Long-term use of docetaxel in cancer treatment

Abstract

To provide a method for treating cancer, the method comprising a combination of different forms of treatment including combinations of different therapeutic agents.SOLUTION: The present invention relates to chemotherapy of tumors using taxanes, in particular docetaxel. More specifically, the present invention relates to a method for the treatment of a cancer in a patient, the method comprising orally administering an effective dose of docetaxel, and controlling side effects by preventing peak plasma levels of docetaxel that induce the side effects, while maintaining an effective plasma level of docetaxel to eradicate tumor cells.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to the chemotherapy of tumors using taxanes, particularly docetaxel. More particularly, it relates to achieving an effective dose of an oral dosage of docetaxel while maintaining acceptable toxicity. More particularly, it relates to achieving an oral dosage of an effective docetaxel that suppresses side effects and enables long-term use.

Background Art

[0002] The treatment of cancer involves a wide range of treatments. The treatments include, among others, surgery, radiotherapy, chemotherapy, immunotherapy, and cell therapy. In many cases, cancer treatment involves a combination of different forms of treatment, including combinations of different therapeutic agents. As part of the front-line chemotherapy, docetaxel, a taxane, is widely used in the treatment of various cancers. Docetaxel is a cytotoxic drug, and its main mode of action is understood to involve interference with the polymerization and disassembly of microtubules that inhibit mitotic cell division. The recommended dosage is intravenous administration every three weeks, and the dosage ranges from 75 to 100 mg / m2 body surface area. Docetaxel is used in the treatment of various cancers, including breast cancer, lung cancer, prostate cancer, gastric cancer, head and neck cancer, and ovarian cancer. While it can bring benefits to patients and potentially improve survival and quality of life, the use of docetaxel is associated with significant side effects. Typical side effects include, among others, neutropenia, a high risk of infections, thrombocytopenia, anemia, alopecia, fluid retention, diarrhea, nail toxicity, peripheral sensory neurotoxicity, and infusion-related reactions. Therefore, the recommended form of use has a limit on the number of cycles of docetaxel (usually 4 to 6 cycles). Furthermore, a standard pre-medication of a high dose of dexamethasone is required for each cycle.

Summary of the Invention

[0003] Surprisingly, it has been found that when using oral administration of docetaxel, an effective treatment with fewer side effects than those seen with intravenous administration can be obtained. By using oral administration, high peak concentrations of docetaxel measured in plasma (which can be measured in serum or whole blood) can be avoided, thereby enabling long-term administration. High peak concentrations of docetaxel in the blood are associated with many of the side effects seen with intravenous administration. When using oral administration and administering docetaxel more frequently, instead of every three weeks which is the standard treatment for intravenous administration of docetaxel, on a daily to weekly basis, the peak concentration can be further reduced while maintaining the docetaxel concentration in plasma and effectively suppressing the cancer in the control patients. Accordingly, the present invention provides a method for treating cancer in a patient, the method comprising orally administering an effective dose of docetaxel and maintaining a plasma concentration of docetaxel effective to eradicate tumor cells while preventing the peak plasma concentration of docetaxel that induces the side effects, thereby suppressing the side effects. The present invention also provides a method for reducing the side effects of treating cancer in a patient, the method comprising administering docetaxel, orally administering the docetaxel, and suppressing the side effects by maintaining a plasma concentration of docetaxel effective to eradicate tumor cells while preventing the peak plasma concentration of docetaxel that induces the side effects. Reducing and suppressing the side effects are generally important when using docetaxel. Also, reducing or suppressing the side effects enables long-term use of docetaxel. This can be important for combination therapy, for example, combinations of anti-cancer therapies can be combined to maintain cancer suppression over a long period. Further, the combined use of orally administered docetaxel and the use of a CYP3A inhibitor such as ritonavir provides a further means of maintaining an effective plasma concentration of docetaxel that suppresses or reduces the side effects associated with the use of docetaxel while eradicating tumor cells. Brief Description of the Drawings

[0004]

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Mode for Carrying Out the Invention

[0005] The present invention provides a method for treating cancer in a patient, the method comprising orally administering an effective dose of docetaxel and suppressing side effects by maintaining a plasma concentration of docetaxel effective to eradicate tumor cells while preventing the peak plasma concentration of docetaxel that induces said side effects. The standard administration route of docetaxel currently used clinically involves intravenous administration of docetaxel. Since intravenous administration is direct into the bloodstream, this administration route results in high peak concentrations of docetaxel measured in plasma or serum. However, while high peak plasma concentrations can induce side effects, high peak plasma concentrations can contribute to the cytotoxic effect of docetaxel on cancer cells and contribute to treatment. Surprisingly, however, the inventors have found that for effective treatment of cancer in patients, it is important to maintain an effective plasma concentration and avoid peak plasma concentrations. By using an alternative administration route, oral administration, such high peak plasma concentrations can be largely avoided. Therefore, the side effects of cancer treatment in patients can be reduced. The present invention also provides a method for reducing the side effects of cancer treatment in a patient, the method comprising administering docetaxel, orally administering said docetaxel, and suppressing side effects, inter alia, by maintaining a plasma concentration of docetaxel effective to eradicate tumor cells while preventing the peak plasma concentration of docetaxel that induces said side effects.

[0006] As used herein, peak plasma concentration is defined as the maximum concentration of a compound that can be measured in plasma obtained from a patient after administration of a pharmaceutical composition. Typically, peak plasma concentration can be measured immediately after administration, but depending on the administration route and the composition of the pharmaceutical composition, there may be a time difference between the time of administration and the measured peak plasma concentration. In the case of intravenous administration of docetaxel, the peak level can be measured, for example, at the end of the infusion. In the case of oral administration of docetaxel, the time at which the peak level occurs after oral administration can vary. The peak level occurs about 2 to 12 hours, for example 4 hours, after oral administration.

[0007] Plasma docetaxel concentration can be measured by methods known in the art (Hendrikx et al. J. Chrom. B, 2011), and such methods can include, for example, liquid chromatography and mass spectrometry methods such as those described in the Examples. Plasma is a blood component, and of course, instead of measuring docetaxel in plasma, the docetaxel concentration in whole blood or serum can also be determined. In this specification, the measured values of docetaxel, such as peak concentration and the area under the plasma concentration-time curve, are determined with respect to (blood) plasma in the short area under the curve (AUC), but can be easily recalculated to the corresponding peak concentration in whole blood or serum. In any case, the high peak plasma concentration to be avoided can be defined as a peak plasma concentration of docetaxel of 3000 ng / mL or more. Preferably, the peak plasma concentration of docetaxel in oral administration is at most 2500 ng / mL, preferably at most 2000 ng / mL, more preferably at most 1500 ng / mL, and most preferably the peak plasma concentration in oral administration is at most 1000 or 500 ng / mL.

[0008] As used herein, "effective plasma concentration" means the plasma concentration measured in a subject that results in a specific pharmacological effect of docetaxel in the subject, namely eradication of cancer cells. The effective plasma concentration herein is defined as the area under the curve (AUC) determined 48 hours after the first administration of docetaxel, and the AUC is 250 - 2500 ng·h / mL. Preferably, the AUC is 750 - 2500 ng·h / mL. Preferably, the AUC is at least 400 ng·h / mL, at least 500 ng·h / mL, more preferably at least 600 ng·h / mL, at least 1000 ng·h / mL, and more preferably at least 1200 ng·h / mL. Preferably, the AUC is at most 2500 ng·h / mL, more preferably at most 2250 ng·h / mL, more preferably at most 2000 ng·h / mL, at most 1800 ng·h / mL, at most 1700 ng·h / mL, and more preferably at most 1500 ng·h / mL. The AUC can more preferably be 800 - 1400 ng·h / mL. The area under the curve (AUC; ng·h / mL) is determined 48 hours after the first administration of docetaxel, during which the plasma docetaxel concentration can be measured at several time points, and the surface area under the curve can be calculated from the plotted values. Here, the plasma concentration-time curve, the area under the curve, or AUC for docetaxel is used interchangeably and refers to the area under the curve at the first 48 hours (ng·h / mL) after the administration of docetaxel.

[0009] Cancer cell eradication is understood to include the death of cancer cells. For example, in the case of solid tumors, the growth of the solid tumor decreases compared to the growth of a tumor in the absence of an effective plasma concentration of docetaxel. The growth of the tumor can decrease to the extent that the tumor can be similarly eradicated. The emphasized effective plasma concentration is not necessarily effective for the treatment of the subject's condition described herein, even if those skilled in the art consider it therapeutically effective.

[0010] Side effects that can be suppressed or reduced in current treatments include neutropenia. Such neutropenia can be febrile neutropenia. Neutropenia is an abnormally low concentration of neutrophils in the blood. Neutropenia is usually diagnosed by determining the absolute neutrophil count in the blood. For reference, a healthy range of neutrophil count in the blood can be defined as 1500 - 4000 cells / μL of blood. Neutropenia can be diagnosed when the neutrophil concentration is less than 1500 cells / μL of blood. Assays for determining neutrophil count are widely available as part of, for example, a complete blood count analysis and as part of routine laboratory tests. Thus, in the present invention, the occurrence of neutropenia is advantageously reduced in a patient population while providing an effective cancer treatment in the patient. Therefore, preferably, in a method for treating cancer in a patient, the side effect of neutropenia is suppressed or reduced. Other side effects that can be suppressed or reduced are thrombocytopenia, neuropathy, alopecia, fluid stasis, neurotoxicity, and / or nail toxicity.

[0011] Further side effects that can be avoided using oral administration of docetaxel according to the present invention include, for example, infusion-related reactions due to excipients (notably Tween-80, ethanol) used in intravenous formulations of docetaxel. Corticosteroids such as dexamethasone are used as prophylaxis for such infusion-related reactions in current intravenous docetaxel treatments. Oral administration of docetaxel, which does not require corticosteroid prophylaxis, can similarly avoid the toxicity associated with (long-term) treatment with corticosteroids.

[0012] As used herein, oral administration of docetaxel to a subject includes any route for introducing or delivering an agent that exerts its intended function to the subject via the mouth. Pharmaceutical compositions suitable for oral administration include solutions, tablets or capsules. Capsules and tablets may have an enteric coating such that docetaxel is released from the capsule or tablet in the intestine. Capsules and tablets may be formulated as sustained release formulations in which docetaxel is released over a long period of time, for example, for several hours or more, for example, during passage through the intestinal tract. Thus, tablets and capsules may be formulated such that the agent is gradually released therefrom. Tablets and capsules may be formulated such that the agent is released in the stomach or intestine. Tablets and capsules may be formulated such that the agent is released in the stomach and intestine. Administration includes self - administration and administration by others.

[0013] The pharmaceutical composition of the present invention may contain docetaxel, or a pharmaceutically acceptable salt and esters thereof, and / or a CYP3A inhibitor such as ritonavir, (or a pharmaceutically acceptable salt and esters thereof) together with any pharmaceutically acceptable carrier, adjuvant or vehicle. Preparations and / or pharmaceutical compositions suitable for oral administration include those described in WO 2009 / 027644, WO 2010 / 020799 and Moes et al. Drug Deliv. Transl. Res. 2013, the contents of which are incorporated herein by reference. Any suitable preparation suitable for oral administration can be considered.

[0014] The present invention is not limited to oral administration of docetaxel. Any administration of docetaxel via the gastrointestinal tract can be considered. Therefore, enteral administration can be considered as an alternative to oral administration. Preferably, enteral administration is in the form of capsules, tablets, and suppositories. Administration of docetaxel by suppository is advantageous because it can improve the bioavailability compared to oral administration. This is because, in oral administration, after passing through the stomach and intestine, docetaxel is delivered to the liver through the portal vein. Enteral administration can avoid the barrier that metabolizes docetaxel during the first pass. Any enteral administration can be sufficient as long as the peak concentration defined herein is avoided and an effective plasma concentration is obtained.

[0015] For many anticancer drugs such as docetaxel, cytochrome P450 represents the main oxidative drug metabolism enzyme system. Cytochrome P450 (CYP) isoenzymes, especially CYP3A4 (which may also include CYP3A5), (referred to as toasCYP3A herein) are highly expressed in the liver and intestine. Enterohepatic extraction and metabolism of docetaxel by this enzyme system play an important role in limiting oral bioavailability. It also plays a role as part of the metabolic pathway transporter. Intracellular and extracellular transport of compounds such as docetaxel provides the compound as a substrate to the CYP3A4 and / or CYP3A5 enzymes. For example, P-glycoprotein (P-gp, MDR1, ABCB1) plays a role in the metabolic pathway and the transport of docetaxel. Therefore, any compound that can affect the metabolic pathway of docetaxel and inhibit its metabolism can be considered a suitable CYP3A inhibitor. Such compounds can affect CYP3A4 and / or CYP3A5, as well as P-glycoprotein (Er-jiaWang et al., Chem.Res.Toxicol.2001; Wacher et al., Mol Carc.1995), or can have different effects on either CYP3A4 and / or CYP3A5, and P-glycoprotein (Er-jiaWang et al., Chem.Res.Toxicol.2001). Therefore, a suitable CYP3A inhibitor affects both CYP3A4 (and CYP3A5) and P-glycoprotein. A suitable CYP3A inhibitor affects CYP3A4 and / or CYP3A5. A suitable CYP3A inhibitor can affect P-glycoprotein. Therefore, a CYP3A inhibitor is defined herein as a compound capable of reducing the metabolism of intracellular CYP3A4 and CYP3A5. Said compound is preferably a pharmaceutical compound. Preferably, a CYP3A inhibitor that inhibits CYP3A4, such as ritonavir for example, is selected. Ritonavir also inhibits CYP3A5 and P-glycoprotein. Selective inhibition of CYP3A4 is highly preferred.

[0016] A method for treating cancer in a patient, comprising the step of orally administering docetaxel as described herein, preferably controls the plasma concentration of docetaxel at least in part by administering a CYP3A inhibitor. The use of a CYP3A inhibitor helps the transport of docetaxel from the stomach and / or intestine into the bloodstream by reducing and / or inhibiting CYP3A4 and / or CYP3A5 activity within the cells. Thus, the use of a CYP3A inhibitor can increase the bioavailability of docetaxel. While such bioavailability can be increased, the peak concentration of docetaxel is not substantially increased. Therefore, by using a CYP3A inhibitor, an effective plasma concentration of docetaxel can be increased compared to the case without using a CYP3A inhibitor, enabling the use of a lower dosage of oral docetaxel. Instead, by using a CYP3A inhibitor, an effective plasma concentration with the area under the curve as defined herein can be obtained more efficiently compared to the case without using a CYP3A inhibitor, allowing for less frequent dosing of oral docetaxel.

[0017] Therefore, in the method according to the present invention, the plasma concentration of docetaxel is at least partially controlled by administering a CYP3A inhibitor. As described above, oral administration of docetaxel is combined with the use of a CYP3A inhibitor. Any CYP3A inhibitor is sufficient. For example, the CYP3A inhibitor can be a potent CYP3A inhibitor selected from the group consisting of bosentan, clarithromycin, erythromycin, indinavir, itraconazole, ketoconazole, posaconazole, ritonavir, saquinavir, and voriconazole. Preferably, a CYP3A inhibitor having the fewest side effects is used. Most preferably, the CYP3A inhibitor combined with oral administration of docetaxel is ritonavir. Preferably, the CYP3A inhibitor for use in combination therapy according to the present invention, ritonavir administered at a dosage of 100 ng or 200 ng, or an equivalent dosage of another suitable CYP3A inhibitor is included. Since the effects of the CYP3A inhibitor and ritonavir in a subject can be compared, another CYP3A inhibitor can be selected, and the dosage thereof that gives the same effect can be established, the dosage suitable for any other suitable inhibitor can be easily established. The effect is defined as the effect on the docetaxel plasma concentration (AUC) and / or the peak plasma concentration obtained with the dosage of ritonavir used.

[0018] Of course, in the methods and uses according to the present invention, any additional use of compounds including foods and further pharmaceuticals that can affect CYP3A activity is preferably avoidable since such foods can affect the docetaxel concentration achieved in the plasma of the subject being treated. Therefore, no matter which potent CYP3A inhibitor is selected for combination therapy with docetaxel, it is necessary to avoid further use of the CYP3A inhibitor by the subject being treated since it can result in too high an area under the curve. Examples of further inhibitors that are preferably avoided are, for example, HIV antivirals: indinavir, nelfinavir and saquinavir; antibacterial agents: clarithromycin, itraconazole, ketoconazole, nefazodone, telithromycin, erythromycin, fluconazole, chloramphenicol, ciprofloxacin, norfloxacin and voriconazole; cardiac agents: verapamil, diltiazem, cimetidine and amiodarone; other agents such as fluvoxamine; and foods such as starfruit and grapefruit juice. Conversely, preferably, in the methods and uses of the present invention, the use of compounds including foods and further pharmaceuticals that can induce CYP3A activity in the subject being treated is preferably similarly avoided since such use can result in too high peak concentrations of docetaxel in the plasma. Inducers of CYP3A that are preferably avoided are HIV antivirals: efavirenz and nevirapine; other agents: barbiturates, carbamazepine, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampicin, etc., and St. John's wort.

[0019] In one embodiment, in the method according to the present invention, the CYP3A inhibitor is administered simultaneously with docetaxel. Of course, simultaneous administration may include separate administrations, for example, administrations with separate pharmaceuticals. For example, one pharmaceutical suitable for oral administration includes docetaxel, and another pharmaceutical includes a CYP3A inhibitor such as ritonavir. The pharmaceutical preferably includes ritonavir for oral administration. Of course, simultaneous administration may include one pharmaceutical containing both docetaxel and a CYP3A inhibitor such as ritonavir. Also, docetaxel and the CYP3A inhibitor may be administered separately. When administered separately, the CYP3A inhibitor is preferably administered before docetaxel, and more preferably within about 60 minutes before docetaxel administration. As used herein, simultaneously means, for example, administration of docetaxel or the CYP3A inhibitor within about 20 minutes, more preferably within 15 minutes, more preferably within 10 minutes, even more preferably within 5 minutes, and most preferably within 2 minutes of the CYP3A inhibitor or docetaxel. Generally, the CYP3A inhibitor is preferably orally administered simultaneously with the oral administration of docetaxel, as it provides optimal compliance in self-administration by the subject being treated.

[0020] In another embodiment, in the method according to the present invention, the treatment of cancer includes long-term use exceeding 18 weeks. As described above, standard intravenous administration routes and standard use of docetaxel do not recommend long-term use due to serious side effects and increased toxicity associated with multiple administrations. Due to the improved method of the present invention, it is possible to extend the use for a longer period in the treatment method. The method of the present invention enables long-term use exceeding 30 weeks, and the method includes maintaining an effective plasma concentration of docetaxel that eradicates tumor cells while suppressing or reducing side effects associated with the use of docetaxel. Therefore, in one embodiment, preferably, the method of the present invention enables long-term use of treatment for at least 30 weeks. Such use enables long-term use of more than one year.

[0021] By knowing both upper limits, i.e., the range of peak plasma concentration and / or effective plasma concentration, the ranges administered in the methods and uses of the present invention enable both effective tumor cell eradication and suppression or reduction of the side effects of docetaxel. The effective plasma concentration can be considered to represent the range in which docetaxel can effectively eradicate cancer cells. The peak plasma concentration can be considered to represent the upper limit at which the side effects of docetaxel can be suppressed or reduced. Therefore, any suitable pharmaceutically acceptable formulation and / or dosing schedule that moves within this range can be considered, and as described herein, provides favorable tumor cell eradication and suppression or reduction of the side effects of docetaxel, enabling long-term use that cannot be envisioned with the standard approved intravenous administration of docetaxel treatment.

[0022] In the methods or uses according to the present invention, the administration of docetaxel can be three times a day, twice a day or daily, every two days, weekly, every two weeks, every three weeks or any other suitable dosing interval. These dosing schedules can also be combined, for example, twice-daily dosing, once a week or every two weeks or every three weeks. For example, docetaxel can be administered twice a day, once a week. The weekly dose is divided such that the subject takes, for example, a first dose in the morning and a second dose in the evening, once a week. This has the effect of reducing the peak concentration of the drug in the plasma, which can help reduce side effects. The time of systemic exposure of the drug can also be increased. In a preferred embodiment, the method or use according to the present invention comprises administering docetaxel weekly. Also, docetaxel can be administered twice a day, once a week, which means administering docetaxel twice within, for example, an 8 - 16 hour interval, once a week. Such dosing intervals and / or dosages can be considered as long as the dosing intervals and / or dosages of docetaxel and a CYP3A inhibitor (such as ritonavir) are selected that make it possible to maintain an effective plasma concentration for eradicating tumor cells while suppressing or reducing side effects by preventing peak plasma concentration.

[0023] In a further embodiment, since such a dosage can result in a plasma concentration of docetaxel that is effective in eradicating tumor cells and suppressing or reducing the side effects of docetaxel in a patient, docetaxel is administered at a dosage of at least 10 mg per dosage administration. Preferably, the dosage is at least 20 mg per dosage administration. As described above, docetaxel is preferably administered simultaneously with a CYP3A inhibitor such as ritonavir. Preferably, ritonavir is administered simultaneously at a dosage of at least 100 mg. Therefore, in the method according to the invention in which ritonavir is administered simultaneously with docetaxel, 10 mg of docetaxel and 100 mg of ritonavir are administered at each dosing time. Therefore, in a further method according to the invention in which ritonavir is administered simultaneously with docetaxel, at least 10 mg of docetaxel and at least 100 mg of ritonavir are administered at each dosing time. As described above, such administration can be on a weekly schedule or a twice-daily schedule on one day per week. Therefore, in the above twice-daily schedule on one day per week, at each dosing time, there is an administration of at least 10 mg of docetaxel, or an administration of at least 10 mg of docetaxel and at least 100 mg of ritonavir. In another embodiment, a twice-daily schedule on one day per week is provided for the treatment of cancer, docetaxel is administered on one day, the first administration is at a dosage of 30 mg of docetaxel and 100 mg of ritonavir, and the second administration is at a dosage of 20 mg of docetaxel and 100 mg of ritonavir. In another embodiment, a twice-daily schedule on one day per week is provided for the treatment of cancer, docetaxel is administered on one day, the first administration is at a dosage of 30 mg of docetaxel and 200 mg of ritonavir, and the second administration is at a dosage of 20 mg of docetaxel and 100 mg of ritonavir. In another embodiment, a twice-daily schedule on one day per week is provided for the treatment of cancer, docetaxel is administered on one day, the first administration is at a dosage of 30 mg of docetaxel and 200 mg of ritonavir, and the second administration is at a dosage of 20 mg of docetaxel and 200 mg of ritonavir.

[0024] In another embodiment, a schedule of twice a day for one day per week is provided for the treatment of cancer, docetaxel is administered once a day, the first dose is a dosage of 20 mg docetaxel and 200 mg ritonavir, and the second dose is a dosage of 20 mg docetaxel and 200 mg ritonavir. In another embodiment, a schedule of twice a day for one day per week is provided for the treatment of cancer, docetaxel is administered once a day, the first dose is a dosage of 20 mg docetaxel and 100 mg ritonavir, and the second dose is a dosage of 20 mg docetaxel and 100 mg ritonavir. In another embodiment, a schedule of twice a day for one day per week is provided for the treatment of cancer, docetaxel is administered once a day, the first dose is a dosage of 20 mg docetaxel and 200 mg ritonavir, and the second dose is a dosage of 20 mg docetaxel and 100 mg ritonavir.

[0025] In another embodiment, in the method according to the invention, the cancer is a solid tumor. In the method according to the invention, the cancer to be treated can be the same as that currently defined with intravenous administration of docetaxel. Therefore, preferably, the method includes the treatment of cancer where the cancer is a solid tumor selected from the group consisting of gastric cancer, breast cancer, head and neck cancer, lung cancer and prostate cancer.

[0026] In one embodiment, the present invention provides a combination of a CYP3A inhibitor and docetaxel for use in the treatment of cancer, including oral administration of docetaxel, while preventing the peak plasma concentration of docetaxel that induces side effects and maintaining the plasma concentration of docetaxel that eradicates tumor cells. In another embodiment, the present invention provides docetaxel for use in combination therapy in the treatment of cancer, wherein the docetaxel is administered in combination with a CYP3A inhibitor, including oral administration of docetaxel, while preventing the peak plasma concentration of docetaxel that induces side effects and maintaining the plasma concentration of docetaxel that eradicates tumor cells. In yet another embodiment, the present invention provides a CYP3A inhibitor for use in combination therapy in the treatment of cancer, wherein the CYP3A inhibitor is administered in combination with docetaxel, orally administering docetaxel, while preventing the peak plasma concentration of docetaxel that induces side effects and maintaining the plasma concentration of docetaxel that eradicates tumor cells. The CYP3A inhibitor in these embodiments is preferably ritonavir.

[0027] Similar to that described herein for the methods of the present invention, the above use includes a peak plasma concentration of docetaxel of up to 2500 ng / mL. The above upper limit results in a plasma concentration not associated with side effects. The above use preferably includes an effective plasma concentration of docetaxel within the range of an AUC of 800 - 2000 ng·h / mL. Similarly, the above use preferably includes an effective plasma concentration of docetaxel within the range of an AUC of 1000 - 2000 ng·h / mL. The use preferably includes long-term use exceeding 30 weeks. The use preferably includes the treatment of cancer where the cancer is a solid tumor. The use preferably includes cancer where the cancer is a solid tumor selected from the group consisting of gastric cancer, breast cancer, head and neck cancer, lung cancer, and prostate cancer.

[0028] The present invention also provides a kit for long-term use in the treatment of cancer, comprising a pharmaceutical composition for oral administration containing docetaxel and a pharmaceutical composition containing a CYP3A inhibitor. Further provided is a kit for the uses and methods described herein, comprising a pharmaceutical composition for oral administration containing docetaxel and a pharmaceutical composition containing a CYP3A inhibitor.

[0029] In this specification and the claims, unless otherwise expressly stated, the singular forms are used interchangeably and the plural forms are similarly included and are meant to be included in their respective meanings. Also, in this specification, "and / or" refers to and includes not only all possible combinations of one or more of the recited items, but also, when construed as alternatives, the non-combination ("or").

[0030] In this specification, "about" is understood by those skilled in the art and varies to some extent depending on the context in which it is used. Where its use is not clear to those skilled in the art in the context in which the term is used, "about" means up to ± 10% of the particular term.

Examples

[0031] Modradoc006 Modradoc006 is a spray-dried solid dispersion formulation of docetaxel pressed into tablets (ModraDoc006 10 mg tablets) and contains 10 mg of docetaxel. The formulation excipients are polyvinylpyrrolidone K30, sodium dodecyl sulfate, lactose monohydrate, croscarmellose, colloidal anhydrous silica and magnesium stearate. All excipients are included in the FDA guidelines for inactive compounds (oral capsules and tablets).

[0032] Ritonavir Ritonavir is commercially available as 100 mg tablets for oral intake (Norvir®). These tablets were approved by the European Commission in 2010.

[0033] Docetaxel and ritonavir plasma measurements A combined assay for the determination of docetaxel and ritonavir in human plasma is described. The drugs were extracted from 200 μL of human plasma using liquid-liquid extraction with t-butyl methyl ether, followed by high performance liquid chromatography analysis using 10 mM ammonium hydroxide pH 10: methanol (3:7, v / v) as the mobile phase. Chromatographic separation was obtained using a Zorbax Extend C(18) column. A labeled analog of the analyte was used as the internal standard. For detection, positive ion electrospray tandem mass spectrometry was used. The development method, including optimization of mass transitions and reactions, mobile phase optimization, and column selection, was discussed. The method was demonstrated according to the FDA guidelines and the principles of Good Laboratory Practice (GLP). The demonstrated range was 0.5 - 500 ng / mL for docetaxel and 2 - 2000 ng / mL for ritonavir. For quantification, a secondary calibration curve was used (r(2) > 0.99). The total run time of the method was 9 minutes, and the assay combines the analyte with differences in ionization and desired concentration ranges. The accuracy and precision between analytical methods were tested at four concentration levels and were each less than 10% for all analytes. Carryover was less than 6%, and internal interference, or interference between the analyte and the internal standard, was less than 20% of the reaction at the lower limit of the quantification level. Matrix factors and recoveries were determined at low, intermediate, and high concentration levels. The matrix factor was approximately 1 for all analytes, and the total recovery was 77.5 - 104%. Stability was investigated between stock solution, human plasma, dried extract, final extract, and three freeze / thaw cycles. The described method was successfully applied to clinical studies using oral administration of docetaxel in combination with ritonavir.

[0034] mCRPC trial In a Phase I trial, oral treatment with ModraDoc006 / r was shown in patients with several solid tumors (not prostate). From this study, the dose recommended for Phase II efficacy evaluation was ModraDoc006 30 mg + ritonavir 100 mg, taken simultaneously in the morning ModraDoc006 20 mg + ritonavir 100 mg, taken simultaneously in the evening and concluded that.

[0035] This treatment (referred to as ModraDoc006 / r 30 - 20 / 100 - 100) is given once a week, daily.

[0036] Pharmacokinetic studies revealed that the docetaxel AUC0 - 48h for this treatment schedule in cycle 1 was 1126 ± 382 h*ng / mL. The CMAX value was 102 ± 46 ng / mL (average of 16 treated patients).

[0037] In the next step, this oral treatment schedule was investigated in an IB / IIA phase trial (M17DOC) in patients with metastatic castration - resistant prostate cancer (mCRPC). Surprisingly, in the first 5 patients treated at the dose recommended from the phase I trial (ModraDoc006 / r 30 - 20 / 100 - 100), a much lower docetaxel exposure (AUC0 - 48h) of 498 ± 298 h.ng / mL was noted, which was approximately half of what was expected. The CMAX value: 45 ± 31 ng / mL was also half of what was expected. The patients did not experience significant side effects. It was concluded that the clearance of docetaxel was higher in this mCRPC patient population than in patients with other solid tumors.

[0038] A hypothesis was established that by increasing (doubling) the dose of the CYP3A inhibitor ritonavir, a target exposure of approximately 1100 ± 500 h.ng / mL could be achieved. Next, 8 mCRPC patients were treated with ModraDoc006 / r 30 - 20 / 200 - 200 (once a day, once a week). The docetaxel exposure in this group was AUC0 - 48h: 2032 ± 1018 h.ng / mL and CMAX 164 ± 80 ng / mL. These values were higher than expected. Also, the patients experienced more side effects (grade III).

[0039] Next, assuming that reducing the ritonavir dose would lower docetaxel exposure to its target value, three mCRPC patients were treated with ModraDoc006 / r at doses of 30~20 / 200~100. In this treatment group of patients, docetaxel exposure was AUC0~48h: 1130±257 h·ng / mL and CMAX 135±46 ng / mL. They tolerated the treatment well.

[0040] The results are also shown in Figures 2A and 2B.

[0041] Summarized as follows.

Table 1

[0042] The test results described above were obtained during the test and represent intermediate results. The test will continue, and the updated results will be described below. Phase IB / IIA study in mCRPC

[0043] A multicenter clinical phase IB / IIA study of ModraDoc006 (oral docetaxel formulation) combined with ritonavir (ModraDoc006 / r) was conducted in mCRPC (M17DOC).

[0044] The study included patients diagnosed with metastatic castration-resistant prostate cancer (mCRPC) and the patients were dosed on a twice-daily, once-weekly (BIDW) dosing schedule at four dose levels (see table below).

Table 2

[0045] As described above, surprisingly, in the first fifth patient, treatment was carried out at a dose much lower than that recommended from the Phase I trial (ModraDoc006 / r 30~20 / 100~100) (docetaxel exposure at cycle 1 of 454±181 h.ng / mL (central AUC0~48h±SD)), which was about half of what was expected. The CMAX value: 38±18 ng / mL was also half of what was expected. The patient did not experience significant side effects. It was concluded that the clearance of docetaxel in this mCRPC patient population was higher than that in patients with other solid tumors.

[0046] As described above, next, a hypothesis was established that by increasing (doubling) the dose of the CYP3A inhibitor ritonavir, the target exposure of about 1100±500 h.ng / mL could be achieved. Subsequently, eight mCRPC patients (six evaluable) were treated with ModraDoc006 / r 30~20 / 200~200 (once a day, once a week). Docetaxel exposure in this group in cycle 1 was a central AUC0~48h±SD of 1510±990 h.ng / mL and a CMAX of 146±82 ng / mL. These values were higher than expected. Also, the patients experienced more side effects (grade III).

[0047] Next, assuming that docetaxel exposure would decrease to its target value by reducing the ritonavir dose, mCRPC patients (n = 6) were treated with the dose of ModraDoc006 / r 30~20 / 200~100. In this treatment group of patients, docetaxel exposure in cycle 1 was a central AUC of 1189±473 h.ng / mL for 0~48h±SD and a CMAX of 159±49 ng / mL. They tolerated the treatment well.

[0048] In mCRPC patients (n = 3) treated with ModraDoc006 / r 20~20 / 200~100, due to the reduced morning dose of docetaxel, docetaxel exposure in cycle 1 was a central AUC of 419±158 h.ng / mL for 0~48h±SD and a CMAX of 53±21 ng / mL.

[0049] In summary, it is as follows.

Table 3

[0050] The results of the test are further described below and shown in Figures 4 to 8.

Table 4

[0051] (PSA (prostate-specific antigen); SD (stable disease); non-CR (incomplete response); non-PD (non-progressive disease); PD (progressive disease); NE (not evaluable); PR (partial response)).

[0052] Summary of efficacy: This study included 20 evaluable patients diagnosed with metastatic castration-resistant prostate cancer (mCRPC) who were dosed at four dose levels on a twice-daily, once-weekly (BIDW) dosing schedule (see table). In seven patients, a PSA response (PSA decrease of ≧50%) was seen, of which five were confirmed at the second measurement after 6 weeks. In another seven patients, PSA decreased by <50% or was equal to baseline. In the remaining six patients, a PSA increase was seen. Despite a <50% decrease in PSA in one patient and a PSA increase in another patient, a significant clinical response due to pain reduction was achieved during the maximum treatment duration of 30 weeks. A total of five patients completed the treatment weeks up to a maximum of 30 weeks. The median treatment duration was 14 weeks. ModraDoc006 / r 30~20 / 200~100 is a preferred initial dose for further testing in mCRPC, achieving a higher exposure level of docetaxel (measured by AUC) than that achieved with IV docetaxel while allowing acceptable toxicity. Alternatively, ModraDoc006 / r20~20 / 200~100 may be another preferred dose or a preferred initial dose in mCRPC.

[0053] Long-term use N07DOW In the Phase I trial (N07DOW), cancer patients (n = 100) were treated with oral docetaxel in combination with ritonavir. The dose was administered once daily, once a week. Data were shown as mean ± standard deviation. When available, two cycles of dynamic data per patient were used. The treatment duration of 19 patients was 19 to a maximum of 72 weeks. These were patients with the following cancers: head and neck (n = 1), non-small cell lung (n = 8), anal (n = 1), initially unknown (n = 3), ovarian (n = 1), esophageal (n = 1), urothelial (n = 2), leiomyosarcoma (n = 1) and neuroendocrine lung cancer (n = 1). Docetaxel exposure in these patients was AUC0~48h 803 ± 634 h.ng / mL CMAX (peak) 148 ± 113 ng / mL as follows.

[0054] SAE (serious adverse events) and DLT (dose-limiting toxicity) (possible, probably, confirmed; ≥ grade 3) were noted in 15 patients. Docetaxel exposure in these patients was AUC0~48h 2345 ± 1453 h.ng / mL CMAX 351 ± 244 ng / mL as follows.

[0055] Fifty-two patients had SD (disease stability) (n = 42) or PR (partial response) (n = 10) as the best treatment response. Docetaxel exposure in these patients was AUC0~48h 1083 ± 1023 h.ng / mL CMAX 197 ± 186 ng / mL as follows.

[0056] N10BOM In the Phase I trial (N10BOM), cancer patients (n = 64) were treated with oral docetaxel in combination with ritonavir. The dose was continuously administered twice daily, once a week. The treatment duration of 8 patients was 19 to a maximum of 55 weeks. These were patients with the following cancers, head and neck cancer (n = 2; PR), non-small cell lung (n = 4; SD), colorectal (n = 1; SD) and large cell neuroendocrine cancer (n = 1; SD). Docetaxel exposure in these patients was AUC0~48h 1224±620h.ng / mL CMAX 143±67ng / mL as follows.

[0057] SAE and DLT (possible, probable, definite; ≥ grade 3) were noted in 10 patients. Docetaxel exposure in these patients was AUC0~48h 1809±1255h.ng / mL CMAX 175±117ng / mL as follows.

[0058] Twenty-five patients had SD or PR as the best treatment response. Docetaxel exposure in these patients was AUC0~48h 1242±702h.ng / mL CMAX 140±83ng / mL as follows.

[0059] Summarized as follows.

Table 5

[0060] Comparison: The following AUC and CMAX values were obtained by weekly administration of docetaxel (35 mg / m2) as a 0.5 h intravenous infusion. AUC 1480±410h.ng / mL CMAX 1930±600ng / mL Baker SD et al.Clin Cancer Res 2004;10:1976~1983.

[0061] For the twice-daily and once-weekly use of oral docetaxel and ritonavir (ModraDoc006 / r), the following target values can be proposed. AUC 1200±600 h·ng / mL CMAX 140±70 ng / mL

[0062] With this weekly oral treatment schedule, a docetaxel exposure (AUC) similar to that on the dosing day of the weekly intravenous treatment schedule is achieved daily (also, often after 3 consecutive weeks of intravenous administration, there is 1 week remaining, while oral docetaxel is continuously administered without the remaining week). The CMAX value after this intravenous administration (35 mg / m2, 0.5 h) is 10 times higher than that after oral ModraDoc006 / r 30~20 / 100~100 in patients with solid tumors (not prostate).

[0063] · Intravenous (35 mg / m2) docetaxel and oral docetaxel treatment (ModraDoc006 / r 30~20 / 100~100) give similar AUCs and comparable efficacy is expected. · Intravenous (35 mg / m2, 0.5 h) docetaxel gives a CMAX 10 times higher than oral docetaxel treatment (ModraDoc006 / r 30~20 / 100~100), which may explain the higher toxicity with intravenous treatment. · In oral docetaxel treatment (ModraDoc006 / r), higher AUC0~48h-CMAX values are correlated with toxicity. · In oral docetaxel treatment ModraDoc006 / r), an AUC0~48h of 1200±600 h·ng / mL seems to be optimal and can be achieved in cancer patients with solid tumors (not prostate) with the twice-daily, once-weekly schedule of ModraDoc006 / r 30~20 / 100~100.

[0064] Phase IIA study of breast cancer In patients with metastatic breast cancer (M18DMB) who are suitable for taxane-based treatment for recurrent or metastatic HER-2 negative breast cancer, a multi-center phase IIA clinical study of ModraDoc006 (oral docetaxel formulation) combined with ritonavir (ModraDoc006 / r) was conducted. The results of the study are summarized below and shown in Figures 9 and 10.

Table 6

[0065] Tumor measurements represent the change in tumor size over time measured by CT scan, with the initial value being the baseline.

[0066] Summary of Efficacy In this study, a total of 12 patients with recurrent or metastatic breast cancer suitable for taxane-based treatment were treated with a twice-daily, once-weekly (BIDW) dosing schedule of 30 mg of ModraDoc006 combined with 100 mg of ritonavir ( / r) in the morning and 20 mg of ModraDoc006 combined with 100 mg / r in the evening. In 10 patients in whom efficacy was evaluable (i.e., disease assessment according to RECIST 1.1. and who received at least 6 weeks of treatment), responses of 3 confirmed (repeated tumor measurements > 4 weeks later) partial responses (PR), 6 stable diseases (SD), and 1 progressive disease (PD) occurred. The median duration of treatment in the 12 patients is currently 11.3 weeks, and 2 patients are ongoing at 20 and 22 weeks, respectively.

Claims

1. A combination of a CYP3A inhibitor and docetaxel for use in the treatment of cancer comprising oral administration of docetaxel, maintaining plasma concentrations of docetaxel that eradicate tumor cells while preventing peak plasma concentrations of docetaxel that induce side effects.

2. 1. Docetaxel for use in combination therapy in the treatment of cancer, comprising oral administration of docetaxel administered in combination with a CYP3A inhibitor, and maintaining plasma concentrations of docetaxel that eradicate tumor cells while preventing peak plasma concentrations of docetaxel that induce side effects.

3. 1. A CYP3A inhibitor for use in combination therapy in the treatment of cancer, comprising administering docetaxel orally and maintaining plasma concentrations of docetaxel that eradicate tumor cells while preventing peak plasma concentrations of docetaxel that induce side effects.

4. 2. The use of claim 1, comprising a peak plasma concentration of docetaxel of up to 3000 ng / mL.

5. 2. The use according to claim 1, comprising an area under the curve of at least 800 ng.h / mL.

6. 2. The use of claim 1, comprising chronic use for more than 30 weeks.

7. The use according to claim 1, wherein the cancer is a solid tumor.

8. The use according to claim 1, wherein the CYP3A inhibitor is ritonavir.

9. 2. The use according to claim 1, wherein the cancer is selected from the group consisting of gastric cancer, breast cancer, head and neck cancer, lung cancer and prostate cancer.

10. A kit for long-term use in the treatment of cancer, comprising a pharmaceutical composition for oral administration comprising docetaxel, and a pharmaceutical composition comprising a CYP3A inhibitor.

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