans 'about 0.4-1 〇 mg/kg. For the method of the invention using zd(R) 473, a preferred dose of ZD0473 is a single dose of from about 30 to about 250 mg ZD0473 at the end of the course of treatment for 1 to 5 consecutive days. The injection of the sterically hindered platinum complex can be administered 丨_2 times per week and repeated weekly treatments, unless contraindications are present. A unit dosage form such as a lozenge or capsule usually contains, for example, from 50 to 600 mg of the active ingredient. A sub-ingredient of zd〇473 (e.g., 30 mg/m2/day for 5 days instead of 15 mg/m2 for one day) can be used, for example, in conjunction with daily radiation therapy. It can be administered in combination with other traditional procedures, such as adjuvant concomitant therapy, GCSF/EPO. Non-platinum-based anticancer agents can be administered according to the following illustrative, but non-limiting, known routes of administration and dosages of the examples. For example, in the method of the present invention, the parenteral administration of a camptothecin analog compound is usually carried out in a range of about 1 to about 5 days in a row for about 1 to about 5 days. CNS) Specifications (2igx Norgong Dong) 1307628 A7 B7 V. Invention Description (19) " - Body surface, accumulation (U to, about 300.0 mg / day, the better in each successive i to about $ days per square The body surface area of the rice is from about 0.1 to about 1 mg/day. Preferably, the treatment for Topotecan is about 1.0 to about 2.0 mg per square meter of body area in about J to about 5 days. Preferably, during the period from 7 days to about 28 days from the start of a treatment, the course of treatment is repeated at least once according to the initial administration schedule and the normal tissue recovery of the person. The treatment course is repeated according to the tumor reaction. Preferably, the parenteral administration of the camptothecin analog compound is a short-time intravenous input (e.g., 30 minutes) and a long-term intravenous input (e.g., 24 hours). The ^-alkali analog compound was administered by intravenous infusion for 30 minutes. The preferred untreated or slightly pretreated patient has a better T-tecan, and the bowel course is a short-term intravenous infusion for a daily dose of 1>5 mg/m 2 body surface area. The initial course of treatment. For patients who have undergone extensive pretreatment, the initial course of thiophene (T〇p〇tecan) is a short-term intravenous infusion of 1 〇 mg per day for 1 to 5 days. Square meter body surface area. When the patient recovers from the drug-related effects of the initial course of treatment, 'according to the tumor response, repeat the intravenous infusion for at least a short period of time in the consecutive mountain days, at least with the same course of the same course of treatment. In the method of the present invention, when a camptothecin analog compound is to be orally administered, the usual course of treatment is about ! to about 5 〇〇〇 mg/billion of body surface area per day for about 5 days. More preferably, The course of treatment for Physician is about 15 to about 5 mg/m 2 of body area per day for about (1) days. Preferably, 7 days from the start of the treatment start date. -22- 1307628 A7 B7 , invention description (20) between 2 and 8 days 'According to the initial administration schedule and the normal tissue recovery of the patient, repeat the treatment at least once. Best, repeat the treatment according to the tumor response. For example, 'Paclitaxel (Paelitaxel) can be administered in a dose of 135-200 mg/m 2 every three weeks for about 24 hours. Alternatively, for example, it can be used at 135-225 mg/m 2 every three weeks. The dose is administered to the paclitaxel during about 3 hours. Alternatively, for example, it is also possible to use a bait age of about 8 hours at a dose of 80-100 mg/m 2 per week for a period of about 1 hour. Even for several weeks, a dose of milligrams per square meter of paclitaxel (paelitaxel) was injected every week for 1 hour. Alternatively, for example, it is also possible to use a dose of 200 mg/m 2 every three weeks for injection into the yew. Alternatively, for example, taxol can be administered to a dose of 12 〇 丨 40 mg/m 2 every three weeks for about 96 hours. For example, docetaxel can be administered according to known routes of administration and dosage. For example, Docetaxel can be administered to a dose of 55_1 mg/m2 every three weeks for about one hour. As noted above, the amount of each therapeutic dose required for the therapeutic and prophylactic treatment of a particular condition will necessarily vary depending upon the host treated, the route of administration, and the severity of the condition being treated. Therefore, the most appropriate dose is determined by the clinician treating the patient. For example, it may be necessary or desirable to reduce the dose of the above ingredients to the ingredients contained in the treatment to reduce toxicity. As stated above, the ingredients of the present invention can be used in a simultaneous, sequential or separate manner. Preferably, the administration is simultaneous and/or sequential, but the restriction is that each component is present in the living body at a therapeutically effective concentration. Thus, the root -23- paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 public attack _ _ 1307628 A7 B7 five, invention description (21) according to, for example, the pharmacokinetics of individual components and The route of administration, the individual agents can be used separately (interval, for example, 10-20 minutes), so that the combination can effectively reach the same level as that achieved by the simultaneous administration mode, or a similar in vivo type 〇 similarly, according to For example, the pharmacokinetics of the individual components, the components of the invention may be administered in a range of repeated cycles, for example, once a week for several weeks; once a day for 5 days and repeated for several weeks; or once daily for multiple weeks. Depending on the nature of the particular combination and cycle of choice selected, the bolus may be administered orally and/or intravenously or via continuous intravenous infusion. Further, each component of the composition may use the same or different replicates. Periodic administration. Thus, for example, a non-platinum-based anticancer agent can be taken once a week, while ZD0473 is taken once a day for a 5-day period, and then the cycle is repeated for several weeks. The combinations of the invention can be confirmed by non-limiting in vitro assays of ZD0473 and Taxol (paclitaxel) as follows. For details of the cultures used and other experimental details, see Holford et al, Br. J. Cancer, 1998, 7793, 366-373 and KEPestell et al, Molecular

Pharmacology, 57: 503-511, 2000 (the relevant experimental details are incorporated herein by reference). Four human ovarian cancer cell lines are used as follows: two parental cisplatin-sensitive lines, CH1 and A2780; The anti-cis cisplatin subline, A2780cisR; and an A2780 subline, which were transfected with the E6 human papillomavirus gene, caused loss of wild-type p53 function in the parental line A2780 E6. -24- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1307628 A7 B7 V. Invention description (22) For separate ZD0473, and combined with paclitaxel for simultaneous or sequential application (in wash) After the treatment, growth inhibition was measured for 24 hours (using the sulforhodamine B assay). The effect of the drug combination was analyzed using half-effect analysis. After 9 hours of continuous exposure, ZD0473 alone showed strong growth inhibition on these cell lines with IC5(R) (M) values of 3.7 for A2780, 15.6 for oblique A2780cisR, 8_6 for A2780E6 and 3.3 for CH1. Therefore, in these studies, 2780 (^11 vs. 2〇0473 only had 4.2-fold cross-resistance. Paclitaxel itself also gave strong growth inhibition, and the IC5 〇 value in nM was 2_5 for A2780, The A2780cisR is 3.5, the A2780E6 is 20.8 and the CH1 is 3. When Bud and paclitaxel are simultaneously exposed, the 50% effect rate combination index (CI) value has synergistic effect on the four cell lines (A2780 CI is 0.49). , A1780cisR CI is 0.55, 0.31; A2780E6 CI 0.4 is 0.54; CH1 CI is 0.69, 0, 55). When applying ZD0473 24 hours before paclitaxel administration, A2780 (CI is The effects of 1.0, 1.6) were additive/slightly antagonistic, while synergistic effects were observed for the other three cell lines (A2780cisR CI 0.4, 0.70; A2780E6 CI 0.51, 0.91; and CHI CI 0.61, 1.30) When the cells were exposed to ZD0473 for 24 hours after exposure to paclitaxel for 24 hours, a synergistic effect was observed for A2780cisR (CI was 0.37, 1.48), while for other cell lines it showed a weak synergy. Sex/addition effect or antagonistic effect (Α2780Ε6 CI is 0 .89,1·02 ; Α2780 CI is 1.1,12.9; CHI CI is 2.4,2.1). -25- This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X 297 public) 1307628 A7 B7 V. Invention Description (23) The CI index is calculated using the method of Chou &Talalay; Adv. Enzyme Regulation, 1984, 22, 27-55. The first value in each case uses one (average) data point for each level. The second value adds all data points (including repeats) to the same data point. These data indicate that, depending on the cell line, the order of administration of ZD0473 and paclitaxel in combination has a growth inhibition effect. Importance 'Most of the synergistic effects are at the same time, and synergistic effects (depending on the cell line) can be observed when co-administered. Although similar to the cell line, similar synergistic effects are also observed. It can be observed in other cell lines, such as SCLC. The potent tumor cell growth inhibitory activity of the composition of the present invention can also be confirmed in vivo, for example, in a widely used transplantable human swollen mouse. A xenograft model of a tumor (eg, using an anti-shun ammonia-platinum tumor) (ie, a utility greater than that achievable with each of the drugs at their maximum tolerated dose). Promising tumor cell growth inhibitory activity and toxicity interactions are being studied in clinical trials. For example, in a combined experiment with Gemcitabine, intravenous injection of ZD0473 (first day) is performed on human cancer patients at the appropriate dose for 1-2 hours, and the appropriate dose is given for 3 minutes per day. Gemcitabine, two days (first day and eighth day), is planned to be treated every three weeks. On the first day of each cycle, ZD0473 is first used during 1-2 hours, followed by an interval of 3 ’ ' and then given during 30 minutes. Gemcitabine is used. On the eighth day, 'Gemcitabine treatment is given only for the patient during the 30-minute period, -26- This gas sheet is calibrated with the Chinese National Standard (CNS) A4 specification (210X 297 slag) 1307628 A7 B7 V. Description of the invention (24) Same as the first day. The next day and the following cycles are normal dose adjustment recommendations. A total of six dose levels were studied, and the doses of ZD0473 and Gemcitabine increased gradually as follows: Dose level (administered every 3 weeks) ZD0473a (mg/m2) The first day of the cycle (Gemcitabinea) (mg/m2) Cycle 1 day and 8th day level 1 60 750 Level 2 90 750 Level 3 120 750 Level 4 120 1000 Level 5 120 1250 Level 6 120 1500 a ZD0473 tied during 1 - 2 hours It is administered, and Gemcitabine is administered during 30 minutes from the end of the first day of ZD0473 administration 30 minutes later. Gemcitabine is given again on the eighth day of each cycle. There are at least 3 patients at each dose level to get 3 evaluable patients for the toxicity overview. If a single-dose-restricted DLT is encountered in one of the patients, the team member is expanded to have at least 6 evaluable patients for toxicity assessment to determine if the MTD has been reached. The maximum number of patients participating in each dose level was 8. The definition of DLT and maximum tolerated dose (MTD), and the events defining DLT are listed below: • Absolute neutrophil count (ANC) is less than 0.5 X 109 / liter, accompanied by fever or infection -27- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) I3〇7628 A7 B7

• ANC is less than 〇·5χ1〇ν liter for more than 5 days • Platelet count is less than 25 X 1〇9/L • Grade 3-4 treatment-related non-hematologic toxicity, except for alopecia, or alanine transamin Reversible 'slow-onset of enzyme (ALT) or aspartate transaminase (AST), or nausea and vomiting in patients who have not been treated with a suitable vomiting drug • treated for unresolved toxicity The criteria for delaying more than three weeks of further dose increase or the same dose of continued use are related to the number of patients with dlt as follows: 3 out of 3 out of 3 out of 3 out of 6 out of 6 out of 3 out of 3 2 increases to the next dose. Recruit another 3 patients. Increase to the next dose. The MTD 'recommended dose (rd) is lower than the MTD. - Toxicity - MTD is a dose lower than the toxic dose; RD is the lower 2 doses. Duration of at least 3 of 6 treatments: one cycle every three weeks, unless the patient's bone marrow is not restored' and neutrophil The granulocyte count is higher than 15χ1〇9/liter, and the platelet count is 100 X 109/liter or non-hematologic toxicity is not resolved until the first stage treatment can be delayed for up to three weeks (ie, day 42) ). If the criteria for allowing further treatment are not reached by the end of the 21-day append period, the deaf patient is withdrawn. The patient did not show objective progression (every two cycles of evaluation ~, for example, via tumor burden, can be used as cAT scan or label measurement, etc. - 28) This paper scale applies to Chinese national standards (Cf^l4 specification ((10) χ 1307628, invention Explain ( : 2, can continue treatment until it reaches the withdrawal criteria until the withdrawal of control and overall health, the research is limited to the treatment (depending on the case) until the withdrawal criteria is met as a sustainable cancer treatment === : Use: Hefei, base anti-rb m 6 .i-, ~ must be (Gemcitabine) used; 詈 吩 予以 予以 予以 予以 予以 予以 予以 予以 予以 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫 紫Such as in the range of 135_175 mg / m2) and D〇473 (such as in the 1G (M5G mg / m2 range). The above scheme can also be adjusted by physician technology, such as ZDG473 (iiq mg / kg / Day 'better 2·5 mg/kg/day, and better 3_4 mg/kg/day) and IressaUjO mg/kg/day, preferably 3_1〇 mg/kg/day, and better 5 mg /kg/day). Use the appropriate toxicity for the drug being studied . Experience, depending on the fitness scale paper -29- toxicity profile of each drug alone were the expectations; in ® @ Home Standard (CNS) A4 size (210 X 297 male dragon)

Claims (1)

h year month% 13 07 shift 2 sand 112094 patent application basin Chinese patent application scope replacement (November 1997) C8 VI. Patent application scope 1. An anti-cancer effective amount of (SP-4-3)-cis-amine dichloride -[2-methylpyridyl] start (II) (ZD0473) or a prodrug thereof and an anti-cancer effective amount of a non-important anticancer agent for use in the manufacture of a medicament for combination therapy, when administered The combination therapy provides an anticancer effect, and the non-platinum-based anticancer agent is a taxane, a topoisomerase (topois〇merase) I inhibitor, and a valence isomerase. π inhibitors, antimetabolites, protein kinase inhibitors, vinca alkaloid, anthracyclines, alkylating agents, anti-angiogenic agents, anti-hormones or anti-HER- A neu agent, and wherein the ZD04 7.3 is administered prior to the non-invention-based anticancer agent. 2. An anti-cancer effective amount of (SP-4-3)-cis-amine di-[2-methylpyridine] platinum (II) (ZD0473) or a prodrug thereof The use of a basic anticancer agent for the manufacture of a medicament for combination therapy, which provides an anticancer effect when administered to a human suffering from cancer, wherein the non-platinum-based anticancer agent is a yew, a servant Isomerase (1(^〇4〇11^1^86)1 inhibitor, benzoyl isomerase; [1 inhibitor, antimetabolite, protein kinase inhibitor, vinca alkaloid, 蒽Anthracyclin, a burn-in agent, an anti-catheter agent, an anti-negative agent or an anti- ER- neu agent, and wherein the ZD0473 and the non-improved anticancer agent are administered simultaneously. The use of the second aspect of the patent application, wherein the ZD0473 and the non-platinum-based anticancer agent are combined prior to administration. 4. The use of the second item of the patent application 'where the ZD0473 and the non-platinum are The basic anticancer agent is administered together. 70972-971107.DOC This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A8 B8 C8 D8 1307628 Patent Application Fan Park 5 · An anti-cancer effective amount of (SP-4-3)-cis-amine digas-[2-methylindole] platinum (II) (ZD0473) or its prodrugs and anticancer An effective amount of a non-initial-based anticancer agent for use in the manufacture of a medicament for combination therapy, when the dose is administered to a human suffering from cancer at the same time and/or sequentially or separately, the combination therapy provides an anticancer effect. Among the non-platinum-based anticancer agents are taxus, topoisomerase I inhibitor, valence isomerase II inhibitor, antimetabolite, protein kinase inhibitor, vinca alkaloid ( Vinca alkaloid), anthracyclin, an alkylating agent, an anti-angiogenic agent, an anti-Halmonic agent or an anti-HER_neu agent, provided that the drug is paclitaxel or polyene melamine and is administered separately from ZD0473 Or before ZD0473, the paclitaxel or docetaxel is administered about 60 minutes or less before ZD0473. 6_For the use of the first or fifth item of the patent application, wherein the amount is separated or successive 7 _ as applied for the fifth application of the patent scope, where the non-platinum is based The anticancer agent is administered prior to ZD 0 4 7 3. The use of the non-platinum-based anticancer agent prior to ZD 0 4 7 3 is about 1 〇 to 6 as claimed in claim 7 The use of any one of claims 1 to 5, 7 and 8 wherein the cancer is a solid tumor. 10. The use of any one of claims 1 to 5, 7 and 8 wherein the cancer is lung cancer, mesothelioma, ovarian cancer, breast cancer, cervix, uterine cancer, bladder cancer, prostate Cancer, testicular cancer, pancreatic cancer, head and neck 70972-971107.DOC This paper scale uses Chinese National Standard (CNS) A4 specification (210X 297 mm). 1307628 VI. Patent application Fan 8 8 8 8 ABCD Cancer, liver cancer, Gastrointestinal cancer, gastric cancer, colorectal cancer, rectal cancer, skin cancer, bone cancer or kidney cancer or Kaposi's sarcoma, lymphoma or leukemia. 11. The use of any one of claims 1 to 5, 7 and 8 of the patent application, wherein the β-Hai non-platinum-based anticancer agent is a servant isomerase j inhibitor and tyrosine kinase Inhibitors, antimetabolites, vinca bioassay, anthracycline or anti-Η ER · neu agents. 12. For the use of any of the scopes 1 to 5, 7 and 8 of the patent application, wherein the non-platinum-based anticancer agents are irinotecan, Aiteposay, and Tini Posse ( Teniposide), Iressa (ZD 1839), UFT, 5-FU, capecitabine, celecoxib, pemetrexed, vinorelbine, doxorubicin hydrochloride (d0Xii), doxorubicin or He cancer (herceptin). 13. The use of any one of claims 1 to 5, 7 and 8, wherein the non-platinum-based anticancer agent is yew. 14. The use of claim 13 wherein the non-platinum-based anticancer agent is paclitaxel or polyene melamine. 1 5 . The use of the invention in claim 4, wherein the cancer is prostate cancer. 〇 16. The use of the invention is in the scope of claim 10, wherein the cancer is colorectal or rectal cancer. 17. The use of the non-platinum-based anticancer agent, 5-F U, as claimed in claim 16. 18. The use of any one of claims 1 to 5, 7 and 8 wherein the ZD 04 7 3 is suitable for oral administration. 70972-971107.DOC This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1307628 έ88 C8 ________D8___ VI. Patent application scope 19. If the patent application scope is 1 to 5, 7 and 8 A use wherein the ZD 0 4 7 3 and/or non-platinum-based anticancer agent is suitable for intravenous administration. 20. The use of any one of claims 1 to 5, 7 and 8 wherein it is replaced by carboxyplatinum, oxaliplatin or cisplatin (s ρ · 4 _ 3 μ cis _ One or a combination of amine dichloro-[2-puropyridinium]platinum (ruthenium) or a prodrug thereof, which provides reduced neurotoxicity and/or nephrotoxicity. 2 1 as claimed in item 20 The use of the reduced neurotoxicity as a reduced neuropathy. 22. The use of any one of claims 1 to 5, 7 and 8 wherein carboplatin, oxaliplatin or Subsequent ammonia-platinum substitution of (s ρ _ 4 - 3 )-cis-amine dioxo-[2-methylpyridine]platinum (11) or one or more of its prodrugs, the combination treatment provides inherent reduction Or the resulting resistance. 23. The use of any one of claims 1 to 5, 7 and 8 wherein the non-improving anticancer agent is selected to be Zd 〇 4 7 3 Or a prodrug thereof, which provides at least one additive anti-cancer effect. 24. The use of any one of claims 1 to 5, 7 and 8 wherein the non-platinum is based The anti-cancer agent is selected to provide a synergistic anti-cancer effect with ZD0473 or its predecessor. 25. The use of any of claims 1 to 5, 7 and 8 wherein the administration system The use of any one of the claims 1 to 5, 7 and 8 wherein the medicament comprises the amount of ZD0473 and the first pharmaceutical carrier, and the amount is not based on platinum. Anticancer agent and second pharmaceutical carrier. 70972-971107.DOC This paper scale adopts Chinese National Standard (CNS) A4 specification (210X 297 mm). 1307628 bb C8 D8 々, patent application scope 2 7 . The use of any one of clauses 1 to 5, 7 and 8, wherein the medicament is provided to provide a kit comprising a container device comprising the amount of ZD 0473 and the amount is not based on platinum The unit dosage form of the anticancer agent. 28. The use of any one of claims 1 to 5, 7 and 8 wherein the agent provides dosage information for the amount. 70972-971107.DOC This paper size applies China National Standard (CNS) A4 specification (210X297 mm).