Combination treatment for solid tumors using docetaxel and CYP3a inhibitor

Abstract

To provide a treatment method relating to chemotherapy of tumors using docetaxel, which achieves efficacious doses of orally administered docetaxel while maintaining acceptable safety.SOLUTION: Provided is docetaxel for use in a combination treatment of cancer, wherein the docetaxel is orally administered in combination with a CYP3A inhibitor, and a dose of the CYP3A inhibitor is sufficient to obtain a level of docetaxel exposure in tumor tissue equivalent to that of the standard of treatment with docetaxel.SELECTED DRAWING: Figure 5A

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.

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 interfere with the polymerization and depolymerization of microtubules, which inhibits mitotic cell division. The recommended dosage is intravenous administration every three weeks, and the dosage is in the range of 75 - 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 serious 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 - 6 cycles). Furthermore, a standard pre-medication with a high dose of dexamethasone is required for each cycle.

Summary of the Invention

[0003] Intravenous administration of docetaxel as a chemotherapeutic agent has been approved and is used in the treatment of various solid tumors. There is variability among patients in their response to treatment. The inventors sought to improve the means and methods of utilizing docetaxel in the treatment of cancer. In particular, the inventors provide different routes of administration of docetaxel, namely oral, in combination with a cytochrome P450 isoenzyme CYP3A (CYP3A) inhibitor to achieve docetaxel exposure levels that are equivalent or at least equivalent to the current standard of care for docetaxel. By providing methods and uses of combining oral docetaxel with a CYP3A inhibitor, the inventors have improved the means and methods of treating cancer, and said methods and means can control to obtain an effective anti-tumor level of docetaxel exposure while improving the safety profile of docetaxel as compared to the current standard of care for docetaxel. Also, by the methods and means of the present invention, the use of standard premedication with high doses of dexamethasone recommended per cycle in the current standard of care for docetaxel can be avoided. Therefore, provided is a combination therapy for the treatment of cancer, wherein docetaxel is orally administered in combination with a CYP3A inhibitor, and the dosage of the CYP3A inhibitor is sufficient to obtain a docetaxel exposure level in tumor tissue that is equivalent or at least equivalent to the current standard of care for docetaxel. In one embodiment, provided is the use of docetaxel orally administered in combination with a CYP3A inhibitor in the treatment of cancer, wherein the dosage of docetaxel is adjusted to compensate for increased clearance of docetaxel in a subject having cancer. The dosages of docetaxel and CYP3A can be selected to provide a docetaxel exposure level in tumor tissue that is equivalent or at least equivalent to the current standard of care for docetaxel for the cancer to be treated. Alternatively, it can be determined to control and monitor the plasma concentration of docetaxel such that the CYP3A activity of a subject receiving and / or undergoing combination therapy and / or the plasma concentration of docetaxel in the subject is adjusted according to the present invention to maintain a docetaxel exposure level in tumor tissue that is at least equivalent to the current standard of care for docetaxel. BRIEF DESCRIPTION OF THE DRAWINGS

[0004]

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Mode for Carrying Out the Invention

[0005] Intravenous administration of docetaxel as a chemotherapeutic agent has been approved and is used in the treatment of various solid tumors. There are variations among patients in their response to treatment. The inventors sought to improve the means and methods of utilizing docetaxel in the treatment of cancer. In particular, the inventors provide an alternative route of administration of docetaxel, namely oral administration, that achieves docetaxel exposure levels equivalent to the current treatment standard. When docetaxel is administered intravenously, high peak concentrations of docetaxel can be measured in the plasma of the subject (measurable in serum or whole blood). The inventors have established that such high peak concentrations are associated with the toxicity of the current treatment standard. When docetaxel is administered orally in combination with a CYP3A inhibitor, such high peak concentrations of docetaxel can be largely avoided. Importantly, the inventors have established that oral administration of docetaxel in combination with a cytochrome P450 3A4 (and P450 3A5) (CYP3A) inhibitor can provide docetaxel exposure levels equivalent to or at least comparable to the current treatment standard, which results in a dose of docetaxel effective in the treatment of cancer while maintaining acceptable toxicity. This is important for combination therapy that combines combinations of anti-cancer treatments.

[0006] 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 counts 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 counts 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 a patient's cancer, 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.

[0007] 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 (especially 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.

[0008] As used herein, oral administration of docetaxel to a subject includes any route of 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 such that docetaxel is released over a long period of time, such as for several hours or more, for example while passing through the intestinal tract. Thus, tablets and capsules may be formulated such that the agent is released therefrom gradually. 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.

[0009] The pharmaceutical composition of the present invention may comprise 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. Formulations 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 formulation suitable for oral administration may be considered.

[0010] 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 since 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.

[0011] For many anticancer drugs such as docetaxel, cytochrome P450 represents the major 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, and 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). Thus, 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. The 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.

[0012] A method for treating cancer in a patient, which comprises the step of orally administering docetaxel as described in this specification, 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 cells. Therefore, 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, so that a lower dosage of oral docetaxel can be used. Instead, by using a CYP3A inhibitor, an effective plasma concentration with the area under the curve as defined in this specification can be obtained more efficiently compared to the case without using a CYP3A inhibitor, so that less frequent dosing of oral docetaxel can be achieved.

[0013] Therefore, in the method according to the 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, it comprises a CYP3A inhibitor for use in combination therapy according to the invention, ritonavir administered at a dosage of 100 mg or 200 mg, or an equivalent dosage of another suitable CYP3A inhibitor. Since the effects of the CYP3A inhibitor and ritonavir in the subject can be compared, another CYP3A inhibitor can be selected and the dosage thereof to obtain 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.

[0014] 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 avoided, 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, further use of the CYP3A inhibitor by the subject being treated needs to be avoided, 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.

[0015] 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 contains docetaxel and another pharmaceutical contains a CYP3A inhibitor such as ritonavir. The pharmaceutical preferably contains 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, 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 administration of docetaxel or the CYP3A inhibitor. Generally, the CYP3A inhibitor is preferably administered orally simultaneously with the oral administration of docetaxel because it provides optimal compliance for self-administration by the subject being treated.

[0016] CYP3A activity can affect, for example in the liver and intestine, the exposure levels obtained in the blood after oral administration of docetaxel (which can be controlled by the use of CYP3A inhibitors and / or the selection of a suitable docetaxel dosage), while there may also be other unknown causes that affect the exposure levels of docetaxel that can be obtained after oral administration of docetaxel. As shown in the examples herein, the clearance of docetaxel appears to increase in mCRPC compared to other solid tumors. Therefore, in patients with increased docetaxel clearance, increasing the docetaxel dosage to obtain higher docetaxel exposure levels may be beneficial for such patients. However, increasing the docetaxel dosage by using intravenous administration of docetaxel results in unacceptable high peak concentrations in the plasma and becomes unacceptable as a treatment standard. In contrast, by using oral administration of docetaxel in combination with a CYP3A inhibitor according to the present invention, the exposure level of docetaxel can be well controlled to avoid unacceptable high peak concentrations. Therefore, the inventors have established that when using orally administered docetaxel in combination with a CYP3A inhibitor, the dosage of docetaxel used and / or the dosage of the CYP3A inhibitor can be selected such that the exposure level obtained with docetaxel can be very effective for the treatment of cancer and result in acceptable toxicity for the subject. Accordingly, the present invention provides docetaxel for use in combination therapy for the treatment of cancer, wherein the docetaxel is orally administered in combination with a CYP3A inhibitor, and the dosage of the CYP3A inhibitor is sufficient to obtain a docetaxel exposure level in tumor tissue that is equivalent to the treatment standard of docetaxel. In docetaxel for use in combination therapy for the treatment of cancer, the docetaxel is orally administered in combination with a CYP3A inhibitor, and the dosage of the CYP3A inhibitor is sufficient to obtain a docetaxel exposure level in tumor tissue that is (at least) equivalent to the treatment standard of docetaxel.

[0017] In another embodiment, docetaxel is provided for use in combination therapy for the treatment of cancer, the docetaxel is orally administered in combination with a CYP3A inhibitor, and the dose of docetaxel is adjusted to compensate for the increased clearance of docetaxel in a subject having cancer.

[0018] In another embodiment, a CYP3A inhibitor is provided for use in combination therapy for the treatment of cancer, the CYP3A inhibitor is administered in combination with an oral formulation of docetaxel, and the dose of the CYP3A inhibitor is sufficient to obtain a docetaxel exposure level in tumor tissue that is equal to or at least equivalent to the standard of care for docetaxel. In yet another embodiment, a CYP3A inhibitor is provided for use in combination therapy in the treatment of cancer, the CYP3A inhibitor is administered in combination with an oral formulation of docetaxel, and the dose of the CYP3A inhibitor is sufficient to substantially reduce the increased clearance of docetaxel in a subject having cancer.

[0019] Accordingly, the inventors have established that when using a combination of a CYP3A inhibitor and orally administered docetaxel, a sufficient docetaxel exposure level can be obtained that eradicates cancer cells while allowing toxicity to be tolerable. For example, a sufficient docetaxel exposure level can be obtained by making the dose of CYP3A sufficient and / or by adjusting the dose of orally administered docetaxel. Such combinations of orally administered docetaxel and a CYP3A inhibitor are contemplated herein as long as an exposure level equal to or at least equivalent to the standard of care for docetaxel is obtained.

[0020] In this specification, the standard of treatment with docetaxel is defined as the intravenous administration of the recommended dose of docetaxel. The recommended dose of docetaxel is usually 75 mg / m2 to 100 mg / m2 every three weeks (mg of docetaxel / m2 of the body surface area of the subject). The recommended dose for non-small cell lung cancer, breast cancer, gastric cancer, head and neck cancer or prostate cancer is usually 75 mg / m2 every three weeks. The recommended dose can also be 35 mg / m2 per week. In this specification, the docetaxel exposure level in tumor tissue can be defined as the area under the curve obtained when docetaxel is administered intravenously and that is consistent with the standard of effective docetaxel treatment. Of course, since docetaxel is measured in plasma, this may not define the actual docetaxel level in the tissue.

[0021] The area under the curve (AUC; ng*h / mL) was determined 48 hours after the administration of the first docetaxel, during which the docetaxel concentration in plasma could be measured at several time points, and the surface area under the curve could be calculated from the plotted values. The plasma docetaxel concentration can be measured by methods known in the art (Hendrikx et al. J. Chrom. B, 2011). Such methods 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 area under the plasma concentration-time curve, are determined for (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. Generally, preferably, the AUC is in the range of 500 to 2500 ng·h / mL. Preferably, the AUC is at least 500 ng·h / mL, at least 600 ng·h / mL, at least 800 ng·h / mL, more preferably at least 1000 ng·h / mL or 1200 ng·h / mL. Preferably, the AUC is at most 2500 ng·h / mL, at most 2250 ng·h / mL, at most 2000 ng·h / mL, at most 1800 ng·h / mL, at most 1700 ng·h / mL, more preferably at most 1500 ng·h / mL. More preferably, the AUC can be in the range of 800 to 1400 ng·h / mL. Here, regarding docetaxel, the plasma concentration-time curve, the area under the curve, or the AUC is used interchangeably and refers to the area under the curve at the first 48 hours (ng·h / mL) after the administration of docetaxel.

[0022] In fact, these dosages can be achieved by orally administering 50 mg of docetaxel at a dosage of once a week, twice a day (e.g., 30 mg in the morning and 20 mg in the evening).

[0023] Preferably, there is provided a docetaxel or CYP3A inhibitor for use according to the invention described herein, and the cancer is a solid tumor. Preferably, in the use of the docetaxel or CYP3A inhibitor, the solid tumor is non-small cell lung cancer, gastric cancer, breast cancer, head and neck cancer or prostate cancer. Since docetaxel has been shown to be very effective in these cancers, the solid tumor is preferably an oral administration route of docetaxel in combination with CYP3A, which provides improved and / or acceptable toxicity in subjects having these cancers.

[0024] Most preferably, said cancer is prostate cancer. Treatment of prostate cancer may involve the use of hormonal therapy, such as androgen deprivation therapy. Prostate cancer may not respond to hormonal therapy, and such prostate cancer is referred to as hormone refractory prostate cancer (HRPC). Prostate cancer may respond to hormonal therapy, and such prostate cancer is referred to as hormone sensitive prostate cancer (HSPC). Such patients may also metastasize or develop metastases during treatment. Such cancer is referred to as mHRPC or mHSPC (m indicates metastatic). Prostate cancer treatment may include castration. In any case, prostate cancer is generally associated with a decrease to very low levels of testosterone in the body. As shown in the examples, in patients with mCRPC, the clearance of docetaxel determined in plasma appears to increase compared to patients with solid tumors that are not mCRPC. The levels of testosterone in such patients are very low. Patients who received intravenous administration of docetaxel simultaneously with androgen deprivation therapy at the early stage of the disease experience more toxicity compared to prostate cancer patients who received intravenous administration of docetaxel at the later stage of the disease. Therefore, in the treatment of prostate cancer involving the use of hormonal therapy including androgen inhibitors, an increased clearance of docetaxel may similarly be expected to result in a reduced docetaxel plasma concentration, but such increased clearance may first need to be established after starting hormonal therapy. Accordingly, the dosage of docetaxel and / or CYP3A inhibitor may be adjusted at the initial stage of the treatment of prostate cancer to compensate for the lower plasma concentration compared to mCRPC patients in such patients. Conversely, the plasma concentration of docetaxel may first need to be established, for example, by administering an initial oral dose of docetaxel in combination with a CYP3A inhibitor according to the present invention and determining the plasma concentration (such as AUC) of docetaxel to confirm that the same dosage suitable for mCRPC can be administered. In any case, the dosage suitable for mCRPC may also be suitable for HSPC, HRPC, mHRPC, mHSPC or CRPC (i.e., non-metastatic). In a preferred embodiment, the dosage suitable for mCRPC is also selected for the treatment of mHSPC.

[0025] In a preferred embodiment, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC). Accordingly, in a further embodiment, a method for treating metastatic castration-resistant prostate cancer (mCRPC) is provided according to the present invention, the method comprising the step of orally administering an effective dose of docetaxel in combination with a CYP3A inhibitor, the dose of the CYP3A inhibitor being sufficient to obtain a docetaxel exposure level in tumor tissue that is (at least) equivalent to the treatment standard of docetaxel without the increased clearance by the enzyme activity, particularly CYP3A, intravenously every three weeks. Preferably, the cancer not being mCRPC is referred to in the said standard care treatment. In another embodiment, a method for treating metastatic castration-resistant prostate cancer (mCRPC) according to the present invention is provided, comprising the step of orally administering an effective dose of docetaxel in combination with a CYP3A inhibitor, the dose of docetaxel being adjusted to compensate for the increased clearance of docetaxel in subjects having mCRPC. In yet another further embodiment, a method for treating metastatic castration-resistant prostate cancer (mCRPC) is provided, the method comprising the step of orally administering an effective dose of docetaxel in combination with a CYP3A inhibitor, the dose of the CYP3A inhibitor being sufficient to substantially reduce the increased clearance of docetaxel in subjects having mCRPC.

[0026] In one embodiment, docetaxel or a CYP3A inhibitor for use in combination therapy according to the present invention for oral administration of docetaxel at a weekly dosage is provided, the docetaxel exposure level being equivalent to the treatment standard that occurs with an area under the curve of 600 to 1800 ng·h / mL, more preferably 1000 to 1500 ng·h / mL. The oral administration of docetaxel in this embodiment is at a dosage similar to the recommended dosage, but is given, for example, at more frequent intervals, i.e., for example, instead of every three weeks. Due to the use of oral administration in combination with a CYP3A inhibitor, this route of administration results in at least equivalent exposure to docetaxel in the subject being treated. However, due to the route of administration, the peak concentration of docetaxel is very much reduced, thereby enabling more frequent dosing while maintaining at least equivalent exposure to docetaxel.

[0027] Therefore, as shown in the examples, the docetaxel exposure levels obtained according to the present invention (determined by AUC as described herein) can be equivalent to the standard of care or can be selected to be higher compared to the standard of care (see especially Figure 5A). Therefore, higher levels may be advantageous and it may be preferred to achieve at least equivalent docetaxel concentrations in the uses and methods according to the present invention.

[0028] Docetaxel is preferably administered on a twice-daily basis once a week. The weekly dose is divided such that the subject takes it, for example, once a week, with the first dose in the morning and the second dose in the evening on the same day. This has the effect of reducing the peak concentration of docetaxel in the plasma, which can help reduce side effects while allowing for a sufficient area under the curve to be obtained. Also, it can increase the time of systemic exposure of the drug. In a preferred embodiment, the method or use according to the present invention includes the step of administering docetaxel twice a day once a week, which means administering docetaxel twice within an interval of, for example, 8 to 16 hours on one day of each week. As long as the dosing interval and / or dosage of docetaxel and a CYP3A inhibitor such as ritonavir are selected to result in docetaxel exposure levels in tumor tissue that are equivalent or at least equivalent to the standard of care for docetaxel, such dosing intervals and / or dosages can be considered.

[0029] In another embodiment, since the dosages shown in the examples can result in docetaxel exposure levels that are equivalent or at least equivalent to the standard of care for docetaxel in tumor tissue, docetaxel is orally administered at a dosage of 50 mg per week for the treatment of solid tumors. Such administration is preferably on a twice-daily schedule once a week. Therefore, a twice-daily schedule once a week for the treatment of solid tumors is provided, and docetaxel is administered on one day of each week with a first dose of 30 mg of docetaxel and 100 mg of ritonavir and a second dose of 20 mg of docetaxel and 100 mg of ritonavir.

[0030] In another embodiment, since the dosage shown in the examples can result in a docetaxel exposure level that is equal to or at least equivalent to the treatment standard of docetaxel in tumor tissue, for the treatment of solid tumors, docetaxel is orally administered at a dosage of 40 mg per week. Such administration is preferably on a schedule of twice a day for one day per week. Therefore, a schedule of twice a day for one day per week is provided for the treatment of solid tumors, and for the treatment of solid tumors, docetaxel is administered on one day per week with an initial dose of 20 mg of docetaxel and 200 mg of ritonavir, and a second dose of 20 mg of docetaxel and 100 mg of ritonavir.

[0031] In one embodiment, a schedule of twice a day for one day per week is provided for the treatment of cancer, and docetaxel is administered on one day per week with an initial dose of 30 mg of docetaxel and 200 mg of ritonavir, and a second dose of 20 mg of docetaxel and 200 mg of ritonavir. In another embodiment, a schedule of twice a day for one day per week is provided for the treatment of cancer, and docetaxel is administered on one day per week with an initial dose of 20 mg of docetaxel and 200 mg of ritonavir, and a second dose of 20 mg of docetaxel and 200 mg of ritonavir. In yet another embodiment, a schedule of twice a day for one day per week is provided for the treatment of cancer, and docetaxel is administered on one day per week with an initial dose of 20 mg of docetaxel and 100 mg of ritonavir, and a second dose of 20 mg of docetaxel and 100 mg of ritonavir. In another embodiment, a schedule of twice a day for one day per week is provided for the treatment of cancer, and docetaxel is administered on one day per week with an initial dose of 20 mg of docetaxel and 200 mg of ritonavir, and a second dose of 20 mg of docetaxel and 100 mg of ritonavir.

[0032] In a further embodiment, since the dosage shown in the examples can result in a docetaxel exposure level that is equal to or at least equivalent to the treatment standard of docetaxel in tumor tissue, in the treatment of mCRPC, docetaxel is orally administered at a dosage of 50 mg per week. Such administration is preferably on a schedule of twice a day for one day per week. As shown in the examples, the CYP3A inhibitor dosage needs to be adapted to mCRPC patients so that the defined AUC can be obtained. Therefore, a schedule of twice a day for one day per week for the treatment of mCRPC is provided for the treatment of cancer, and docetaxel is orally administered on the same day at an initial dose of 30 mg of docetaxel and 200 mg of ritonavir, and a second dose of 20 mg of docetaxel and 100 mg of ritonavir.

[0033] As described above, the present invention provides methods and uses of combinations of docetaxel and CYP3A inhibitors for the treatment of cancer. Such methods and uses can result in a docetaxel exposure level in tumor tissue that is equivalent to the treatment standard of docetaxel by providing a suitable dosage of docetaxel and / or a suitable dosage of CYP3A inhibitor. As also described above, the present invention provides methods and uses of combinations of docetaxel and CYP3A inhibitors for the treatment of cancer. Such methods and uses can result in a docetaxel exposure level in tumor tissue that is at least equivalent to the treatment standard of docetaxel by providing a suitable dosage of docetaxel and / or a suitable dosage of CYP3A inhibitor.

[0034] The present invention also provides means and methods for determining a suitable dosage of docetaxel and / or CYP3A inhibitor and / or monitoring that a suitable dosage is used throughout the treatment.

[0035] As described herein, docetaxel levels in a subject can be controlled prior to treatment and / or monitored and controlled during treatment following the use of oral administration of docetaxel and a CYP3A inhibitor. Such monitoring and control can also be performed, alternatively (or additionally), by measuring docetaxel in the plasma. Such monitoring and control can also be performed by monitoring for side effects. As noted above, a subject's docetaxel clearance can vary due to unknown causes to CYP3A activity. Therefore, by monitoring docetaxel concentration in a subject during treatment, the docetaxel dosage can be adjusted to maintain an appropriate docetaxel concentration in the subject. Monitoring for side effects is similar. As shown in the examples, when an area under the curve determined by a treatment standard is provided, a dosage of a CYP3A inhibitor and a docetaxel combination suitable to achieve a tumor tissue exposure level equivalent to the treatment standard can be determined. As shown in the examples, monitoring of plasma concentrations in mCRPC patients with a selected docetaxel and CYP3A inhibitor combination treatment has shown that the treatment needs to be adapted to achieve a defined area under the curve. In the first adaptation, the increase in the area under the curve is too high and undesirable side effects occur, while in the second adaptation, a defined area under the curve is achieved, resulting in a defined tumor tissue exposure level while significantly reducing side effects. Accordingly, the present invention also provides a method of treating cancer comprising a combination of a CYP3A inhibitor and orally administered docetaxel, the method comprising: administering a combination of a CYP3A inhibitor and docetaxel; determining the plasma concentration of docetaxel in the subject; optionally, comparing the docetaxel concentration to a reference level; determining a docetaxel dosage for administration of the next combination of a CYP3A inhibitor and docetaxel; and administering the next combination of a CYP3A inhibitor and docetaxel.

[0036] By determining the plasma concentration of docetaxel after the initial administration, it can be confirmed that the selected dosage (of both the CYP3A inhibitor and docetaxel) of the initial administration is an appropriate dosage. Conversely, if the plasma concentration is too high or too low, the dosage of the next combination of the CYP3A inhibitor and docetaxel can be adjusted. The dosage of the CYP3A inhibitor or the docetaxel dosage or the dosages of both the CYP3A inhibitor and docetaxel can be adjusted. Therefore, the CYP3A inhibitor dosage can remain the same as that in the initial administration, and the next dosage, the docetaxel dosage, can be adjusted to compensate for an increase or decrease in the docetaxel plasma concentration compared to the treatment standard of docetaxel. Thus, in such a treatment method according to the present invention including determining the docetaxel plasma concentration, the CYP3A inhibitor is administered at a predetermined dosage. Also, the docetaxel dosage can remain the same as that of the initial administration, and the next dosage of CYP3A can be adjusted to compensate for an increase or decrease in the docetaxel plasma level compared to the treatment standard of docetaxel. Preferably, the dosage of docetaxel is adjusted to eradicate tumor cells. Thus, throughout the treatment, at least the docetaxel dosage of the next combination of the CYP3A inhibitor and docetaxel is sufficient to obtain a docetaxel exposure level in tumor tissue that is equivalent or at least equivalent to the treatment standard of docetaxel. Preferably, the cancer treatment method includes multiple administrations of a combination of a CYP3A inhibitor and docetaxel, and after each administration, determining the docetaxel concentration and determining the docetaxel dosage for the next administration of the combination of the CYP3A inhibitor and docetaxel. Therefore, when the docetaxel concentration increases in the subject compared to the reference level, the dosage of docetaxel is decreased, and when the docetaxel concentration decreases during treatment compared to the reference level, the dosage of docetaxel is increased compared to the previously administered dosage.

[0037] In another embodiment, the present invention provides a method for treating cancer comprising a combination of a CYP3A inhibitor and orally administered docetaxel, the method comprising determining the activity of CYP3A in a subject; and Optionally, a step of comparing the activity of CYP3A with a reference level; A step of determining the dosage of a CYP3A inhibitor based on the activity level of CYP3A determined in a subject; A step of administering a combination of a CYP3A inhibitor and docetaxel at the determined dosage, and The dosage of docetaxel is sufficient to obtain a docetaxel exposure level in tumor tissue that is equivalent to the treatment standard of docetaxel.

[0038] Since the activity of CYP3A in a subject can affect the dosage of docetaxel administered to obtain a sufficient exposure level, determining the activity of CYP3A can have the advantage of accounting for possible variations among subjects. This can be done before starting treatment. The CYP3A activity of a subject can be determined by any known means, but can also be determined by measuring the plasma concentration of ritonavir or other indirect methods. By knowing what the appropriate dosage of a CYP3A inhibitor is before starting treatment, a desirable exposure level of docetaxel can be obtained in the subject immediately from the start of treatment. Therefore, in a preferred embodiment, in the method according to the present invention, the step of determining the activity, any subsequent comparison step, and the step of determining the dosage of the CYP3A inhibitor are carried out before the first administration of the combination of the CYP3A inhibitor and docetaxel. More preferably, docetaxel is administered at a predetermined dosage. For example, if the CYP3A activity is relatively high before treatment, the dosage of the CYP3A inhibitor can be selected to be relatively higher, and if the CYP3A activity is low, the dosage can be selected to be relatively lower. Naturally, the CYP3A activity can also vary during treatment with the combination of oral docetaxel and a CYP3A inhibitor. For example, if the cancer being treated contains substantial CYP3A activity (Hendrikx et al., Int J Cancer, 2015; Ikezoe et al., Cancer Res, 2004), during treatment, to reduce the cancer, the CYP3A activity in the subject is similarly reduced, and less of the CYP3A inhibitor is required to maintain an effective docetaxel concentration. Therefore, in this treatment method, the steps of the method can be carried out during treatment including the administration of the combination of the CYP3A inhibitor and docetaxel. Therefore, in a further embodiment, in a method of treatment including determining the CYP3A activity in a subject, when the activity of CYP3A increases during treatment, the dosage of the CYP3A inhibitor is increased, and when the activity of CYP3A decreases during treatment, the dosage of the CYP3A inhibitor is maintained or decreased compared to the dosage administered previously.Thus, after oral administration of docetaxel and a CYP3A inhibitor, an optimal exposure level can be obtained in a subject to avoid docetaxel concentrations that are too high or too low.

[0039] As is clear from the above, by determining or monitoring CYP3A activity in a subject and / or by monitoring the docetaxel plasma concentration in a subject, and then, if necessary, using information to adjust the dosage of the CYP3A inhibitor and / or the dosage of docetaxel for oral administration, the docetaxel plasma concentration can be controlled to obtain a docetaxel exposure level in tumor tissue that is equivalent to the therapeutic standard of docetaxel. Therefore, the above method including measuring CYP3A activity or docetaxel plasma concentration in a subject is not limited to measuring only CYP3A activity or docetaxel, and may also include measuring both docetaxel and CYP3A activity. Therefore, for example, if the docetaxel level in a subject varies due to (unknown) causes other than CYP3A activity, in such a situation, it may be preferable to adjust the docetaxel dosage instead of changing the dosage of the CYP3A inhibitor, so that control at the docetaxel exposure level in the subject can be more excellent. Therefore, a further method for treating cancer is provided, which includes a combination of a CYP3A inhibitor and orally administered docetaxel, and the method includes determining the activity of CYP3A in a subject; optionally, comparing the activity of CYP3A with a reference level; optionally, determining the dosage of the CYP3A inhibitor based on the activity level of CYP3A determined in the subject, and administering a combination of a CYP3A inhibitor and docetaxel; determining the plasma concentration of docetaxel in the subject, and optionally, comparing the docetaxel concentration with a reference level; Determining a docetaxel dosage and / or a CYP3A inhibitor dosage for administration of a combination of a CYP3A inhibitor and docetaxel based on the determined CYP3A activity and docetaxel concentration,

[0040] Of course, as described above, the CYP3A activity and docetaxel plasma concentration can be carried out only during treatment, i.e., only after the first administration of the combination of the CYP3A inhibitor and docetaxel. Also, of course, in the treatment method, after selecting the first dosages of docetaxel and the CYP3A inhibitor in consideration of the subject's first CYP3A activity, during treatment, the CYP3A activity and / or the docetaxel plasma concentration is monitored, and a suitable dosage for the CYP3A inhibitor and / or orally formulated docetaxel is determined. In a further embodiment, there is provided a kit for use in the methods and uses described herein for a combination of docetaxel and a CYP3A inhibitor. In one embodiment, there is provided a kit comprising a pharmaceutical composition comprising docetaxel for oral administration and a pharmaceutical composition comprising a CYP3A inhibitor. In another embodiment, There is provided a kit comprising a pharmaceutical composition comprising docetaxel for oral administration and a pharmaceutical composition comprising a CYP3A inhibitor, which is for the treatment of solid tumors, particularly non-small cell-lung cancer, gastric cancer, breast cancer, head and neck cancer or prostate cancer, more particularly mCRPC. In yet another embodiment, There is provided a kit comprising a pharmaceutical composition comprising docetaxel and a pharmaceutical composition comprising a CYP3A inhibitor, which kit is for use in combination therapy as defined in any one of the methods and uses according to the invention described herein.

[0041] The pharmaceutical composition of the present invention may comprise any pharmaceutically acceptable carrier, adjuvant or vehicle together with docetaxel, or a pharmaceutically acceptable salt and their esters, and / or a CYP3A inhibitor such as ritonavir, (or a pharmaceutically acceptable salt and their esters).

[0042] 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 to be construed as being 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 interpreted as alternatives, the non-combination case ( "or").

[0043] 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

[0044] Modradoc006 Modradoc006 is a spray-dried solid dispersion formulation of docetaxel pressed into tablets (ModraDoc006 10mg tablets) and contains 10mg 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).

[0045] Ritonavir Ritonavir is commercially available as 100mg tablets for oral ingestion (Norvir®). These tablets were approved by the European Commission in 2010.

[0046] Docetaxel and ritonavir plasma measurements A combined assay for the determination of docetaxel and ritonavir in human plasma will be described. 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 principles of FDA guidelines and Good Laboratory Practice (GLP). The demonstrated ranges were 0.5 - 500 ng / mL for docetaxel and 2 - 2000 ng / mL for ritonavir. A secondary calibration curve was used for quantification (r(2) > 0.99). The total run time of the method was 9 minutes, and the assay combines the analyte with ionization and differences in the desired concentration range. 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 internal standard, was less than 20% of the response 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 examined 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.

[0047] mCRPC study 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.

[0048] This treatment (referred to as ModraDoc006 / r 30~20 / 100~100) is given once a week per day.

[0049] Pharmacokinetic studies revealed that the docetaxel AUC0~48h of 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).

[0050] 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 noticed, 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.

[0051] A hypothesis was established that by increasing the dose of the CYP3A inhibitor ritonavir (doubling it), 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).

[0052] 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.

[0053] The results are also shown in Figures 2A and 2B.

[0054] Summarized as follows.

Table 1

[0055] The above-described test results are those 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

[0056] A multicenter clinical phase IB / IIA study of ModraDoc006 (oral docetaxel formulation) combined with ritonavir (ModraDoc006 / r) was conducted in metastatic castration-resistant prostate cancer (mCRPC) (M17DOC).

[0057] The study included patients diagnosed with metastatic castration-resistant prostate cancer (mCRPC) and the patients were dosed at four dose levels twice a day, once a week (BIDW) (see the following table).

Table 2

[0058] 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.

[0059] 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, 8 mCRPC patients (6 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).

[0060] 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.

[0061] 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.

[0062] The summary is as follows.

Table 3

[0063] The results of the tests are further described below and shown in Figures 4 to 8.

Table 4

[0064] (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)).

[0065] 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 7 patients, a PSA response (PSA decrease of ≧50%) was seen, of which 5 were confirmed at the second measurement after 6 weeks. In another 7 patients, PSA decreased by <50% or was equal to baseline. In the remaining 6 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 a maximum treatment duration of 30 weeks. A total of 5 patients completed a maximum of 30 weeks of treatment. 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) that allows for acceptable toxicity while being higher than that achieved with IV docetaxel. Alternatively, ModraDoc006 / r20~20 / 200~100 could be another preferred dose, or a preferred initial dose, in mCRPC.

[0066] 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 a day, 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.

[0067] SAEs (serious adverse events) and DLTs (dose-limiting toxicities) (possible, probably, definite; ≥ 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.

[0068] 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.

[0069] 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 a day, once a week. The treatment duration for 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 carcinoma (n = 1; SD). Docetaxel exposure in these patients was AUC0~48h 1224±620h.ng / mL CMAX 143±67ng / mL as follows.

[0070] SAE and DLT (possible, probably, 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.

[0071] 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.

[0072] In summary, it is as follows.

Table 5

[0073] 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.

[0074] 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

[0075] 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, in many cases, after 3 consecutive weeks of intravenous administration, there is 1 remaining week, 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).

[0076] · 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. · With oral docetaxel treatment (ModraDoc006 / r), higher AUC0~48h-CMAX values correlate with toxicity. · With 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.

[0077] Phase IIA study of breast cancer In patients with metastatic breast cancer (M18DMB) who are suitable for treatment with taxanes and have 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

[0078] Tumor measurements represent the change in tumor size over time measured by CT scan, with the initial value being the baseline.

[0079] Summary of Efficacy In this study, a total of 12 patients with recurrent or metastatic breast cancer suitable for treatment with taxanes 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 disease stabilizations (SD), and 1 progressive disease (PD) occurred. The median duration of treatment in the 12 patients was currently 11.3 weeks, and 2 patients are ongoing at 20 and 22 weeks, respectively.

Claims

1. 1. Docetaxel for use in combination therapy for the treatment of cancer, characterized in that docetaxel is orally administered in combination with a CYP3A inhibitor, the dose of the CYP3A inhibitor being sufficient to achieve a tumor tissue exposure level of docetaxel that is equivalent to a therapeutic standard of care for docetaxel.

2. 1. Docetaxel for use in a combination therapy for the treatment of cancer, comprising orally administering docetaxel in combination with a CYP3A inhibitor and adjusting the dose of docetaxel to compensate for increased clearance of docetaxel in a subject with cancer.

3. The docetaxel for use according to claim 1, wherein the cancer is a solid tumor.

4. 4. The method of claim 3, wherein the tumor is non-small cell lung cancer, gastric cancer, breast cancer, head and neck cancer or prostate cancer.

5. 5. The method of claim 4, wherein the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

6. 1. A CYP3A inhibitor for use in combination therapy for the treatment of cancer, characterized in that the CYP3A inhibitor is administered in combination with an oral formulation of docetaxel, and the dose of the CYP3A inhibitor is sufficient to obtain a tumor tissue exposure level of docetaxel that is equivalent to a therapeutic standard of care for docetaxel.

7. 1. A CYP3A inhibitor for use in combination therapy in the treatment of cancer, characterized in that the CYP3A inhibitor is administered in combination with an oral formulation of docetaxel, and the dose of the CYP3A inhibitor is sufficient to substantially reduce increased clearance of docetaxel in a subject having cancer.

8. The CYP3A inhibitor for use according to claim 6, wherein the cancer is a solid tumor.

9. 9. The CYP3A inhibitor for use according to claim 8, wherein the tumor is non-small cell lung cancer, breast cancer, gastric cancer, head and neck cancer or prostate cancer.

10. 10. The CYP3A inhibitor for use according to claim 9, wherein the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

11. 2. The method of claim 1, wherein the CYP3A inhibitor is ritonavir.

12. 2. The docetaxel or CYP3A inhibitor for use in combination therapy according to claim 1, wherein said use does not include the use of a corticosteroid such as prednisone.

13. 2. Docetaxel or a CYP3A inhibitor for use in the combination therapy of claim 1, wherein docetaxel is administered orally in a dosage of 50 mg weekly.

14. 2. The docetaxel or CYP3A inhibitor for use in combination therapy according to claim 1, wherein the CYP3A inhibitor ritonavir is administered in a weekly dosage of 200-300 mg.

15. A kit comprising a pharmaceutical composition for oral administration comprising docetaxel and a pharmaceutical composition comprising a CYP3A inhibitor.

16. The kit according to claim 15 for the treatment of solid tumors, in particular non-small cell lung cancer, gastric cancer, breast cancer, head and neck cancer or prostate cancer, more particularly mCRPC.

17. 2. The kit for use in combination therapy according to claim 1, comprising a pharmaceutical composition comprising docetaxel and a pharmaceutical composition comprising a CYP3A inhibitor.

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