HK1116409A - Combination chemotherapy - Google Patents

Description

Combination chemotherapy

The application is a divisional application of an invention patent application named 'combined chemotherapy' with the international application number of PCT/GB01/02060, the international application date of 2001, 5-10.2001 and the Chinese national phase application number of 01809337. X.

The present invention relates to a therapeutic combination product and a kit comprising a sterically hindered platinum coordination compound in combination with a non-platinum based anti-cancer agent, and to a pharmaceutical composition comprising a sterically hindered platinum coordination compound and a non-platinum based anti-cancer agent together with a pharmaceutically acceptable carrier or diluent. The invention also relates to a method of inhibiting tumor cell growth in a human afflicted therewith, comprising administering to such human an effective tumor cell growth inhibiting amount of such a therapeutic combination product or pharmaceutical composition of the invention. The invention also relates to the use of a sterically hindered platinum coordination compound in combination with a non-platinum based anti-cancer agent as defined herein for the manufacture of a medicament capable of inhibiting the growth of tumor cells in a human afflicted therewith.

Cisplatin, or cis-dichlorodiammineplatinum (II), is a chemotherapeutic agent that has been used for many years in the treatment of various human malignant solid tumors, and has produced a wide range of effects. Although cisplatin has been reported to have antitumor activity against tumors such as refractory testicular teratomas and ovarian cancers, the occurrence of side effects such as renal injury and nausea and vomiting was initially unacceptable. This side effect has been reduced to some extent (e.g., renal toxicity is alleviated by increasing water with isotonic saline solution, 5-hydroxytryptamine type 3 (5-HT)₃) Antagonists to combat nausea and vomiting), but there is a major synthetic route to develop platinum analogs that are more toxic and acceptable. More recently, platinum analogs such as carboplatin (cis-diammine-1, 1-cyclobutyl dicarboxylplatinum (II)) have shown efficacy as chemotherapeutic agents in the treatment of various human malignant solid tumors. Carboplatin, although less neurotoxic and less nephrotoxic than cisplatin, still causes nephrotoxicity and is significantly more myelotoxic than cisplatin.

However, although platinum-based agents such as cisplatin and carboplatin are widely used as chemotherapeutic agents in humans, they are not effective in all patients or in all types of solid tumors. Furthermore, resistance or resistance of tumors to cisplatin is a major obstacle to successful treatment, and such resistance is generally considered to be either intrinsic (e.g., as it occurs at the beginning of treatment) or acquired (e.g., as it occurs in chemotherapy). The typical tumors with intrinsic resistance to cisplatin are rectal cancer and non-small cell lung cancer, and acquired resistance is commonly found in patients with ovarian or small cell lung cancer.

As mentioned above, the main objective of improving cisplatin/carboplatin is to overcome resistance. The discovery that agents in which the amino ligand is replaced by Diaminocyclohexane (DACH) are effective against cisplatin resistant cell lines has led to the development of a range of such agents. Among them, oxaliplatin, either as a sole agent or complexed with 5 fluorouracil (5-FU), shows activity in advanced rectal cancer. However, oxaliplatin can produce severe neurotoxicity, including blunted facial sensations upon exposure to cold. Peripheral sensory neuropathy may also occur. In addition to this neurotoxicity, this drug does not cause significant renal toxicity, and oxaliplatin represents an advance in the treatment of advanced rectal cancer.

However, in addition to advances in overcoming cisplatin resistance and alleviating toxic side effects, the field of platinum anticancer agents lacks an agent that demonstrates antitumor activity in a clinically important tumor range while having acceptable toxicity. In addition, the results of current chemotherapy for cancer patients are often unsatisfactory. A number of different approaches have been investigated to overcome resistance to cisplatin, and at the same time, prevention of platinum-related toxicity is also of considerable concern.

Platinum-based chemotherapy is commonly used in conjunction with one or more other agents in the treatment of various tumors. For example, cisplatin and etoposide are often the initial options for combination chemotherapy for most SCLC patients. Carboplatin can replace cisplatin without loss of efficacy. In limited stage disease, there is some improvement in survival by the addition of radiation therapy to standard chemotherapy, while in a wide range of disease, radiation therapy does not improve survival, but plays an important palliative role. Another interesting compound is cisplatin plus paclitaxel (paclitaxel), which is used in the treatment of advanced ovarian cancer.

Although complexes may provide enhanced efficacy, many such complexes are unsatisfactory due to unacceptable toxicity and other difficulties (e.g., scheduling and need for fluid hydration) of previous platinum-based anticancer agents. Accordingly, there is a need to improve the effectiveness of known chemotherapeutic complexes (including complexes of platinum) on tumor cell growth inhibitory activity and/or to provide a means to reduce the dose of chemotherapeutic agents to reduce potential or harmful side effects to the patient. Despite this need, synergy is not commonly found in complexes for the treatment of cancer. The therapeutic combination products, pharmaceutical compositions, and uses and methods of the present invention address this need.

(SP-4-3) - (cis-aminodichloro- [ 2-methylpyridine ] platinum (II), hereinafter referred to as ZD0473, is a newly developed complex of platinum to overcome the steric inhibition of acquired or re-resistance to cisplatin U.S. Pat. No. 5,665,771 describes SD0473, wherein say: "the complexes of the invention may be used alone or in combination with other chemotherapeutic agents, such as cisplatin, as monotherapy or as a course of therapy, or as part of a combination therapy with other agents to overcome or reduce side effects or to increase bioavailability, or in combination with other therapies (e.g. radiation therapy), "however, there is no suggestion in US5,665,771 that the use of any of the complexes of this invention in combination with other therapeutic agents can produce surprising beneficial effects.

At the 35 th american society for clinical oncologists conference (5 months 1999, atlanta), provisional results were presented for a monotherapy first phase trial involving ZD0473, demonstrating that the dose-limiting toxicity of ZD0473 is myelosuppression without significant renal or neurological toxicity.

For ZD0473, both neutropenia and thrombocytopenia were observed but recovery was rapid and patients who had not undergone severe pretreatment could be treated at 3 week intervals. Cumulative anemia and thrombocytopenia have been studied. There is no clinically relevant evidence for peripheral neurotoxicity, ototoxicity or nephrotoxicity. Ototoxicity can be problematic, especially when cisplatin is used, because it is generally irreversible. The recommended dose and course of treatment for the second phase study was initially 120mg/m every 3 weeks². Patients who have been heavily pretreated with cytotoxic agents that destroy bone marrow stem cells may require reduced doses and may not tolerate the drug once every 3 weeks. However, higher doses, such as 150mg/m, may be tolerated by patients²(the presently recommended dosage), or higher. Evidence of antitumor activity has been observed in patients with various malignancies, including small and non-small cell lung cancer, mesothelioma, head and neck tumors, and tumors of the breast and ovary. ZD0473 has been studied to determine the maximum amount of drug that can be safely administered to a patient, to test how the body handles the drug and to determine the nature of the dose-limiting toxicity.

Unexpectedly and surprisingly we have now found that the particular compound ZD0473 used in combination with a non-platinum based anti-cancer agent has an anti-cancer (anti-cell-proliferation) effect which is significantly better than that of ZD0473 or the non-platinum based anti-cancer agent used alone. ZD0473 is also included in this particular class of compounds in which prodrugs are present which produce active ZD0473 in vivo (e.g. the Pt (IV) trihydroxy, monochloro, monoamino prodrugs of ZD 0473). A preferred embodiment of the present invention relates to the sterically hindered platinum coordination compound (SP-4-3) - (cis-aminodichloro- [ 2-methylpyridine ] platinum (II) we believe that ZD0473 (and similar sterically hindered platinum (Pt (II) and Pt (IV)) complexes, wherein the 2-methylpyridine ligand of ZD0473 is replaced by other sterically hindered substituted amines, as described in US5,665,771, the relevant definitions and examples of which are incorporated herein by reference) possess the highly desirable activity and side effects that are lacking in the current platinum-cytotoxic complex, a particular benefit of the combination is the combination of ZD0473 which has satisfactory myelosuppressive properties but no significant neurotoxicity and nephrotoxicity.

Thus, it has been found that a sterically hindered platinum coordination compound such as ZD0473 may be beneficial in therapy when used in combination with other non-platinum based chemotherapeutic agents, thereby potentially increasing the growth inhibition of tumour cells compared to the use of each component alone. It has also been found that this advantage results in a lower dosage requirement for such sterically hindered platinum coordination compounds and/or other non-platinum based chemotherapeutic agents than would be required if each component were used alone. Thus, where, for example, such a complex exerts a protective effect on normal (non-neoplastic) cells, each (or both) components may be delivered at higher doses, thereby allowing higher doses to be tolerated. The particularly satisfactory toxicity of ZD0473 (including satisfactory neurotoxicity and nephrotoxicity) allows it to be used with other non-platinum based anti-cancer agents which might otherwise have limited their binding potential due to their own toxicity (e.g. paclitaxel's own neurotoxicity limits its binding to earlier platinum agents). The advantages of the present invention will be demonstrated by suitable in vitro tests or improved in vivo performance (e.g. as compared to monotherapy or to complexes using early platinum agents, such as evidence of improved toxicity or platelet sparing effects).

As described above, platinum-based drugs such as cisplatin and carboplatin are widely used in the treatment and testing of solid tumors such as lung cancer, ovarian cancer, and the like. Many of these tumors initially respond to platinum-based therapies, but in most cases, the tumors develop resistance and the disease recurs. The purpose of ZD0473 is to overcome this resistance to platinum-based drugs and to provide a broad spectrum of anti-tumour activity. In vivo studies in xenografted human tumours have shown that ZD0473 activity is at least comparable to, and in some cases superior to, cisplatin. Even after treatment with ZD0473 on the basis of cisplatin treatment, the activity against cisplatin-resistant CH1 xenograft ovarian tumors was maintained. The activity against murine tumors was retained when the drug was taken orally and some activity against acquired cisplatin resistant ADJ/PC6cisR tumors, which were completely resistant to other platinum agents, could be seen.

ZD0473 was studied in vitro in a human tumour cell line with some sensitivity to platinum agents and a corresponding cell line with acquired resistance to cisplatin, whilst demonstrating its ability to overcome platinum resistance due to various mechanisms. In addition, better retention of activity was observed in cell lines treated to obtain relatively higher levels of glutathione or metallothionein. Interestingly, in addition to reducing the susceptibility to inactivation by glutathione, ZD0473 also overcomes the resistance of the 41McisR cell line, where resistance to cisplatin is due to reduced uptake. The study of the nature of the response between ZD0473 and DNA confirmed the differences in sequence specificity of the DNA addition structure and the appearance of the unique ZD0473 binding site.

It is therefore a further advantage of the present invention that a sterically hindered platinum coordination compound such as ZD0473 may be administered in combination with other non-platinum based chemotherapeutic agents to produce therapeutically beneficial tumour cell growth inhibiting activity in tumours and in cell lines which are resistant and insensitive to other platinum based (non-sterically hindered) coordination compounds. Combination therapies containing platinum-based coordination compounds may be ineffective, but are now effective because of the sterically hindered platinum coordination compounds such as ZD 0473. Thus, second line treatment of patients previously thought to be unlikely to benefit from combination therapy with platinum-based coordination compounds is now possible with combination therapy employing sterically hindered platinum coordination compounds such as ZD 0473.

Thus, the present invention provides a therapeutic combination preparation comprising a sterically hindered platinum coordination compound and a non-platinum based anti-cancer agent suitable for simultaneous, sequential or separate administration. Preferably, the components of the complex should be administered simultaneously and/or separately so as to deliver both agents simultaneously in vivo (i.e., simultaneous exposure). The skilled artisan will know whether these components are present simultaneously in vivo by using standard techniques.

According to another aspect of the present invention there is provided a kit consisting of a sterically hindered platinum coordination compound as herein mentioned and a non-platinum based anti-cancer agent.

According to another aspect of the present invention, there is provided a kit comprising:

a) a sterically hindered platinum coordination compound in a first unit dosage form;

b) a non-platinum based anti-cancer agent in a second unit dosage form; and

c) a container containing said first and second dosage forms.

According to another aspect of the present invention, there is provided a kit comprising:

a) the sterically hindered platinum coordination compound contained in the first unit dosage form is provided with a pharmaceutically acceptable excipient or carrier;

b) a non-platinum based anti-cancer agent contained in the second unit dosage form with a pharmaceutically acceptable excipient or carrier; and

c) a container containing said first and second dosage forms.

According to another aspect of the present invention there is provided a pharmaceutical composition comprising a sterically hindered platinum coordination compound as herein mentioned and a non-platinum based anti-cancer agent, a platinum anti-cancer agent, together with a pharmaceutically acceptable excipient or carrier.

According to a further aspect of the present invention there is provided a combination product comprising a sterically hindered platinum coordination compound as herein mentioned and a non-platinum based anti-cancer agent, which is useful as a medicament and which may be further used in a method of treatment of the human or animal body by therapy.

According to a further aspect of the present invention there is provided a pharmaceutical composition as defined herein for use as a medicament and further for use in a method of treatment of the human or animal body by therapy. According to a further aspect of the present invention there is provided a sterically hindered platinum coordination compound used in the manufacture of a medicament in combination with a non-platinum based anti-cancer agent as defined herein for use in the manufacture of an anti-cancer agent effective in warm-blooded animals such as humans.

According to a further aspect of the present invention there is provided a therapeutic combination product or pharmaceutical composition as defined herein for use in the manufacture of a medicament for use in the production of an anti-cancer agent effective in warm-blooded animals such as humans. According to another aspect of the present invention there is provided a method of manufacture of an anti-cancer agent effective in warm-blooded animals such as humans, comprising administration of a sterically hindered platinum coordination compound in combination with a non-platinum based anti-cancer agent as defined herein.

According to another aspect of the present invention there is provided a method of manufacture of an anti-cancer agent effective in warm-blooded animals such as humans, comprising administration of a therapeutic combination product or pharmaceutical composition as defined herein.

In the various aspects of the invention described above, the preferred sterically hindered platinum coordination compound is ZD 0473.

According to a further aspect of the present invention there is provided a method of combination treatment comprising the administration of an effective amount of ZD0473, preferably with a pharmaceutically acceptable excipient or carrier, and the simultaneous, sequential or separate administration of an effective amount of a non-platinum based anti-cancer agent as herein defined to a warm-blooded animal such as a human in need of such treatment.

According to another aspect of the present invention the effect of a method of treatment of the present invention is at least equivalent to the addition of the effects of each of the components of said method of treatment used alone (i.e. ZD0473 and the preferred non-platinum based anti-cancer agents mentioned herein). This addition is very advantageous if both agents in the complex attack the same tumor cells and/or at the same stage of the cell cycle.

According to a further aspect of the present invention the effect of a method of treatment of the present invention is greater than the sum of the effects of each of the components of said method of treatment (i.e. ZD0473 and the preferred non-platinum based anti-cancer agent mentioned herein) when taken alone. This synergy would be very beneficial when the MTD level is lower than each individual agent. This benefit is seen when the normal cells are able to tolerate higher doses (e.g., stronger antagonism) of either or both components than the tumor cells.

The combination therapy as defined herein may be used as monotherapy or may include surgery and/or ionizing radiation therapy in addition to the combination therapy of the present invention. Surgery includes the excision of part or all of the tumor before, during, or after the combination therapy described herein.

These combination therapies of the invention are effective in the prevention and treatment of a number of diseases including cancer (e.g., lung cancer (such as SCLC or NSCLC), mesothelioma, ovarian cancer, breast cancer, cervical/uterine cancer, bladder cancer, prostate cancer, testicular cancer, pancreatic cancer, head and neck cancer, liver cancer, kaposi's sarcoma, lymphoma (NHL), leukemia, and other cell proliferative disorders, such as psoriasis, arthritis, and fibrosis (e.g., pulmonary fibrosis)). In particular, these combination therapies of the present invention effectively slow the growth of primary and recurrent solid tumors, such as (but not limited to) those occurring in the GI/stomach, colon, rectum, breast, prostate, lung, testis, skin, bone and sarcoma, and kidney.

In a particular embodiment of the invention, the ionizing radiation used may be X-radiation, gamma-radiation and beta-radiation. The dose of ionizing radiation should be a known dose for clinical radiotherapy. The radiation therapy used includes, for example, the use of gamma rays, X-rays and/or direct input of radiation from a radioisotope. Other types of DNA damaging factors are also encompassed by the present invention, such as microwaves and ultraviolet light. It is likely that all of these factors will cause extensive damage to DNA, precursor DNA, DNA replication and repair, and chromosome assembly and maintenance. For example, X-rays should be administered in a dose of 1.8-2.0Gy per day, 5 days per week, for 5-6 weeks. Typically the total fractionated dose will be in the range 45-60 Gy. A larger dose (e.g., 5-10Gy) may be administered once as a course of radiation therapy. A single dose may be administered at the time of surgery. High-fraction radiotherapy, in which small doses of X-rays are regularly administered at regular intervals, e.g., 0.1Gy per hour for several consecutive days, may be employed. The dosage range of radioisotopes varies widely, and is determined by the half-life of the isotope, the intensity and type of radiation emitted, and the amount absorbed by the cells.

The term "sterically hindered platinum coordination compound" refers to any sterically hindered tumor cell growth inhibiting platinum coordination compound described and included in U.S. Pat. No. 5,665,771 (which compounds and methods for their preparation are included herein by reference). A preferred sterically hindered platinum coordination compound is ZD 0473.

By "non-platinum based anti-cancer agent" is meant a compound having anti-cancer and/or anti-cell proliferation activity but not containing platinum, in particular a compound or drug selected from the following classes:

1. compounds of the camptothecin analogue class, e.g. any compound inhibiting tumor cell growth which is structurally related to camptothecin and which inhibits topoisomerase I; or compounds of the podophyllotoxin analog class which inhibit topoisomerase II; or camptothecin analogs that are both topoisomerase I and II inhibitors. Suitable camptothecin analogue class of compounds include, but are not limited to, pure topoisomerase I inhibitors such as Topotecan, irinotecan, 9-aminocamptothecin, Rubitecan, and Exatecan (DX-8951 f); mixed topoisomerase I and topoisomerase II inhibitors, such as XR-5000 and XR-11576; and suitable podophyllotoxin analog compounds, such pure topoisomerase II inhibitors including, but not limited to, epipodophyllotoxin glucopyranoside and epipodophyllotoxin thiophenoside. Such compounds also include, but are not limited to, WO 93/09782 and any of the camptothecin analogs claimed or described in the reference treatments listed herein (incorporated by reference in their entirety). The manufacture of Topotecan (including pharmaceutically acceptable salts, hydrates, and solvates thereof), and the manufacture of oral and parenteral pharmaceutical compositions containing Topotecan and an inert, pharmaceutically acceptable carrier or diluent, is widely described in U.S. patent No. 5,004,758 and european patent application publication No. EP 0,321,112.

2. Taxanes such as paclitaxel (paclitaxel) or Taxotere (docetaxel).

3. Growth factor receptor inhibitors, for example, protein kinase inhibitors such as type I tyrosine kinase inhibitors (e.g., Iressa (ZD1839)), and inhibitors of growth factor function (such growth factors include, for example, platelet-derived growth factors and hepatocyte growth factors, such inhibitors including growth factor antibodies, growth factor receptor antibodies, and serine/threonine kinase inhibitors).

4. Antimetabolites such as 5-FU, S1, UFT, Capecitabine (Capecitabine); a thymidine synthase inhibitor, such as Tomudex or ZD9331, or LY231514(MTA, pemetrexed) or gemcitabine, or an antifolate, such as methotrexate.

5. Vinca alkaloids, such as vinorelbine (Navelbine), vincristine, vinblastine or vindesine.

6. Anti-angiogenic compounds, as described in international patent application publication nos. WO 97/22596, WO 97/30035, WO 97/32856, WO 98/13354, WO 00/21955 and WO 00/47212.

7. Alkylating agents, such as melphalan, cyclophosphamide, ifosfamide (Ifophamide), or nitrosoureas, such as nitrosourea mustard or chlorocycloheximide.

8. Anthracyclines, such as doxorubicin, epirubicin, flavocholin or Doxil.

9. anti-HER-neu compounds, such as Herceptin (Herceptin).

10. Cytostatics, such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene, iodoxylene), progestins (e.g., cyproterone acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazone, exemestane), antiprogestogens, antiandrogens (e.g., flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH agonists and antagonists (e.g., goserelin acetate, luprolide), testosterone 5 α -dihydroreductase inhibitors (e.g., finasteride) and anti-invasiveness agents (e.g., metalloproteinase inhibitors like marimastat, and inhibitors of urokinase activator factor receptor function)

11. Natural and synthetic antimitotic agents.

12. Interleukins and cytokines, such as TNF.

13. A vaccine.

14. Inhalation/efflux modulators, such as mdr 2.

15. A rescue agent.

A Ca antagonist.

Other platinum agents with different modes of action or effectiveness (e.g. BBR3464 or oxaliplatin) may also be used with ZD 0473.

All of the listed non-platinum based anti-cancer agents are commercially available and can be manufactured by conventional techniques, including the methods described in the reference treatments listed above. Other formulations, such as polyglutamate polymers (polymers that are biodegradable by attack by cytotoxic agents) and liposomal formulations of the above non-platinum based anticancer agents are also included.

Preferred non-platinum based anti-cancer agents are selected from classes 1, 2, 3, 4, 5,6 and 8 above, and most preferably from classes 2, 3, 5 and 8 above.

Of these non-platinum based anti-cancer agents, particularly suitable for use in the present invention are taxol, Topotecan, gemcitabine, Navelbine, Doxil and 5-FU.

Thus, the components preferably used in the various embodiments of the present invention are the sterically hindered platinum coordination compound ZD0473, and a non-platinum based anti-cancer agent selected from taxol or Topotecan or gemcitabine or Navelbine or Doxil or 5-FU. ZD0473 and Taxotere are also preferred.

As a further feature of the invention there is provided a triad complex (e.g. ZD0473 plus taxol plus Iressa or gemcitabine; or ZD0473 plus anthracycline plus hormonal agents) in which agents with different modes of action are used.

As a further feature of the present invention there is provided a sequential doublet complex (e.g. ZD0473 plus taxol followed by (e.g.) ZD0473 plus gemcitabine) in which a different second agent (with a different mode of action) is subsequently administered. Sequential triplet complexes may also be used if the toxicity profile of the agents in the complex permits. The term "anti-cancer effect" includes inhibiting the growth of and/or killing cancer cells with a cytotoxin, wherein the cancer cells are susceptible to the complex preparations, compositions, and treatments of the present invention.

The term "inhibiting the growth of cancer cells" as used herein refers to inhibiting the growth of cancer cells that are susceptible to the methods of the present invention. Anti-cancer effects produced by the treatment methods of the present invention include (but are not limited to): inhibiting tumor growth, delaying tumor growth, tumor regression, shrinking tumor, increasing time for tumor regrowth after treatment is stopped, and slowing disease progression. It is desirable that when cancer, including solid tumors, is in need of treatment, the treatment methods of the present invention can be used in warm-blooded animals such as humans, and the use of such treatment methods will be effective, as measured, for example, by one or more of the following phenomena: the degree of antitumor effect, the response speed, the time to disease progression and the mortality rate.

Preferably, such treatment may also result in regression of tumor growth, e.g., a decrease in tumor size may be measured. Most preferably, the treatment is complete regression of the tumor. The invention may also be used, for example, in the elderly, in children, or in patients with kidney or liver damage.

The terms "effective tumor cell growth inhibiting amount" and "effective amount" as used herein refer to a course of therapy which results in inhibition of tumor cell growth in a patient susceptible to such therapy. Preferably, such a treatment would result in the administration of a sterically hindered platinum coordination compound and/or a non-platinum based anti-cancer agent at a lower dosage than would be required if such a compound were used as a single chemotherapeutic agent. Preferably, such a treatment would result in a non-platinum based anti-cancer agent and/or a sterically hindered platinum coordination compound having a higher inhibitory effect on tumor cell growth than when the compound is used as a sole chemotherapeutic agent. Most preferably, a classical synergistic effect is produced wherein the effect of the combination of the two components is greater/higher than would be expected (e.g., greater than additive) for the administration of the two components together. In practice, the preferred course of treatment will vary depending upon, inter alia, the mode of administration of the compound, the particular compound formulation employed, the mode of administration, the particular tumor cells being treated, and the particular individual being treated. The desired course of treatment may be determined by those skilled in the art by routine experimentation to determine the course of treatment for a given set of circumstances and taking into account the various factors described above.

The pharmaceutical compositions of the present invention comprise both a sterically hindered platinum coordination compound as defined herein and a non-platinum based anti-cancer agent, together with a pharmaceutically acceptable carrier or diluent. Preferred pharmaceutically acceptable carriers or diluents for use in the compositions of the invention are well known to those skilled in the art of formulating compounds into pharmaceutical compositions. The pharmaceutical compositions of the present invention will be in a form suitable for parenteral or oral administration. The compositions may be formulated with pharmaceutically acceptable carriers (e.g., saline) for intravenous infusion or injection in a variety of ways well known to those skilled in the art. Preferably, these pharmaceutical compositions are lyophilized mixtures of the two active ingredients in unit dosage form, which may be manufactured by conventional methods and reconstituted with water or other suitable infusion fluid when administered.

One skilled in the art will recognize that the composition of the active ingredients in the pharmaceutical compositions of the present invention may vary greatly depending on a number of factors, such as the desired dosage and the pharmaceutically acceptable carrier employed. When administered, the ratio of the amount (weight ratio) of the sterically hindered platinum coordination compound to the non-platinum based anti-cancer agent in the pharmaceutical compositions and other aspects of the invention is generally in the range of 10: 1 to 1: 1000. Preferably, the complex preparations and pharmaceutical compositions of the present invention contain from 50mg to 600mg of the sterically hindered platinum coordination compound and from 5mg to 5,000mg of the non-platinum based anti-cancer agent per unit dosage form. Preferably, mannitol and/or sodium chloride may be present in conventional amounts. The physiological pH of the injectable or infusible drug complex can be controlled with buffers known in the art of pharmaceutical formulation.

The composite articles or compositions described herein may be in a form suitable for oral administration, for example, as tablets or capsules (suitably enteric coated), for example as powders or solutions; forms suitable for parenteral administration (including intravenous, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), for example sterile solutions, suspensions or emulsions; forms suitable for topical administration, such as ointments or creams; forms suitable for rectal administration, such as suppositories; or by direct injection into the tumor or by local delivery. In another embodiment of the present invention ZD0473 for use in combination therapy may be delivered endoscopically, intratracheally, intralesionally, transdermally, intravenously, subcutaneously, intraperitoneally or intratumorally. In general, the compositions described herein can be manufactured in a conventional manner using conventional excipients. The compositions of the present invention may conveniently be presented in unit dosage form.

The size of each therapeutic dose required for therapeutic or prophylactic treatment of a particular disease state will necessarily vary depending on the patient being treated, the route of administration and the severity of the disease state being treated. Thus, the optimal dosage may be determined by the physician treating any particular patient. For example, it may be desirable or necessary to reduce the dosage of certain components of the combination therapy to reduce toxicity. As used herein, "administering" includes parenteral and/or oral administration. By "parenteral" is meant intravenous, subcutaneous, intramuscular or intraperitoneal or infusion administration. It will be appreciated that, in practice, the preferred method and order of administration will vary depending, inter alia, on the particular formulation/class employed, the particular tumor cells being treated and the particular patient being treated. The optimal method and order of administration for a given set of circumstances may be determined by those skilled in the art using routine skill and reference to the information set forth herein.

In the method of the present invention, the sterically hindered platinum coordination compound may be administered in the same manner as in previous clinical practice. In particular, for ZD0473, slow subcutaneous infusion is a frequently selected method. To facilitate urination when ZD0473 is used, a dextrose/saline solution with mannitol is the preferred carrier. The regimen may include administering a glucose/saline solution to the patient for pre-hydration. In the methods of the present invention, the dosage regimen of the sterically hindered platinum coordination compound may be based on a dosage regimen of about 25-500mg per square meter of surface area (mg/m) per course of treatment²) For example, about 0.4-1.0mg/kg in humans. When ZD0473 is used for the methods of the invention, the preferred dose of ZD0473 may be a single dose of from about 30mg/m²Initially, it is about 250mg/m after 1-5 days of continuous treatment². The sterically hindered platinum coordination compound can be infused 1-2 times a week over several weeks until side effects cause contraindications. Unit dose forms such as tablets or capsules usually contain, for example, 50 to 600mg of the active ingredient. Methods of using divided doses of ZD0473 (e.g. 30mg/m per day)²150mg/m for more than 5 days compared with one day²Preferably) can be effectively employed, for example, in conjunction with daily radiation therapy. In thatOther conventional therapies, such as supportive adjuvant, GCSF/EPO, may be used in conjunction with the administration of the drug. The dose of the non-platinum based anticancer agent can be given by the methods as exemplified in the following examples, but not limited thereto, according to known administration routes and doses.

For example, in the methods of the present invention, when the camptothecin analogs are administered parenterally, the course of treatment is typically about 0.1-300.0mg per square meter of surface area per day for about 1-5 days; preferably, about 0.1 to about 100.0mg per square meter of surface area per day for about 1 to about 5 days. More preferably, the treatment regimen for Topotecan is about 1.0 to about 2.0mg per square meter of surface area per day for about 1 to about 5 days. Preferably, the treatment is repeated at least once after an interval of about 7 days to about 28 days (from the start of treatment), depending on the initial dose and the recovery of normal tissue in the patient. Preferably, the treatment process is repeated continuously according to the response of the tumor.

Preferably, the camptothecin analogs can be administered parenterally by intravenous infusion over a short period of time (e.g., 30 minutes) or over a long period of time (e.g., 24 hours). More preferably, the camptothecin analogue compound is administered by intravenous infusion over 30 minutes. The preferred course of parenteral treatment with Topotecan is 1.5mg per square meter of surface area per day for the initial period of treatment, using a short intravenous infusion for 1-5 days, in a previously untreated or lightly pretreated patient. For severely pretreated patients, the initial phase of Topotecan treatment was 1.0mg per square meter of surface area per day for 1-5 days by short intravenous infusion. When the patient is completely free of the initial drug-related effect, another course of treatment is administered by intravenous infusion for a short period of time at least at the same dose per day as the initial dose for 1-5 days, and is repeated in response to the tumor.

In the methods of the invention, when camptothecin analogs are administered orally, the course of treatment is typically about 1.0-500.0mg per square meter of surface area per day for about 1-5 days. More preferably, the treatment regimen for Topotecan is about 1.5 to 5.0mg per square meter of surface area per day for about 1 to 5 days. Preferably, the treatment is repeated at least once after an interval of about 7 days to about 28 days (from the start of treatment), depending on the initial dose and the recovery of normal tissue in the patient. Preferably, the treatment process is repeated continuously according to the response of the tumor.

For example, paclitaxel (paclitaxel) may be used at 135-200mg/m every 3 weeks²Is administered by infusion over about 24 hours. Alternatively, for example, taxol may be 135-225mg/m every 3 weeks²Is administered by infusion over about 3 hours. Alternatively, for example, taxol may last for several weeks at 80-100mg/m per week²Is administered by infusion over about 1 hour. Alternatively, for example, taxol may be administered at 200mg/m every 3 weeks²Is administered by infusion over about 1 hour. Alternatively, for example, taxol may be administered at 120mg/m 140mg/m every 3 weeks²Is administered by infusion over about 96 hours.

For example, the dose of Docetaxel can be determined according to known routes and dosages. For example, Docetaxel may be used at 55-100mg/m every 3 weeks²Is administered by infusion over about 1 hour.

As mentioned above, the size of each therapeutic dose required for therapeutic or prophylactic treatment will necessarily vary depending on the patient to be treated, the route of administration and the severity of the condition being treated. Thus, the optimal dosage may be determined by the physician treating any particular patient. For example, it may be desirable or necessary to reduce the dosage of certain components of the combination therapies described above to reduce toxicity.

As mentioned above, the components of the invention may be administered simultaneously, sequentially or separately. Preferably, administration is simultaneous and/or sequential, such that therapeutically effective concentrations of each component are present simultaneously in the body. Thus, depending on, for example, the pharmacokinetics and route of administration of the individual components, the individual agents may be administered independently (with a time interval of, for example, 10 to 60 minutes) so that an in vivo profile of the complex equivalent or similar to that achieved by simultaneous administration may be effectively achieved.

Similarly, the components of the invention may be administered in a repetitive cycle, depending, for example, on the pharmacokinetics of the individual components. For example, once a week for several weeks; once a day for more than 5 days, repeated after several weeks, or repeated continuously on a daily basis for several weeks. Depending on the particular compound selected and the nature of the repetitive cycle, administration may be via oral bolus administration and/or intravenous administration or via continuous intravenous infusion. In addition, each component of the complex may be administered with the same or different repetition cycles. Thus, for example, a non-platinum based anti-cancer agent may be administered once a week whilst ZD0473 is administered once a day for more than 5 days, and this cycle is then repeated for more than a few weeks.

Examples and results

The following (but not limited to) in vivo experiments combined ZD0473 with paclitaxel (paclitaxel) to demonstrate the complexes of the invention. Details of the culture used, as well as other experimental details, can be found in Holford et al, br.j.cancer, 1998, 7793, 366-: 503-511, 2000 (the relevant experimental details are incorporated herein by reference in their entirety).

Four human ovarian cancer cell lines were used: two parental cisplatin-sensitive cell lines, CH1 and a 2780; a 15-fold acquired cisplatin resistant subline, a2780 cisR; and an a2780 subline, a2780E6, stably transfected with E6 human papilloma virus gene to deprive the parental cell line of wild-type p53 functionality. Growth inhibition (using the amine thiocyanate B assay) was determined for ZD0473 alone and after 24 hours of simultaneous or sequential (post-wash) administration with paclitaxel. The efficacy of the drug complex was analyzed by median efficacy analysis.

ZD0473 alone (96 hours of continuous exposure) showed strong growth inhibition on these cell lines. IC thereof₅₀The values (μ M) are: a2780 of 3.7, A2780cisR of 15.6, A2780E6 is 8.6 and CH1 is 3.3. Thus, A2780cisR was only 4.2-fold cross-resistant to ZD0473 in these studies. Paclixel alone also showed strong growth inhibition, its IC₅₀The values (nM) are: a2780 was 2.5, A2780cisR was 3.5, A2780E6 was 20.8, and CH1 was 3.1.

The value of the Combination Index (CI) at 50% infected fraction when exposed with paclitaxel was synergistic for all four cell lines (CI for A2780 was 0.49, 0.61; CI for A2780cisR was 0.55, 0.31; CI for A2780E6 was 0.41, 0.54; and CI for CH1 was 0.69, 0.55).

ZD 047324 hours before paclitaxel was used, the results were additive/moderately synergistic in A2780 (CI 1.0, 1.6), while some synergistic effects were observed in the other three cell lines (CI 0.4, 0.70 for A2780 cisR; 0.51, 0.91 for A2780E 6; 0.61, 1.30 for CH 1).

When cells were retained in paclitaxel for 24 hours before ZD 047324 hours, a synergistic effect was observed in A2780cisR (CI 0.37, 1.48), while other cell lines had weak synergistic/additive or antagonistic effects (CI 0.89, 1.02 for A2780E 6; 1.1, 12.9 for A2780CI sR; 2.4, 2.1 for CH 1).

CI values were calculated using the method of Chou and Talalay, Adv. enzyme Regulation, 1984, 22, 27-55. The first number in each case uses one data point (average) for each level, and the second number includes all data points on the same data point (including duplicate results).

These data show that, depending on the cell line, while most synergy is observed with half the doses, the order of use of ZD0473 and paclitaxel is important in determining growth inhibition, although synergy (depending on the cell line) can be observed regardless of the order of administration. Similar synergy can also be observed in other cell lines, such as SCLC.

The beneficial tumor cell growth inhibitory activity of the complexes of the invention may also be demonstrated in vivo, for example in a widely used xenograft model of human tumors (e.g., tumors using cisplatin) in mice (e.g., a greater effect may be obtained than with either drug used alone at the maximum tolerated dose).

The interaction of the activity favoring the inhibition of tumor cell growth and the toxicity of the complexes of this aspect was studied in clinical trials. For example, when combined with gemcitabine in a test, a suitable dose of ZD0473(1-2 hours of intravenous (iv) infusion, day one) and a suitable dose of gemcitabine (30 minutes of infusion per day, two days, day one and day eight) is administered to a human cancer patient and treatment is planned once every 3 weeks. On the first day of each cycle ZD0473 was administered for more than 1-2 hours, then discontinued for 30 minutes and gemcitabine administered for more than 30 minutes. On day eight, patients were treated with gemcitabine only, as on day one, at intervals exceeding 30 minutes. Treatment is recommended from the beginning of the second cycle and in subsequent cycles, according to the modification of the conventional dose. The dose levels for ZD0473 and gemcitabine were studied at 6 different dose levels and were escalated as follows:

dosage level (once every 3 weeks)	ZD0473a(mg/m2) First day of each cycle	Gemcitabinea(mg/m2) Day one and day eight of each cycle
			Level 1 level 2 level 3 level 4 level 5 level 6	6090120120120120	750750750100012501500

^aThe first day of ZD0473 administration is over 1-2 hours and gemcitabine administration is over 30 minutes, beginning 30 minutes after ZD0473 administration is complete. Gemcitabine was administered once more on day eight of each cycle. At least 3 patients were tested at each dose level to obtain a toxicity assessment for 3 patients. If dose-limiting toxicity (DLT) occurs in one patient, the number of trial patients will be expanded to obtain a toxicity assessment for 6 patients, so that it can be determined whether the MTD has been reached. The maximum number of patients tested per dose level was 8.

The definition of DLT and Maximum Tolerated Dose (MTD), and the factors that determine DLT are shown below (based on CTC grading system):

absolute Neutrophil Count (ANC) less than 0.5X 10⁹/L with fever or infection

ANC less than 0.5X 10⁹L lasts for more than 5 days

The number of platelets is less than 25X 10⁹/L

Non-hematologic toxicities associated with grade 3-4 treatment do not include alopecia (or just the opposite), temporary elevation of alanine aminotransferase [ ALT ] or aspartate transferase [ AST ] levels, nausea, and vomiting in patients not given the best antiemetics

Delay of treatment for at least more than 3 weeks due to insurmountable toxicity

The criteria for further increasing the dose or continuing the dose at the same dose will be a function of the number of patients with the following DLT:

none of 3 people 1 → escalation to the next dose

1 out of 3 → another 3 patients

Of 6 people, 1 person → increase to the next dose

2 of 6 → MTD, Recommended Dose (RD) lower than MTD

At least 2 of the 3 people

Or → poisoning: MTD is a dose below the toxic dose; at least 3 people with RD lower than two dose of 6 people

Duration of treatment: each cycle was repeated every 3 weeks unless the patient's bone marrow failed to recover to a neutrophil count in excess of 1.5X 10⁹(ii)/L and platelet count of more than 100X 10⁹the/L or non-hematologic toxicity did not return to grade 1. A delay of more than 3 weeks (e.g., 42 days) between successive treatments is permissible. Patients were excluded if the criteria for allowing further treatment at the end of the 21 days of supplementation were not met. Patients who do not have the observed disease progression (examined once every two cycles, e.g., by tumor size, such as CAT scan or measurement markers) may continue to receive treatment until a termination of treatment is encountered. Treatment may be continued (as judged by the condition) until the investigator deems that this is the best condition for the patient from a disease control and general standpoint, unless a condition is encountered that stops the treatment.

Similar protocols can be used to determine the efficacy of the present invention when other non-platinum based anti-cancer agents are used. For example, by using a suitable dose of taxol (e.g., at 135-175 mg/m)²In the range of) and ZD0473 (for example at 100-150 mg/m)²Within the scope of (a), the above-described protocol for gemcitabine, using techniques typically available to physicians, may also be used with taxol. General tools for doctorsThe above-described protocol for gemcitabine in the prior art may also be used with, for example, ZD0473(1-10 mg/Kg/day, preferably 2-5 mg/Kg/day, more preferably 3-4 mg/Kg/day) and Iressa (1-20 mg/Kg/day, preferably 3-10 mg/Kg/day, more preferably 5 mg/Kg/day). Toxicity tests suitable for the drugs under study were performed based on the toxicity of each drug alone.

Claims (46)

1. Use of an anti-cancer effective amount of (SP-4-3) -cis-aminodichloro- [ 2-methylpyridine ] platinum (II) (ZD0473) or a prodrug thereof and an anti-cancer effective amount of a non-platinum anti-cancer agent in the manufacture of a medicament for use in combination therapy, said medicament being capable of providing an anti-cancer effect following administration of the above amounts of the medicament to a cancer patient, said ZD0473 being administered prior to the non-platinum anti-cancer agent.

2. Use of an anti-cancer effective amount of (SP-4-3) -cis-aminodichloro- [ 2-methylpyridine ] platinum (II) (ZD0473) or a prodrug thereof and an anti-cancer effective amount of a non-platinum anti-cancer agent in the manufacture of a medicament for use in combination therapy, said medicament being capable of providing an anti-cancer effect following administration of the aforementioned amounts of the medicament to a cancer patient, the ZD0473 and the non-platinum anti-cancer agent being administered simultaneously.

3. The use as claimed in claim 2 of ZD0473 and a non-platinum anti-cancer agent in combination prior to administration.

4. The use as claimed in claim 2 of ZD0473 in combination with a non-platinum anti-cancer agent.

5. Use of an anti-cancer effective amount of (SP-4-3) -cis-aminodichloro- [ 2-methylpyridine ] platinum (II) (ZD0473) or a prodrug thereof and an anti-cancer effective amount of a non-platinum anti-cancer agent in the manufacture of a medicament for use in combination therapy, the medicament being capable of providing an anti-cancer effect following simultaneous and/or sequential or separate administration of the aforementioned amounts of the medicament to a cancer patient, with the proviso that, when the non-platinum anti-cancer agent is paclitaxel or docetaxel and is administered separately from ZD0473 and before ZD0473, docetaxel or paclitaxel is administered within about 60 minutes or 60 minutes before ZD 0473.

6. The use of claim 1 or 5, wherein the amounts of the agents are administered separately or sequentially.

7. The use according to claim 5 wherein the non-platinum anti-cancer agent is administered before ZD 0473.

8. The use of claim 7 wherein the non-platinum anti-cancer agent is administered about 10 to 60 minutes before ZD 0473.

9. The use of any one of claims 1-8, wherein the cancer is a solid tumor.

10. The use of any one of claims 1-9, wherein the cancer is lung cancer, mesothelioma, ovarian cancer, breast cancer, cervical/uterine cancer, bladder cancer, prostate cancer, testicular cancer, pancreatic cancer, head and neck cancer, liver cancer, gastrointestinal cancer, stomach cancer, colon cancer, rectal cancer, lung cancer, skin cancer, bone cancer, or kidney cancer, or is kaposi's sarcoma, lymphoma, or leukemia.

11. The use as claimed in any one of claims 1 to 10, wherein the non-platinum anti-cancer agent is a topoisomerase I and/or II inhibitor, an antimetabolite, a protein kinase inhibitor, vinblastine, an anthracycline, an alkylating agent, an antiangiogenic agent, an anti-hormonal agent or an anti-HER-neu compound.

12. The use as claimed in any one of claims 1 to 11, wherein the non-platinum anti-cancer agent is a topoisomerase II inhibitor, a cytokine inhibitor, an antimetabolite, vinblastine, an anthracycline or an anti-HER-neu compound.

13. The use of any one of claims 1 to 12, wherein the non-platinum anti-cancer agent is irinotecan, etoposide, teniposide (teniposide), iressa (ZD1839), UFT, capecitabine, gemcitabine, pemetrexed, vinorelbine, doxorubicin (doxorubicin) or herceptin.

14. The use of any one of claims 1-10, wherein the non-platinum anti-cancer agent is a taxane.

15. The use of claim 14, wherein the non-platinum anti-cancer agent is paclitaxel or docetaxel.

16. The use of claim 14 or 15, wherein the cancer is prostate cancer.

17. The use of claim 9 or 10, wherein the cancer is colon or rectal cancer.

18. The use of claim 17, wherein the non-platinum anti-cancer agent is 5-FU.

19. Use according to any one of claims 1 or 5 to 8 wherein ZD0473 is formulated for oral administration.

20. The use according to any one of claims 1 to 19 wherein ZD0473 and/or a non-platinum anti-cancer agent is formulated for intravenous administration.

21. The use of any one of claims 1-20, wherein the combination therapy reduces neurotoxicity and/or nephrotoxicity resulting from replacement of one or more doses of (SP-4-3) -cis-aminodichloro- [ 2-methylpyridine ] platinum (II) or prodrug with a combination of carboplatin, platinum oxalate or cisplatin.

22. The use of claim 21, wherein the reduced neurotoxicity occurs in a neurological therapy.

23. The use of any one of claims 1-22, wherein the combination therapy reduces the intrinsic or acquired resistance resulting from the replacement of one or more doses of (SP-4-3) -cis-aminodichloro- [ 2-methylpyridine ] platinum (II) or prodrug with a combination of carboplatin, platinum oxalate or cisplatin.

24. The use as claimed in any one of claims 1 to 23, wherein a non-platinum anti-cancer agent is selected which has at least a synergistic anti-cancer effect with ZD0473 or a prodrug thereof.

25. The use as claimed in any one of claims 1 to 23, wherein a non-platinum anti-cancer agent is selected which has at least a synergistic anti-cancer effect with ZD0473 or a prodrug thereof.

26. The use of any one of claims 1-25, in combination with radiation therapy.

27. The use according to any one of claims 1 or 5 to 26, which comprises a combination of said amount of ZD0473 and a first pharmaceutical carrier and a combination of said amount of a non-platinum anti-cancer agent and a second pharmaceutical carrier.

28. The use according to any one of claims 1 or 5 to 27 in the manufacture of a medicament for use according to a suitable form comprising providing a kit comprising a container which comprises said amount of ZD0473 and said amount of a non-platinum anti-cancer agent in unit dosage form.

29. The use of any one of claims 1-28, wherein the medicament is provided in a suitable form, comprising providing administration information regarding the amount of said medicament.

30. A unit dosage form for use in a patient with cancer comprising about 50-600mg of (SP-4-3) -cis-aminodichloro- [ 2-methylpyridine ] platinum (II) (ZD0473) or a prodrug thereof and a physiologically acceptable amount of sodium chloride in a liquid carrier to form a sterile solution, said solution having a physiologically acceptable pH.

31. The unit dosage form of claim 30, wherein the solution further comprises glucose.

32. The unit dosage form of claim 30, wherein said liquid carrier comprises water.

33. The unit dosage form of claim 30, 31 or 32, which is buffered to physiological pH.

34. The unit dosage form of claim 33, which is suitable for parenteral administration.

35. The unit dosage form of claim 34, wherein said administration is by intravenous infusion.

36. A solid unit dosage form for use in a patient with cancer comprising about 50-600mg ZD0473 and a pharmaceutically acceptable carrier, said dosage form being suitable for oral administration.

37. The unit dosage form of claim 36, which is a capsule.

38. The unit dosage form of claim 36, which is a tablet.

39. The unit dosage form of claim 37 or 38, having an enteric coating.

40. A solid unit dosage form made by freeze-drying a solution comprising about 50-600mg of ZD0473A into a powder.

41. The solid unit dosage form of claim 40, wherein the solution further comprises sodium chloride.

42. The solid unit dosage form of claim 40 or 41, said solution further comprising glucose.

43. The solid unit dosage form of claim 40 or 41, wherein the solution further comprises mannitol.

44. The unit dosage form of claim 30 or 40, further comprising at least one non-platinum anticancer agent.

45. The unit dosage form of claim 44, wherein the ratio of the dose of ZD0473 to non-platinum anti-cancer agent is from 10: 1 to 1: 1000 by weight.

46. The unit dosage form of claim 44, wherein the non-platinum anti-cancer agent is present in an amount of about 5 to 5000 mg.