TW200808803A - Unit dosage forms of temozolomide - Google Patents

Abstract

This invention relates to unit dosage forms of temozolomide. These unit dosage forms are particularly well-suited for decreasing the pill burden and increasing patient compliance. The invention also relates to methods of treating proliferative disorders in a patient with these unit dosage forms. The invention additionally relates to kits comprising these unit dosage forms.

Description

200808803 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to unit dosage forms of temozolomide. These unit dosage forms are particularly suitable for reducing pill loading and increasing patient compliance. The invention is also directed to a method of treating a proliferative disorder in a patient with such unit dosage forms. The invention further relates to kits comprising such unit dosage forms. [Prior Art] '

Brain tumors account for about 2% of all malignant diseases. Stupp et al., L 〇nc., 20(5): 1375-1382 (2002). In the United States, 17 cases are diagnosed each year, and the cases are more than 'the towel (four), and (10) 0 cases are related to the death. Standard protocols for the treatment of malignant glioma include cytoreductive surgery, and if available, radiotherapy (RT) with or without adjuvant chemotherapy. Stupp et al., ibid. The chemotherapeutic agent approved for the treatment of brain tumors is Temozolo c〇rP_, which is named Temodar8 in the United States and Temod, in Europe. The chemical name of temozolo is 3,4_two gas _3_methyl I side oxy imi" 幷[5,^]*tetrazine_8_formamide (see U.S. Patent No. 5,260,291). It is believed that the cytotoxicity of temorozol or its metabolite, methyl _ (tri-gum-i-based) miloxime 4-carboamine, is mainly attributed to occupational alkylation. The alkylation (methylation) occurs mainly at the 〇6 position and the N7 position of the guanine. Iemoaar® is currently in the United States, is an adult patient with pleomorphic glioblastoma and refractory degenerative astrocytoma, ie, containing nitrosourea and procarbazine.肼121049.doc 200808803 (pr〇carbazine) has experienced the first recurrence of disease progression in drug therapy. Temodal8 is currently approved in Europe for the treatment of patients with malignant gliomas such as glioblastoma multiforme or degenerative astrocytoma (for newly diagnosed wives, XI^4Φ rt hearts) and Patients who show relapse or progression after quasi-therapy.

j patients with neuroma tumors treated with Temozolo H therapy consisted of two phases' a companion phase followed by a maintenance phase. In the concomitant phase, 2 patients received 75 mg/m2 (about 14 mg for patients with a body surface area (BSA) between u m2 and u m). Oral administration of temozolo was performed with RT. Mai sees the table. Four weeks after the completion of the phase, the patient received 6 maintenance treatment cycles. 2 In the first maintenance cycle, 15 mg/m2 (about 28 〇g for patients with a BSA between I·8 m2 and I·9 m2) was administered Temazoro once a day for 5 days. Then no treatment was given for 23 days. For each 5 days after the subsequent cycle, the dose can be gradually increased to 2 〇〇 mg/m2 (about 36 〇 mg for patients with a batch of between 8 m and 1.9 m2). Currently, the capsule form of temozolo contains 5 mg, 2Q mg, i〇q or 250 mg temorozol. Given a therapeutic dose of 15 〇mg/m2, patients with a bsa between 1.8 m and 1.9 m2 will need to take 4 capsules per day to administer a dose of 280 mg of temozolo (1χ25〇mg,1χ2〇^ ^ and two skill mg). See Table 2. This high pill load may result in poor patient compliance with the need for self-administration of temtrozolo, which may result in a non-optimal therapeutic benefit of the drug. Other factors that may affect the patient's compliance with the appropriate number of pills are the strength of the glioma treatment regimen (including brain surgery and RT). In addition, patients may have to take a large number of different medications to relieve the side effects of the surgery or to heal or relieve other unrelated conditions to further exacerbate the already higher pill load. In addition, patients are at risk of cognitive impairment and impaired neurological status due to high-intensity treatment regimens. Therefore, there is a need to improve the unit dosage form of temorozol. This improved dosage form reduces pill load and increases patient compliance. Table 1 · Total dose of BSA (m2) calculated from body surface area (BSA) 75 mg/m2 (mg/day) 100 mg/m2 (mg/day)* 150 mg/m2 (mg/day) 200 mg/m2 (mg/day) 1.0 75 100 150 200 1.1 82.5 110 165 220 1.2 90 120 180 240 1.3 97.5 130 195 260 1.4 105 140 210 280 1.5 112.5 150 225 300 1.6 120 160 240 320 1.7 127.5 170 255 340 1.8 135 180 270 360 1.9 142.5 190 285 380 2.0 150 200 300 400 2.1 157.5 210 315 420 2.2 165 220 330 440 2.3 172.5 230 345 460 2.4 180 240 360 480 2.5 187.5 250 375 500 *100 mg/m2 per day indicates the current duration of the patient’s administration Minimum dose. 121049.doc 200808803 Table 2. Recommendations based on adult sputum doses Currently available capsule combinations Total number of capsules per day according to strength Total 曰 dose (mg) 250 100 20 5 75 0 0 3 3 82.5 0 0 4 0 90 0 0 4 2 97.5 0 1 0 0 105 0 1 0 1 112.5 0 1 0 2 120 0 1 1 0 127.5 0 1 1 1 135 0 1 1 3 142.5 0 1 2 0 150 0 1 2 2 157.5 0 1 3 0 165 0 1 3 1 172.5 0 1 3 2 180 0 1 4 0 187.5 0 1 4 1 195 0 1 4 3 200 0 2 0 0 210 0 2 0 2 220 0 2 1 0 225 0 2 1 1 240 0 2 2 0 255 1 0 0 1 260 1 0 0 2 270 1 0 1 0 280 1 0 1 2 285 1 0 1 3 300 0 3 0 0 315 0 3 0 3 320 0 3 1 0 330 1 0 4 0 340 0 3 2 0 345 0 3 2 1 360 0 3 3 0 370 1 1 1 0 380 1 1 1 2 400 0 4 0 0 121049.doc 200808803 [Summary of the Invention] The present invention provides a 1 4 Π main ^ 3, the force 140 is called Temozolo Improved temozolo early ^ 诏 type. The present invention also provides a unit dosage form of 艮莫佐罗, which is about 180 mg of Temozolo. Stalk stem ^ φ This special dosage form reduces pill load and increases patient compliance. / - In some embodiments, the unit dosage forms are in the form of a kneecap. In some embodiments, the capsules are sold by the head of the knife. In some embodiments, the color of the 140 mg*, Zorro capsule is different from the color of the 18 〇mg Temozolo capsule. The present invention also provides a method of increasing compliance by administering such unit agents (4). The present invention also provides methods of treating a proliferative disorder with such unit dosage forms. In some embodiments, the proliferative disorders are selected from the group consisting of gliomas, black lung cancer lymphomas, head and neck cancers, Indian cancer, colorectal cancer and/or colon or esophageal cancer, or other solid tumors or blood. Malignant tumors. In some embodiments, the method of treating a proliferative disorder comprises administering the units to the left homing early mu according to a dosing regimen. In some embodiments, the protocol is based on the methylation status of the promoter region of the 〇6m-pNA-dNA transferase (MGMT) gene in a sample obtained from a patient. In other embodiments, the regimen is based on the presence or absence of a sample obtained from a patient + MGMT protein in other embodiments, the Fangan·Technology|V/A A rb T 4 million case is based on patient acquisition The content or enzyme activity of the MGMT protein measured in the sample. In other embodiments, the protocol is based on the presence (or amount) of the messenger of mgmt in the sample obtained from the patient. The invention also provides kits comprising such unit dosage forms. The set of embodiments 121049.doc -10- 200808803 includes two unit dosage forms. In some embodiments, the kits further comprise an early dosage form comprising about 5 mg, 20 mg * 100 Å ^ 另 、, and in some embodiments, the kit The present invention described in the present specification can be fully understood, and the following embodiments are not to be construed as otherwise. All the technical terms and scientific terms used herein have the same general knowledge as the present invention. The same or similar methods and materials described herein may be used to practice or test the invention', but suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patents, and other documents mentioned herein are hereby incorporated by reference in their entirety. In order to further illustrate the invention, the following terms and definitions are provided herein. [6] A therapeutically acceptable carrier or adjuvant" means a non-toxic carrier or adjuvant that can be administered to a patient with Thai without destroying its pharmacological activity. The term "capsules classified by color" means any part of the capsule or the entire waist. This color indicates a specific meaning. For example, the specific capsule color indicates the special agent Xiazhi Te Mozolo. The term 'treating' means reducing or alleviating the symptoms of a cell proliferative disorder, such as a mammalian human, or improving the determinability associated with a cell proliferative disorder. The term "patient" refers to a snorkelling animal ( For example, humans. Animals. 121049.doc -]1 · 200808803 The sputum of the proliferative disease is 警 for the police; the tumor. 兮楚# + 」" The horse is negative from the Hehai tumor is benign or malignant. The term "tumor" refers to the growth of abnormally new cells that are newly grown abnormally or faster than normal cells. Tumors produce unstructured masses (tumors) that can be benign or malignant. The term "benign" refers to a non-cancerous tumor, for example, whose cells do not invade surrounding tissues or metastasize to a distal site. The term "malignant" refers to a cancerous metastasis that invades adjacent tissues or is no longer controlled by normal cell growth. Tumor. - The term "brain tumor" includes glial fibroma, pleomorphic f-blastoma, ependymoma, astrocytoma, blastocytoma, glioma, oligodendroglioma and meningioma The term "sample" means a sample that can be obtained or isolated from normal tissue or tumor tissue, brain tissue, cerebrospinal fluid, blood, plasma, serum, urine, feces, salivary lymph, lymph nodes, spleen, liver, bone marrow, or any Other biological samples containing MGMT protein or MGMT gene nucleic acid. The term "MGMT" refers to 〇6-methyl guanine 呤DNA methyltransferase. MGMT is also not a 6-alkylguanine_dna_alkyltransferase (Agat). The term "GM_CSF" means the following protein: (4) amino acid sequence and Lee et al. Pr.c. Nat. Acad. Sci. USA, 82: 4360 (1985), a sputum (ie lack of signal peptide) human The sequences of GM-CSF are substantially identical and (b) the biological activity is shared by native GM-CSF. __术=”The amino acid sequence of the amino acid sequence, meaning that the sequence is consistent or because of the amino acid change that does not consistently attenuate the biological activity (missing, 121049.doc 200808803 increase, substitution The term "set" used in the unit dosage form containing the invention refers to one or more containers. Unit dosage form - The present invention provides a unit dosage form comprising temozolo which is about 14 mg of temozolo and a pharmaceutically acceptable carrier. The present invention also provides an early dosage form of temozolo comprising (iv) 0 mg temozolo and a pharmaceutically acceptable carrier. In some embodiments, the unit dosage form is suitable for oral administration. The pharmaceutically acceptable carriers which can be used in the dosage form of the present invention include those well known in the art (see 1, for example, Reming_)

Pha let aceutical ~ India (10), i6 edition, "deduction p wish ^ (four) - ny (10) 0)). These pharmaceutically acceptable carriers, genetic carriers, adjuvants, excipients, inert diluents , lubricants, etc., such as human serum albumin preparations or blood preparations. Non-aqueous vehicles such as non-volatile, oil and ethyl oleate are also suitable for use herein. Examples of diluents include calcium citrate, potato starch, Alginic acid and lactose. Examples of inert diluents include lubricants such as magnesium stearate. Preferably, the pharmaceutically acceptable carrier is anhydrous lactate, colloidal cerium oxide, sodium starch glycolate, tartaric acid. And stearic acid. According to the unit dosage form of the present invention, it can be prepared into a tablet, a pill, a granule, a can, a sputum, or a capsule. Preferably, the unit dosage form is in the form of a capsule, in some embodiments, The capsules are sorted by color for easy identification. In some embodiments, the color of the 140 mg temozolo capsule is different from the color of the 18 〇mg temozolo capsule. In some embodiments, each capsule is 121049.doc -13 - 200808803 Intensity has different colors, This indicates the dose of temolozol. Methods of increasing patient compliance The unit dosage form of the present invention can be used to increase patient compliance by reducing the pill load. In some embodiments, the present invention provides for sputum administration to a patient - or A variety of dosage regimens containing about 14 mg or just Temazolo to increase the t-should. In some embodiments, these methods have a dosage of about 5 mg, 2 G. Or a unit of 1 (8) mg of temozolo which can be administered according to the dosing schedule and/or the time course of administration. Non-limiting examples of the king, f are illustrated in Table 3. 121049.doc 200808803 Table 3 · ΤΜΖ Dosing regimen And dose intensity program number dosing schedule total dose of administration time λ (mg / m / 4 weeks) dose / week (mg / m2) dose strength 1 5 / 28 150-200 mg / m2, 5 days / 28 days cycle (200 mg) 1000 250 1 2 high dose 250 mg/m2, 5/28 250 mg/m2, 5/28, concomitant growth factor 1250 312 1.2 3 14/28 100 mg/m2, 14 days/28 day period 1400 350 1.4 4 high dose 300 mg/m2, 5/28 300 mg/m2, 5/28, concomitant growth factor 1500 375 1.5 5 21/28 75 mg/m2, 21 days/28 Cycle 1575 393.75 1.6 6 42/56 75 mg/m2, 6 weeks/8 weeks cycle 3150 393.75 1.6 7 21/28 85 mg/m2, 21 days/28 day cycle 1785 446.25 1.8 8 High dose 350 mg/m2, 5/ 28 350 mg/m2, 5/28, concomitant growth factor 1750 437.5 1.8 9 continuous 14 days/interval 7 days 100 mg/m2, 14 days/21 day period 1400* 467 1.9 10 high dose 400 mg/m2, 5/28 400 mg/m2, 5/28, concomitant growth factor 2000 500 2.0 11 7/7 150 mg/m2, 7 days/14 day period 2100 525 2.1 12 21/28 100 mg/m2, 21 days/28 day period 2100 525 2.1 13 14/28 150 mg/m2, 14 days/28 days period 2100 525 2.1 14 Continuous administration 75 mg/m2, daily 2100 525 2.1 15 High dose 450 mg/m2, 5/28 450 mg/m2, 5/ 28, concomitant growth factor 2250 562.5 2.25 16 continuous 14 days / interval 7 days 150 mg / m2, 14 days / 21 days cycle 2100 * 700 2.8 17 continuous administration of 100 mg / m2, 2800 700 2.8 18 per day high dose 250 mg / M2,7/7 250 mg/m2,7/7, concomitant growth factor 3500 875 3.5 19 high dose 300 mg/m2, 7/7 300 mg/m2, 7/7, concomitant growth factor 4200 1050 4.2 for 3 weeks cycle The total dose accepted within the 121049.d Oc -15 - 200808803 The dosing regimen of Table 3 can be effected by using the unit dosage form of the present invention by using too σ. ^ ^ The build 4 capsule combination is illustrated in Table 4. Among the 29 daily doses listed in Table 4, the combination of the capsules of the present invention is lower than the capsule combination for the current ° 曰 jT. See Table 5. Importantly, the proposed capsule combination of the present invention, M.0rb, is only increased in two Japanese agents® (see Table 255 mg & 37〇tb in Table 2...to g, compared with Table 4) . By simplifying, the “Fangshu” patient's Pill load is significantly reduced. The sheep in the 195-day Temexolo regimen may need to take 8 current capsules to achieve the therapeutic dose (ie lxl00mg: 4x20 mg) And 3x5 mg). 夂目本0 Ώ r 口口) > See Tables 2 and 5. However, using the unit dosage form of the present invention, the patient may only need to take 4 unit dosage forms (ie, 1x180 mg and 3x5). See the table 4 and Table 5. For another example, a patient who is in the 280-day Temexolo program may need to take 4 current capsules to achieve a therapeutic dose (ie, 1χ25〇). Call, "squeak and g", see Table 2 and Table 5. However, with the unit dosage form of the present invention, the patient may only need to take 2 unit dosage forms (i.e., 2 χΐ 4 )). See Table 4 and Table 5. By way of further example, a patient who is in the 38-year-old Temexolo regimen may need to take 5 of the current capsule dosage form to achieve a therapeutic dose (ie, ' ixMO mg, lxl 〇〇 mg, ΐχ 2 screaming and called mg) 〇 See Table 2 and Table 5. In contrast, the patient may only need to take 3 units of the unit dosage form of the invention (ie, 2 x 18 mg and 1 χ 2 illusion. See Table 4 and Table 5. " Table 6 further illustrates how the unit dosage form of the invention The pill load of the patient is reduced. As shown in Table 6, when the patient receives the unit dosage form of the present invention, the number of capsules of the 28 regimens of the 121049.doc -16-200808803 45 regimen is reduced. See Table 6. Importantly, Of the remaining 17 regimens, the number of only 8 regimens has increased. Table 4 • Suggested capsule combinations based on adult daily doses Number of capsules per day based on strength Total dose (mg)* 180 140 100 20 5 135 0 1 0 0 0 142.5 0 1 0 0 0 150 0 1 0 0 2 157.5 0 1 0 1 0 165 0 1 0 1 1 172.5 0 1 0 1 2 180 1 0 0 0 0 187.5 1 0 0 0 1 195 1 0 0 0 3 200 1 0 0 1 0 210 1 0 0 1 2 220 1 0 0 2 0 225 1 0 0 2 1 240 0 1 1 0 0 255 0 1 1 0 3 260 0 1 1 1 0 270 1 0 1 0 0 280 1 0 1 0 0 285 1 0 1 0 1 300 0 0 3 0 0 315 0 2 0 1 3 320 1 1 0 0 0 330 1 1 0 0 2 340 0 1 2 0 0 345 0 1 2 0 1 360 2 0 0 0 0 370 2 0 0 0 2 380 2 0 0 1 0 400 0 0 4 0 0 $ Assumed rounding 121049.doc 200808803 Table 5. Total number of capsules Total dose (mg)* Current recommended capsule combination Suggested capsule combination of the invention 135 5 1 142.5 3 1 150 5 3 157.5 4 2 165 5 3 172.5 6 4 180 5 1 187.5 6 2 195 8 4 200 2 2 210 4 4 220 3 3 225 4 4 240 4 2 255 2 5 260 3 3 270 2 2 280 4 2 285 5 3 300 3 3 315 6 6 320 4 2 330 5 4 340 5 3 345 6 4 360 6 2 370 3 4 380 5 3 400 4 4 121049.doc 18- 200808803 Table 6 · Dosage 75 mg/m2 150 mg/m2 200 mg/m2 BSA/capsule when 180/140 BSA/dose when 180/140 BSA/current 180/ before dose before dose 140 1.50/113 250 1.50/225 1.50/300 1 180 1 140 100 1 1 2 3 20 1 2 2 5 3 3 1 1 2 Total 4 4 4 4 5 3 1.55/116 250 1.55/233 1.55/310 1 180 1 140 100 1 1 2 3 20 1 2 3 5 3 3 3 2 2 Total 4 4 6 5 4 5 1.60/120 250 1.60/240 1.60/320 1 180 1 140 1 1 100 1 1 2 1 20 1 1 2 3 5 2 Total 2 2 4 2 6 2 1.65/124 250 1.65/248 1 1.65/330 1 180 1 140 1 1 100 1 1 1 20 1 1 4 5 1 1 1 2 Total 3 3 1 3 5 4 1.70/128 250 1.70/ 255 1 1.70/340 1 180 140 1 1 100 1 1 1 2 20 1 1 4 5 2 2 1 3 2 Total 4 4 2 5 7 3 1.75/131 250 1.75/263 1 1.75/350 1 180 140 1 1 100 1 1 1 1 2 20 1 1 1 5 2 2 3 2 Total 4 4 4 3 2 5 121049.doc -19- 200808803 Dose 75 mg/m2 150 mg/m2 200 mg/m2 BSA/ Dosage Capsule Field 180/140 BSA /Dose Current 180/140 BSA/Dose Current 180/140 1.80/135 250 1.80/270 1 1.80/360 1 180 2 140 1 100 1 1 1 1 20 1 1 1 1 5 3 3 2 2 Total 5 5 2 5 4 2 1.85/139 250 1.85/278 1 1.85/370 1 180 1 2 140 1 100 1 1 1 20 2 1 1 5 1 2 Total 3 1 4 2 3 4 1.90/143 250 1.90/285 1 1.90/380 1 180 1 2 140 1 100 1 1 1 20 2 1 1 1 5 3 1 2 Total 3 1 5 3 5 3 1.95/146 250 1.95/293 1 1.95/390 1 180 1 2 140 1 100 1 1 1 20 2 2 2 1 5 1 1 1 3 2 Total 4 2 4 5 4 5 2.00/150 250 2.00/300 2.00/400 1 180 140 1 100 1 3 3 1 4 20 2 2 5 2 2 2 Total 5 3 3 3 6 4 2.05/154 250 2.05/308 2.05/410 1 180 1 140 1 1 100 1 3 1 4 20 2 2 5 3 3 2 2 Total 6 4 5 2 6 4 121049.doc -20- 200808803 200 mg/]

2.10/420 1 3 2 Ύ 2.20/165

Method for treating proliferative disorders dose 75 mg/m2 150 mg/rir 1 BSA/capsule when 180/140 BSA/dose field 180/140 pre-dose-XU 刖2.10/158 250 2.10/315 1 180 1 140 1 1 100 1 20 5 3 1 3 1 Total 4 2 5'* 2.15/161 Proliferation The unit dosage form of the present invention can be used to treat proliferative disorders in patients: ΓΓ 限于 is limited to benign/malignant tumors, such as brain tumors, anterior iliac crest: Γ Breast cancer, cancer, testicular cancer, liver cancer, kidney cancer, brand 7 bladder cancer, colorectal cancer and / or colon cancer, cancer, sarcoma, lymphoma, "carcinoma, melanoma lymphoma, mycosis fungoides" Taking hematological malignant tumors. In some embodiments: disease or other glioma, lining I# method for treating god, melanoma, lung cancer, lymphoma, sputum, intestinal cancer, head and neck cancer, , colorectal cancer and/or knot, red sputum nest cancer. In some embodiments to treat glioma. The sputum method is used in a case A / , t her case, the unit dosage form of the present invention is The dosing party proposed in 121049.doc -2J - 200808803 in Table 3 and Table 4 In one of the two yoke cases in the 28-day cycle, 5 days for the scalpel and 15 〇 2 〇〇 mg/m 2 for the mother's day. The dosing or abandonment was 14 days in a 21-day cycle of 1 mg/m per day. In other examples, the sputum and oral protocols were 150 mg/m2 per day in a 14-day cycle. ^7天天' 2::: In the case of 'the unit dosage form of the invention is used to treat the nerve gel shells, the unit dosage forms are based on the administration of the prescriptions in Tables 3 and 4' In some K regimens, the dosing regimen is $ days in a 28-day cycle, 150-200 mg/m per day. In other examples, the dosing regimen is η. Days of the day cycle, 1 GG mg/m2 per day. In other preferred embodiments, the dosing regimen is 7 days of a 14 day cycle, 15 mg/m2 per day. In some embodiments, such unit dosage forms The system is administered in combination with growth factors. Suitable growth factors include, but are not limited to, gm_csf, g_csf, IL-1, IL-3, IL-6 or erythropoietin. Non-limiting growth factor package Epogen® (Epoetin alfa (ep〇etin alfa)), pr〇cHt⑧ (epoetin primary Ting), Neupogen® (Filgrastim (fngrastim), human G-CSF),

Aranesp® (high glycosylated recombinant fabep〇etin alfa),

Neulasta8 (trade name is also Neup〇peg, PEGylated recombination non-geus τ t-alcoholized pegfilgrastim),

Albupoietin® (long-acting erythropoietin) and Albugranin (g) (albumin G_ CSF 'long-acting G-CSF). In some embodiments, the growth factor is G_CSF 〇 In some embodiments, the unit dosage forms are administered in combination therapy. In some embodiments, 121049.doc -22- 200808803, the unit dosage forms are administered in combination with a poly(ADP-ribose) polymerase (PARP) inhibitor. The PARP inhibitor can be administered concomitantly with or after administration to the unit dosage form of the invention. Suitable PARP inhibitors include, but are not limited to, CEP-6800 (Cephalon; described in Miknyoczki et al, Mol Cancer Ther, 2(4): 371-382 (2003)); 3-aminobenzamide ( Also known as 3-AB; Inotek; described in Liaudet et al, Br J Pharmacol, 133(8): 1424-1430 (2001); PJ34 (Inotek; described in Abdelkarim et al, Int J Mol Med, 7 ( 3): 255-260 (2001)); 5-iodo-6-amino-1,2-benzoquinone (also known as INH(2)BP; Inotek; described in Mabley et al., Br J Pharmacol, 1 33(6): 909-9 1 9 (200 1), GPI 1 5427 (described in Tentori et al, Int J Oncol, 26(2): 415-422 (2005)); 1,5 - Dihydroxyisoquinoline (also known as DIQ; described in Walisser and Thies, Exp Cell Res, 25 1(2): 401-413 (1999)); 5-aminoisoquinolinone (also known as 5) - AIQ; described in Di Paola et al, Eur J Pharmacol, 492 (2-3) 203-210 (2004); AG 14361 (described in Bryant and Helleday, Biochem Soc Trans, 32 (Pt 6): 959 -961 (2004); Veuger et al., Cancer Res, 63(18): 6008-6015 (2003); and Veuger et al., Oncogene, 23(44): 7322-7329 (2) 004) t); ABT-472 (Abbott); INO-1 00 1 (Inotek); AAI-028 (Novartis); KU-59436 (KuDOS; described in Farmer et al., ''Targeting the DNA repair defect in BRCA mutant Cells as a therapeutic strategy, ''Nature, 434 (7035): 917-921 (2005)); and described in Jagtap et al, Crit Care Med, 30(5): 1071-1082 (2002); Loh 121049. Doc -23 - 200808803 et al., Bioorg Med Chem Lett, 15(9): 2235-2238 (2005); Ferraris et al, J Med Chem, 46(14): 3138-3 15 1 (2003); Ferraris et al. , Bioorg Med Chem Lett, 13(1 5): 25 13-25 1 8 (2003); Ferraris et al, Bioorg Med Chem, 1 1(17): 3695-3707 (2003); Li and Zhang IDrugs, 4 ( 7): 804-812 (2001); Steinhagen et al, Bioorg Med Chem Lett, 12(21): 3187-3190 (2002)); WO 02/06284 (Novartis); WO 02/06247 (Bayer) And other PARP inhibitors; PARP inhibitors developed by MGI Pharma Inc. (formerly Guildford Pharmaceutical, Inc.), including the paRP inhibitors described in WO 99/1 1645, which is incorporated herein by reference in its entirety, Including the name nl, llb-dihydrogen (1) PARπ辰幷 (4,32-de) a PARP inhibitor of isoquinolin-3(2H) ketone π, such as the name ''1〇_(4_methyl-pyrazine)-1-yl fluorenyl) -2H-7-oxa-1,2-diazaphenyl hydrazone [de] 蒽-3-顚], GPI 15427; named "2-(4.methyl-azizin-1-yl) -5H-benzoquinone [c][l,5] acridine-6-one, GPI 16539; GPI21016, GPI 16346 and GPI 18180, GPI 6150, GPI 18078; GPI 6000 and 2-phenyl phenyl hydrazine Meter. Sitting on 4-carbamide, including those described by Agouron/PHzer in WO/09524379, including, for example, the 16th edition of NCI-EROTC Symposium New Drugs Cancer Therapy (Amsterdam) 1998 Abs 116;

Agouron 91th Edition AACR (San Francisco) 2000, Abs. 5164, including AG-014699, AG-14361, AG-14073, and Kudos KU59436, KU-0687, etc., in some embodiments, such The unit dosage form is combined with a 〇6_ 基 ϋ ϋ - DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA 049 049 049 049 049 049 049 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 Benzylguanine (〇6BG) or Lomeguatrib [6-(4-bromo-2 succinyl)methoxy]lotammine-2-amine] (aka PatrinTM or Patrin-2) (described in US patent) No. 6,043,228 (Cancer Research UK)). The Atase inhibitor of ruthenium 6BG can be administered concomitantly with or after administration of the unit dosage form of the present invention. In some embodiments, the unit dosage forms are administered in combination with an antiemetic. & [Stop inhibitors include (but are not limited to) Palonosetron, Tr0pisetron, 昂ndansetr〇n, Granisetron, Pome Bemesetron or a combination of both of the above agents to J. In some embodiments, the amount of active antiemetic material in a unit dose is from 2 mg to 10 mg, and the active substance in an amount of from 5 mg to 8 mg per unit dose is especially preferred. The bismuth dose generally comprises from 2 (f) to 2 Torr of the active substance, particularly preferably from 5 11 to 16 mg. In some embodiments, a neurokinin q antagonist (NK 1 #口抗抗) such as aprepitant can be used alone or in combination with a steroid such as dexamethasone. Sputum) is administered in combination. In other embodiments, the unit dosage forms are administered in combination with an agonist alone or in combination with a steroid. In some cases, the NK-1 antagonist is one or more of the NK-1 antagonists described in U.S. Patent No. 7, 〇49,32, which is either alone or in combination with a 5ΗΤ3 inhibitor and 甾. One or more of the classes are combined. In some embodiments, the unit dosage forms are administered in combination with a farnesyl protein transferase inhibitor. In other embodiments, the unit dosage form is administered with another anti-tumor agent & δ suitable anti-tumor agent includes, but is not limited to, uracil mustard 121049.doc -25 - 200808803 (Uracil Mustard), Chlormethine, Cyclosporin, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine , tri-ethyl thiophosphoramide, busulfan, carmustine, lovastatin, lomu stine, streptozocin, dacarbazine, a Methotrexate, 5-fluorouracil, Fluxuridine, Cytarabine, 6-mercaptopurine, 6-thiotoxin, sulphate, and sulphate ), pentastatin, gemcitabine, Vinblastine, Vincristine, Vindesine, Bleomycin, actinomycin D (Dactinomycin), Daunorubicin, Doxorubicin (Doxoru) Bicin), Epirubicin, Idarubicin, Paclitaxel, Mithramycin, Deoxycoformycin, Mitomycin-C ), L-Asparaginase, Interferon, Etoposide, Teniposide, 17α-Ethynylestradiol, Diethylstilbestrol ), Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate ), Tamoxifen, Methylprednisolone, methyl sterolone, prednisolone 121049.doc -26- 200808803 (Prednisolone), Triamcinolone, Chlorotrianisene , Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide Flutamide (Flut Amide), Toremifene, Goserelin, Cisplatin, Carboplatin, Rhizobine, Amsacrine, Procarbazine, Rice Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Ray Reloxafine, Droloxafine, hexamethylene melamine, alixaliplatin (Eloxatin®), lressa (gefinitib, Zdl 839) , XELODA8 (cacitabine),

Tarceva® (erl〇tinib), Azacitidine (5__ azacytidine; 5-AzaC) and mixtures thereof. In some embodiments, such unit dosage forms can be administered with other anti-cancer agents such as those disclosed in U.S. Patent Nos. 5,824,346, 5,939,098, 5,942,247, 6,096,757, 6,251,886. , No. 6, 316, 462, No. 6, 333, 333, No. 6, 346, 524, and No. 6, 7, 3, 4, 0, all of which are incorporated by reference. Method for Assessing the Methylation Status of MGMT Gene As a alkylating agent, temolozol causes cell death by binding to DNA. 121049.doc -27-200808803 is dying, which distort the DNA helix structure, thereby preventing DNA transcription and Translation. In normal cells, the damaging action of the alkylating agent can be repaired by cellular DNA repair enzymes (especially MGMT). In tumor cells, even in the same type of tumor, the content of MGMT is different. The gene encoding MGMT is usually not mutated or deleted. Conversely, lower levels of MGMT in tumor cells are attributed to epigenetic modification; the MGMT promoter region is thiolated, thereby inhibiting transcription of the MGMT gene and preventing MGMT expression. U.S. Patent Publication No. 20060100188, which is hereby incorporated by reference, discloses a method for treating cancer in a patient, which comprises administering Temozolo according to a modified dosing regimen and/or time course based on the MGMT content of the patient. In some embodiments, the dosing regimen is based on the thiolated state of the MGMT gene in a sample obtained from a patient. In some embodiments, the methylation status is assessed by determining whether the MGMT gene is methylated. In other embodiments, the methylation status is assessed by quantitatively determining the degree of methylation of the MGMT gene. In other embodiments, the methylation status is assessed by determining whether the MGMT protein is expressed. In other embodiments, the methylation status is assessed by determining the amount of MGMT protein expressed in a patient sample or measuring the enzyme activity of MGMT in a patient sample. Assessing whether the MGMT gene is thiolated can be carried out using any method known to those skilled in the art. Techniques suitable for detecting gene or nucleic acid methylation include, but are not limited to, those described by the following: Ahrendt et al, J. Natl. Cancer Inst., 91: 332-339 (1999); Belsinky et al, Proc. Natl. Acad. Sci. USA? 95:11891-1 1896 (1998); 121049.doc -28- 200808803

Clark et al, Nucleic Acids Res., 22: 2990-2997 (1994); Herman et al, proc Natl Acad Sci USA, 93: 9821-9826 (1996); Xi〇ng and Laird, Nucleic Acids Res·, 25 :2532-2534 (1997); Eads et al, Nuc. Acids. Res., 28:e32 (2002); Cottrell et al., Nucleic Acids Res. 32:1-8 (2004). Thiolation-specific PCR (MSP) allows rapid assessment of the thiolation status of almost any CpG site population within a CpG island without relying on the use of a thiolation sensitive restriction enzyme. See, MSP; Herman et al, proc Natl Acad Sci. USA, 93(18): 9821-9826 (1996); Esteller et al.

Cancer Res., 59: 793-797 (1999), see also U.S. Patent No. 5,786,146, issued July 28, 1998; U.S. Patent No. 6,017,7, 4, issued Jan. 25, 2000; US Patent No. 6, 2, 756 issued on March 13; and US Patent No. 6, 2, 65,171 issued in July 2001; US Patent No. 6, issued on August 10, 2004 No. 6,773,897; the entire contents of each of which are incorporated herein by reference. The MSP assay requires DNA to be initially modified with sodium bisulfite to convert all unmethylated (rather than methylated) cytosine to uracil and subsequently methylated relative to unmethylated DNA. DNA has specific primers for amplification. MSP requires only a small amount of ^1, which is sensitive to the 0.1% methylation allele of a particular CpG island locus, and the DNA extracted herein is performed. The MSP is eliminated, and it can be embedded in the stone.

in. Those skilled in the art will appreciate that a small amount of tissue or a small number of cells can be used to detect MGMT protein if the gene encoding MGMT is not methyl 121049.doc -29-200808803, and can be detected as detailed herein below (eg By Western blot, immunohistochemistry or enzymatic assay for MGMT activity, etc.). An illustrative example of a Western blot assay for measuring the mgmt protein benzin i in a patient sample is described in U.S. Patent No. 5,817,514, the entire disclosure of which is incorporated by reference. The manner is incorporated herein. The monoclonal antibody described by Li et al. binds specifically to the native human mgmt protein or the human mgmt protein having an alkylation active site. An illustrative example of an immunohistochemical technique suitable for use in measuring the mgmt protein content of a patient sample in this embodiment of the invention is found in U.S. Patent No. 5,407,804, the entire disclosure of which is incorporated herein by reference. A monoclonal antibody capable of specifically binding to a MGMT protein in a single cell preparation (immunohistochemical staining assay) and a cell extract (immunoassay) is disclosed. Describe the use of fluorescent ray (j 0llt) in combination with the digitization of cell images and which allows quantitative measurement of mgmt content in patient and control samples including, but not limited to, tumor biopsy samples. Techniques for measuring the enzymatic activity of MGMT proteins include, but are not limited to, those described by: Myrnes et al, Carcinogenesis, 5: 1061-1064 (1984); Futscher et al, Cancer Comm, 1: 65- 73 (1989), Kreklaw et al., j. Pharmacol·Exper. Ther., 297(2).524-530 (2001); and Nagel et al., Anal. Biochem., 321(1): 38-43 (2003) The entire disclosure of these documents is hereby incorporated by reference in its entirety in its entirety in its entirety the content of the MGMT protein expressed in the sample obtained from the patient, for example by using the Western blot method for MGMT. The antibody is measured by MGMT protein to assess 'see, for example, U.S. Patent No. 5,8,7,5,14. The amount of MGMT expressed in the sample can also be determined by using immunohistochemical techniques for a defined number of patient cells, for example Adopting a label specific to MGMT The antibody is assayed for MGMT protein to be assessed and compared to the amount of the same number of normal lymphocytes known to exhibit MGMT (see, for example, U.S. Patent No. 5,407,804 to Yarosh for applicable quantitative immunohistochemical assays). Or), the content of MGMT can be assessed by enzymatic assay, and even the ability of DNA 06 or N7 guanine position thiolation. In each of these methods, the measurement will be performed. The amount of MGMT protein expressed is compared with the content of MGMT protein expressed by normal lymphocytes known to express MGMT. The MGMT protein content of patients is classified as follows: low: = 0-30 of MGMT expressed by normal lymphocytes %; medium = 3 1-70% of MGMT expressed by normal lymphocytes; and high = 71-300% or higher of MGMT expressed by normal lymphocytes. The MGMT content of patients is classified as follows: low == 0-30% of MGMT enzyme activity of normal lymphocytes; 31% to 70% of MGMT enzyme activity of normal = normal lymphocytes; and 71-300% or more of MGMT enzyme activity of high = normal lymphocytes.

The specific activity of MGMT can be assessed and classified as follows based on comparison with cell lines known to express MGMT. Low = less than 20 fmol/mg; medium = 20-60 fmol/mg; or higher than 60 fmol/mg The specific activity of MGMT in LOX cells is 6-9 fmol/mg, the specific activity of MGMT 121049.doc -31 - 200808803 in DAOY cells is 60 -1 00 fmol/mg, and the specific activity of MGMT in A3 75 cells is The degree of thiolation of 80-1 50 fmol/mg 〇MGMT can be assessed by quantitative determination of the thiolation of the gene encoding MGMT. A quantitative technique called COBRA can be used in this assay (Xiong et al, Nuc Acids Res., 25:2532-2534 (1997)). Eads et al., Nuc. Acids Res., 28(8): e32 (2000); U.S. Patent No. 6,331,393, "methyl light" technology can also be used to encode MGMT in patient cells. The degree of methylation of the gene is compared with the known number of equal cells. The degree of thiolation of the gene encoding MGMT in normal lymphocytes of MGMT is compared. Those skilled in the art should understand that the MGMT gene of normal lymphocytes expressing MGMT is The degree of basalization is low; conversely, cells with a high degree of thiolinylation of the MGMT gene exhibit low MGMT protein content (see, for example, Costello et al, J. Biol. Chem., 269(25). 17228-17237 (1994); Qian et al, Carcinogen, 1 6(6): 1385-1390 (1995)). The methylated MGMT gene content of patients was classified as follows: 0-20% CpG thiolation in the promoter region of the low MGMT gene Medium = 21-50% CpG methylation in the promoter region of the MGMT gene; and high = 51-100% CpG thiolation in the promoter region of the MGMT gene. COBRA can be used to quantify small amounts of genomic DNA The degree of DNA thiolation at a specific locus. Restriction enzyme digestion to reveal transsulfur Sequence differences associated with thiolation in PCR products of sodium hydrogencarbonate treated DNA (Tano et al, Proc. Natl. Acad. Sci. USA? 87:686-690 (1990) Describe the isolation and sequence of human MGMT genes The degree of thiolation in the original DNA sample is expressed by the relative amount of digested and undigested PCR products in a linear quantitative manner over the broad range of 121049.doc -32 - 200808803 DNA thiolation. This technique can be reliably It is applied to DNA obtained from tissue samples that have been microdissected in paraffin-embedded tissue. Therefore, the COBRA combination is easy to use, quantitatively accurate and has strong compatibility with paraffin sections. RT-PCR for assessing MGMT mRNA content Illustrative examples of assays are described in Watts et al, Mol. Cell. Biol., 17(9): 5612-5619 (1997). Briefly, lysis by guanidinium isothiocyanate cells followed by a gradient of 5.7 MCsCl Total cellular RNA was isolated by centrifugation at 205,000 μg for 2.5 h. RNA was quantified by measuring the absorbance at 260 nm on a Beckman TL - 00 spectrophotometer by placing 40 μΐ of the reaction mixture containing the following in 42 Incubate for 60 min at °C to allow total cellular RNA to enter Reverse transcription: 200 ng RNA; lxPCR buffer (10 mM Tris [pH 8.3], 50 mM KC1, 1.5 mM MgCl2); 1 mM dATP, dCTP, dGTP and dTTP; 200 pmol random hexamer, 40 U RNasin And 24 U avian myeloblastic virus reverse transcriptase (Boehringer Mannheim, Indianapolis, Ind.), and then stopped by incubation at 99 ° C for 10 min. MGMT-specific PCR was performed by adding 80 μM amplification reaction buffer (lxPCR buffer, 25 pmol MGMT-specific primer and/or control sequence, and 2 U Taq DNA polymerase) to 20 μΐ reverse transcription The reaction mixture was then incubated at 94 ° C for 5 min; at 94 ° C for 1 min, at 60 ° C for 15 s and at 72 ° C for 1 min, cycle 30 times; finally at 72 ° C for 5 Min ; and rapid cooling to 4 ° C. For example, an upstream primer sequence from exon 4 (nt 665 to 684) of the MGMT gene can be used. Nucleotide positions can be obtained from cDNA sequences (Tano et al., Proc. Natl. Acad. Sci. 12l049.doc -33 - 200808803 subsequences can be used for the same cDNA. For analysis, via 3% and by ethidium bromide Dyeing to USA, 8 7:686-690 (1990)). A control reaction (for example, a primer for the histone 3.3 gene) was used to isolate 10% of individual PCR products for observation on an agarose gel. Method for treating a patient suffering from glioma based on the methylation status of the MGMT gene ~ The unit dosage form of the present invention is for treating a patient suffering from glioma. In some embodiments, the dosing regimen is based on (4) the methylated MGMT gene in the sample. When MGMT gene methylation was detected in samples obtained from patients with glioma, the dosing regimen was 5 days in a 28-day cycle, 150-200 mg/m2 per day. When no methylation was detected, the dosing regimen was 14 days in the (1) day cycle, 1 mg/m2 per day; (ii) 7 days in the i4 day cycle, 150 mg/m2 per day; or (iii) ) Days in the 28-day cycle, 1 〇〇 mg/m2 per day. In some embodiments, the sample is a tumor biopsy sample. In some embodiments, the MGMT gene is detected using Msp. In other embodiments, the dosage regimen is based on the presence or absence of MGMT protein. In the examples based on the presence or absence of MGMT protein, when no MGMT protein was detected in the sample obtained from a patient with glioma, the dosing regimen was 5 days in a 28 day cycle, 150-200 mg/m per day, when MGMT protein is detected, the dosing regimen is selected from (1) 14 days in a 21-day cycle, 1 〇〇 mg/m2 per day, 7 days in a 14-day cycle , 150 mg/m2 per day; or (iii) 21 days of the 28-day cycle, 100 mg/m per day. In some embodiments, the sample is a tumor biopsy 121049.doc-34 - 200808803 sample. In some embodiments, the MGMT protein is detected using Western blotting, immunohistochemical techniques, or enzymatic assays for M-white matter. In other embodiments, the dosage regimen is based on the amount or activity of the MGMT protein detected in the sample. When the MGMT protein content or enzyme activity detected by the sputum in the sample obtained from the patient is low compared with the normal lymphocyte, the dosage regimen is (1) 5 days in the 28-day cycle, 15 〇 _ _ mgW per day; Or (ii) 5 days of the 28-day cycle, 25 〇mg/m^ disk growth per day, sub-combination. When the MGMT protein content or enzyme activity is moderate, the dosing regimen is (1) 14 days in a 28-day cycle, 1 mg/m2 per day; (ii) 5 days in a 28-day cycle, 300 mg/m2 per day and Growth factor combination; (out) 2 days in a 28-day cycle, 75 mg/m2 per day; or (iv) 42 days in a 56-day cycle, 75 mg/m2 per day. When the content or enzymatic activity of the MGMT protein detected in the sample obtained from the patient is high, the dosing regimen is selected from (1) 14 days in a 21-day cycle, 1 〇〇 mg/m 2 per day; (ii) 14 7 days in the day cycle, 150 mg/m2 per day; or (iii) 21 days in the 28-day cycle, 1 mg/m2 per day. In some embodiments, the sample is a method for treating a patient having certain proliferative disorders based on the methylation status of the MGMT gene in a tumor biopsy sample 0. In some embodiments, the unit dosage form is for treatment A patient suffering from a proliferative disorder selected from the group consisting of melanoma, lung cancer, lymphoma, head cancer, neck cancer, ovarian cancer, colorectal cancer, colon cancer, and esophageal cancer. In some embodiments, the dosing regimen is based on the detection of methylation in the sample] 21049.doc -35 - 200808803 MGMT gene. When MGMT gene thiolation was not detected in the samples obtained from the patient, the dosing regimen was (丨) 14 days in the 21-day cycle, 100 mg/m2 per day; (ii) 7 days in the 14-day cycle , 15〇mg/m2 per day; or (iii) 2 days in a 28-day cycle, 1〇〇mg/m2 per day. In some embodiments, the sample is a tumor biopsy sample. In some embodiments, the MGMT gene is detected using MSP. In other embodiments, the dosing regimen is based on the detection of MGMT protein in the sample. When no MGMT protein was detected, the dosing regimen was selected from (1) 14 days in a 21-day cycle, 1 mg/m2 per day; 7 days in a 14-day cycle, ISO mg/m2 per day; Or (iii) 21 days of the 28-day cycle, ι〇〇mg/m per day in some of the shells, the sample is a tumor biopsy sample. In some examples, the MGMT protein is immunostained using Western blots. Detection by immunocytochemistry or enzymatic assays for MGMT proteins. In other embodiments, the dosage regimen is based on the amount or activity of the MGMT protein as measured in the sample. # The amount of protein (10) protein or enzyme activity measured in the sample obtained from the patient is positive or low, and the dosage regimen is (i) 14 days in the 21-day cycle. /m2; (10) 7 days in a 4-day cycle, 21 days per day in a maternal (four) take-up period, (10) mg/m2 per day. In ^, the sample is a tumor biopsy sample. Kit of dosage forms The unit dosage form of the present invention can be included in a kit. Any known method known in the art is a method of formulating a form or form of medicinally acceptable I21049. Made of materials of .doc -36- 200808803, such as carton or cardboard box plastic bottles or plastic cans H~Y (four) times glass jars, or plasticized in "refills" of different contents such as preserved tablets Out of the package h; or metal thread or plastic drop, such as for individual treatment time course door 2; or sachet or envelope-like container, the root group is foaming package:: galaxia. In some implementations In the example, the set of containers is sold in a lock-tr example. The set may include more than one, and the bottle is AA i. For example 'Winner's capsule or scent may be contained in the bottle one h A 3 in the box. In some embodiments, the set is rented and right-handed. Here every 4 / taste, and has a 虱 - some real nr The kit is made of a light-resistant material. 1.1. 2' The f-group contains - or a plurality of contains about ~2. - In some embodiments, ':80 is a unit dosage form called temozolo. The capsules and the swabs are blister packs. These different dosage forms can be placed in close proximity to each other in a glue pack, and the medicines will be placed in a short period of time (especially at the time of 'the patient' will be in a short period of time under various conditions). 〃 “Intra-infant” In the examples of taking capsules, lozenges or pills in succession from each column, the kit may be an fda approved kit. In-this :: The kit is accompanied by a dosing instructions. The kit may also be accompanied by: a form of Tongfu institution regulating the production, use or sale of the drug referred to by humans _::; = the composition of the form or the drug administration (us; The notification may, for example, be prepared by the United States Food and Drugs Pharmacy: a product insert: the unit dosage form may also be placed in a suitable container and act on the treatment of the specified condition 121049 Docs *37-200808803 In order to more fully understand the present invention, the following examples are set forth. This example is for illustrative purposes only and should not be considered as limiting the invention. Examples will have gliomas The patients were enrolled in a clinical trial to receive temtrozolo. Use only the currently recommended combination of capsules in Table 6, ie 5 mg, 20 and 100 mg capsules, 75 mg/m2, 1 50 mg/m2 Or the dose of 200 mg/m2 is administered. The dose is determined by the patient's bsa. The majority of patients selected for this trial have BSA in the range of 1.8 to 2.0 (149/284). Read about the pill load. After the data, the inventors found that an increase of about 14G mg and/or (10) mg of Thai was found. The unit dose of Mozolo will be beneficial in reducing the patient's pill load. See Table 7. None of the 24 possible dosing regimens in Table 7 are the pills of the patient in the unit dosage form of the present invention. The load will decrease.

Can be reduced. In the "6 of the schemes", the pill load 121049.doc 38- 200808803 Table 7 BSA patient number dosing scheme number is the same as the higher 1.4 6 fine return - —— 1.5 9 1 2 0 1.6 23 2 1 0 1.7 40 1 1 1 1.8 40 1 1 1 1.9 66 3 0 0 2.0 43 2 1 0 2.1 26 3 0 0 2.2 21 3 0 0 2.3 5 One - one - -- 2.4 4 —— —— -- 2.5 1 — — -- -- 121049.doc 39-

Claims (1)

200808803, the scope of the patent application: It comprises about 140 mg of temozolo and a pharmaceutically acceptable carrier in a unit dosage form comprising about 180 mg of temozolo and one temolozol. 2. 3. 4. 5. 6. 8. 9. A unit dosage form of temozolo pharmaceutically acceptable carrier. A unit dosage form according to claim 1 or 2, wherein the dosage form is a capsule. The unit dosage form of claim 3, wherein the capsule is classified by color. The unit dosage form of claim 4 wherein the 14 泰Temozool color is different from the color of the 180 mg temozolo capsule. A use of a unit dosage form or combination thereof as claimed in claim 2, in the manufacture of a medicament for increasing patient compliance with a regimen. The use of a unit dosage form, or a combination thereof, such as a sputum or sputum, for the manufacture of a medicament for treating a patient having a glioma. The use of a unit dosage form of the formula 1 or 2, or a combination thereof, for the manufacture of a medicament for treating a patient having a proliferative disorder selected from the group consisting of: Tumor, lung cancer, tumor, head cancer, neck cancer, nest cancer, colorectal cancer, cancer and esophageal cancer. And the use of a unit dosage form or a combination thereof of the intestinal tract, or a combination thereof, for the manufacture of a medicament for treating a patient suffering from glioma, wherein sputum. The system is administered according to a protocol selected from the group consisting of: (a) 5 days in a 28-day cycle, 15 〇 2 (10) mg/m 2 per day; (b) 5 days in a 28-day cycle, 2 mother days 250 mg/m, and growth factor group 121049.doc 200808803 (C) I4 days in a 28-day cycle, 100 mg/m2 per day; (4) 5 days in a 28-day cycle, 300 mg/m2 per day, combined with growth factors; (e) 21 days in the 28-day cycle, 75 mg/m2 per day; (1) 42 days in the 56-day cycle, 75 mg/m2 per day; (g) 21 days in the 28-day cycle, 85 mg/m2 per day; 5 days in the day cycle, 350 mg/m2 per day, combined with growth factors; (1) 14 days in the 21-day cycle, 1 mg/m2 per day; (j) 5 days in the day cycle, 400 mg/m2 per day, Combined with growth factors; (k) 7 days in a 14-day cycle, 150 mg/m2 per day; (1) 21 days in a 28-day cycle, 1 mg/m2 per day; () 14 days in an 8-day cycle, daily 150 mg/m2; (n) mother's day 75 mg/m2, daily; () 5 days in an 8-day cycle, 450 mg/m2 per day, combined with growth factors; (P) 14 days in the 21-day cycle, daily 150 mg/m2; (q) 100 mg/m2 per day, daily; () Period of 4 days, 7 days MO mg / m2, together with the growth factor group; and () day period of seven days, 300 mg daily / m2, combined with growth factors. • The use of claim 9, wherein the scheme is selected from the group consisting of 121049.doc 200808803: (4) 5 days in a 28-day cycle, 150-200 mg/m2 per day; (b) days in the 21-day cycle, 1 mg/m2 per day; and 7 days in the 11 (4) 14-day cycle, 150 mg/m2 per day. A kind of request for work, today. The use of the early dosage form of Bayer 1 or 2, or a combination thereof, for the manufacture of a medicament for treating a patient with a glioma of the heart, wherein the drug is selected from the group consisting of Α u τ & The protocol of the following group consisted of: (a) The field detected the glycosylation of the mgmt gene in the sample obtained from the patient: (1) 5 days in the 28-day cycle, 150-200 mg/m2 per day; b) The field did not detect methylation of the mgm-butyl gene in samples obtained from self-defective patients: (1) 14 days in the 21-day cycle, 1〇〇mg/m2 per day; (ii) 7 days in the 14-day cycle, I5〇mg/m2 per day; or 21 days in the 28-day cycle of the upper (out), i〇〇mg/m2 per day. The use of the moon picker 11 'where the sample is a tumor biopsy sample. 1 3 • As for the use of the request item i i, the i, T, and MWMT genes are detected using methylation-specific PCR. 14. The use of a unit dosage form of claim 1 or 2, or a combination thereof, for the manufacture of a medicament for treating a patient having a glioma, wherein the medicament is selected from the group consisting of: The group's protocol is administered. (a) When the MGMT protein is not detected in the sample obtained from the patient: , 121049.doc 200808803 (1) 5 days in the 28-day cycle, daily; and b) When MGMT protein is detected in a sample from the patient's current and present: (.) 14 days in a 1-day cycle, mg/m2 per day; (u) 7 days in a 14-day cycle, daily Mg/m2; or 15. 16. 17. () 21 days in the 8-day cycle, 1〇〇mg/m2 per day. If the eye is used for the choice of 4, the heart 'where the sample is a tumor biopsy For example, the MGMT protein is detected by Western blotting or immunoassay for MGMT protein. Use of a unit dosage form of 1 or 2, or a combination thereof, for the manufacture of a patient for treating a glioma The drug, wherein the drug is administered according to a regimen selected from the group consisting of: (a) MGMT protein content or enzyme activity detected in a sample obtained from a patient" When compared to low: (1) 5 days in the 28-day cycle '150-200 mg/m2 per day; or 5 days in the (Π) 28-day cycle, daily mg/m2, combined with growth factors; () Tian, Hai The MGMT protein content or enzyme activity detected in the sample obtained by the patient is moderate compared with normal lymphocytes: (1) 14 days in the 28-day cycle, i〇〇mg/m2 per day; () day cycle 5 days/day, 3〇〇mg/m2, 盥 growth factor combination; ^ 121049.doc 200808803 (III) 21 days in a 28-day cycle, 75 mg/m2 per day; or (IV) 42 of the 56-day cycle Day, 7S mg/m2 per day; and (4) When the MGMT protein content or enzyme activity measured in the sample obtained from the patient is higher than normal lymphocytes: (1) 14 days in the 21-day cycle, daily 10〇mg/m2; 7 days in a 14-day cycle, 150 mg/m2 per day; or 21 days in a (111) 28-day cycle, 1〇〇mg per day /m2 18. 18. 20. 21. 22. The use of the syllabus of claim 1 wherein the sample is a tumor biopsy sample. A use of the unit dosage form of claim 1 or 2 or a combination thereof, For the manufacture of a medicament for treating a patient suffering from melanoma, wherein when a MGMT gene thiolation is detected in a sample obtained from the patient, the drug is administered according to a protocol of a group consisting of the following programs: : (a) 14 days in the 21-day cycle, 1 〇〇 mg/m2 per day; (b) 7 days in the H-day cycle, 15 〇 mg/m2 per day; and (c) 21 days in the 28-day cycle, 1〇〇mg/m2 per day. The use of claim 19, wherein the sample is a tumor biopsy sample, such as the use of claim 19, wherein the MGMT gene is detected using methylation specific P C R . Use of a unit dosage form of claim 1 or 2, or a combination thereof, for the manufacture of a medicament for treating a patient having melanoma, wherein no MGMT protein is detected in a sample obtained from a patient presently The drug is administered according to a regimen selected from the group consisting of: 121049.doc 200808803 (a) 14 days in a 2 day cycle, 1 mg/m2 per day; (b) 7 of a 14-day cycle Days, 15 mg/m2 per day; and (c) 21 days in the 28-day cycle, 1 mg/m2 per day. 23. 24. 25. 26. 27. The use of claim 22, wherein the sample is a tumor biopsy sample, such as the use of claim 22, wherein the protein is Western blot immunoassay Detection by immunohistochemical techniques or enzymatic assays for MGMT proteins. The use of a unit dosage form or a combination thereof, such as the formula or the combination thereof, for the treatment of a patient suffering from melanoma in & 彳', /α, wherein in a sample obtained from the patient The amount of MGMT protein detected or the enzyme [when the ratio is low or medium compared to the positive hanging lymphocyte, the drug is administered according to a protocol selected from the group consisting of: (a) in a 21-day cycle μ days (b) 7 days of the 14-day cycle, (c) η days in the 28-day cycle, as claimed in claim 25, which is 〇 '100 mg/m2 per day; 150 mg/m2 per day; '100 mg/m2 per day. The sample is a tumor biopsy sample, such as the unit dosage form of claim 1 or 2, or a combination thereof, wherein: ί, a drug for treating a patient suffering from lung cancer, wherein when When the mgmt gene is detected in the k-sample, the drug is administered according to a protocol selected from the group consisting of: (a) in the 21-day cycle (b) 14 days in the 14-day cycle' 1〇〇mg/m2 per day; 7 days, 150 mg/m2 per day; and 121049.doc 200808803 (c) 21 days in the 28-day cycle, l〇〇mg/m2 per day. The use of the item 27 is the use of the tumor, and the sample is a tumor biopsy. The use of 9's π to claim 27, wherein the MGMT gene is detected using methylation-specific PCR. = the use of a unit dosage form or a combination thereof as claimed in claim 2, for the manufacture of a medicament for the treatment of a patient suffering from lung cancer, wherein no % detected in the sample obtained from the patient In the case of a protein, the drug is administered according to a regimen selected from the group consisting of: (a) 14 days in a 21-day cycle, 1 mg/m2 per day; (b) 7 days in a 14-day cycle, daily 15 〇 mg/m2; and (c) 21 days in the 28-day cycle, i〇〇mg/m2 per day. The use of the monthly claim 30, wherein the sample is for use in a tumor biopsy sample length 30, wherein the MGMT protein is performed using Western blot immunoassay, immunohistochemistry, or enzymatic assay for mgmt protein. Detection. 33. Use of a unit dosage form of claim 1 or 2, or a combination thereof, for the treatment of a drug for a patient suffering from lung cancer, wherein the test is obtained from a sample obtained from the patient When the content or enzyme activity of the MGMT protein is low or moderate compared to normal lymphocytes, the sputum drug is administered according to a protocol selected from the group consisting of: (a) 14 days in the 21-day cycle, 1 每天 per day 〇mg/m2 ; (b) 7 days in a 14-day cycle, 150 mg/m2 per day; and 121049.doc 200808803 (c) 21 days in a 28-day cycle, 1 mg/m2 per day. 34 35 36. 37. 38. 39. 40. • For the purposes of claim 33, where the sample is a tumor. And weaving inspection samples such as #求项1 or 2 in the manufacture of drugs for the treatment of patients with lymphoma, A one with a string of 嬅俨 + i丄丄 /, T s in the heart of the k When MGMT gene methylation was detected in the sample of babies, j was administered according to a protocol selected from the group consisting of: (a) 14 days in the 21-day cycle, 1 〇〇 mg/day M2 ; (b) 7 days in a 14-day cycle, 15 〇 mg/m 2 per day, and (C) 21 days in a 28-day cycle, 1 〇〇 mg/m 2 per day. The purpose of the monthly request for 3 5, wherein the sample is a tumor biopsy sample. For example, the use of claim 35, wherein the ^(}%7 gene is detected by methylation-specific PCR. A unit dosage form of claim 1 or 2 or a combination thereof is used for A medicament for treating a patient having a lymphoma, wherein when no MGMT protein is detected in a sample known from the heart, the drug is administered according to a protocol selected from the group consisting of: (a) 14 days in the 21-day cycle, i〇〇mg/m2 per day; (b) 7 days in the 14-day cycle, 150 mg/m2 per day; and (c) days in the 28-day cycle, i〇〇mg per day /m2. The use of claim 38, wherein the sample is a tumor biopsy sample, such as the use of claim 38, wherein the MGMT protein system uses Western ink 121049.doc 200808803 point immunoassay m histochemical technique or 41. A unit dosage form of claim 1st2, or a combination thereof, for use in the manufacture of a medicament for treating a patient having a lymphoma, wherein from the patient The amount of MGM protein or enzyme detected in the obtained sample: sex and When the ratio of normal lymphocytes is low or medium, the drug is administered according to the protocol of the group consisting of: (a) 14 days in the 21-day cycle, 1〇〇mg/m2 per day; (b) 14 7 days in the day cycle, 150 mg/m2 per day; and (C) 21 days in the 28-day cycle, l〇〇mg/m2 per day. Monthly request for 4 1 return, where the sample is a tumor biopsy Sample 〇 43. A use of a unit dosage form, or combination thereof, of claim 1 or 2 for the manufacture of a medicament for treating a patient having head and neck cancer, wherein when detecting from a sample obtained from the patient Upon merging of the MGMT gene, the drug is administered according to a regimen selected from the group consisting of: (a) 14 days in the 21-day cycle, 100 mg/m2 per day; (b) 7 of the 14-day cycle Day, 150 mg/m2 per day; and (C) 21 days in a 28-day cycle, 1 mg/m2 per day. 44. For the use of claim 43, wherein the sample is a tumor biopsy sample. The use of claim 43, wherein the gene is detected using methylation-specific PCR. 46. A unit dosage form according to claim 1 or 2 or For its purpose, it is used in the manufacture of a medicament for treating a patient suffering from head and neck cancer using 121049.doc 200808803, wherein when no mgmt protein is detected in the sample obtained from the patient and the patient, the drug is selected according to The following program consists of a group of programs: (a) 14 days in the 21-day cycle, 1 〇〇 mg/m2 per day; (b) 7 days in the 14-day cycle, l5 〇 mg/m2 per day; and (028 21 days in the day cycle, 1 〇〇 mg/m2 per day. The use of π to find item 46, wherein the sample is a tumor biopsy sample. 48. The use of claim 46, wherein the cerebral palsy protein is detected using Western blot immunoassay, immunohistochemistry or against MGMT protein: enzymatic assay. ' 49. - The use of a unit dosage form as claimed in claim 2 or 2, or a combination thereof, for the manufacture of a medicament for the treatment of a patient suffering from head and neck cancer, wherein the test is performed in a sample obtained from a patient with j When the content or enzymatic activity of the protein is low or moderate compared to normal lymphocytes, the drug is administered according to a protocol selected from the group consisting of: 乂 (a) 14 days in the 21-day cycle, 10〇mg/m2 per day; (b) 7 days in a 14-day cycle, 150 mg/m2 per day; and (C) 21 days in a 28-day cycle, l〇〇mg/m2 per day. ★ The use of claim 49, wherein the sample is for the use of a tumor biopsy sample 51, a breeder (7) unit dosage form of claim 1 or 2, or a combination thereof, which is used for the treatment of ovarian cancer The patient's drug, wherein when in the sample obtained from the patient (4) to the brain milk gene methylation, the drug 121049.doc -10- 200808803 is administered according to a program selected from the group consisting of: (4) 21 days 14 days in the cycle, 1〇〇mg/m2 per day; (b) 7 days in the 14-day cycle, 15〇mg/m2 per day; and (C) 21 days in the 28-day cycle, 1〇〇mg/day M2. 52. If the use of the item 5 1 is used, wherein the sample is a tumor biopsy sample 〇 5 3 · the use of the item 5 1 , wherein the MGMT gene is detected by methylation-specific PCR 54. Use of the unit dosage form of claim 1 or 2, or a combination thereof, for the manufacture of a medicament for treating a patient having ovarian cancer, wherein the sample is not detected in the sample from the patient When it comes to white matter, the drug is administered according to a program selected from the group consisting of: (a) 21 14 days in the cycle, 1〇〇mg/m2 per day; () 7 days in the 14-day cycle, mg/m2 per day; and (c) 21 days in the 28-day cycle, 100 mg/m2 per day. 54. The use of the sample, wherein the sample is a tumor biopsy sample. A 7 56. The use of claim 54 wherein the MGMT protein is used in Western inks:, immunonuclear, immunohistochemical techniques or enzymology against proteins The assay is used for detection. 57 - a unit dosage form or a combination thereof as claimed, for the manufacture of a medicament for treating a patient suffering from (4) a nest cancer, wherein the pain is in the sample obtained from the patient When the content or enzyme activity of the MG Μ τ protein is low or moderate compared with normal lymphocytes, the drug is administered according to the scheme of the group consisting of the following schemes: 121049.doc 200808803: (a) 21-day cycle 14 days, 1〇() mg/m2 per day, (b) 7 days in a 14-day cycle, 15〇mg/m2 per day; and (c) 21 days in a 28-day cycle, 1〇〇mg per day /m2. 58 59. 60. 61. 62. The return of the month’s elders, which is a tumor biopsy Use of the unit dosage form of claim 1 or 2, or a combination thereof, for the manufacture of a medicament for treating a patient having colorectal cancer and/or colon cancer, wherein the sample is taken from a sample obtained from the patient To the methylation of the helper gene, the drug is based on a group of two (a) 21-day cycles consisting of the following regimen, 14 days per day, 1 〇〇 mg/m2; (b) 7 of the 14-day cycle Days, 15 mg/m2 per day; and (c) 21 days in the 28-day cycle, 1 mg/m2 per day. The tissue test sample, such as the use of claim 59, wherein the sample is for tumor activity, such as the use of claim 59, wherein the gene system uses a heterogeneous P C R for speculation. - the use of a unit dosage form of the claimed item or a combination thereof for the manufacture of a patient for the treatment of colorectal cancer and/or colon cancer, wherein when the sample obtained from the patient is too toweled #, I , , , , 彳贞 MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG MG 049; 121049.doc -12- 200808803 (b) 7 days in a 14-day cycle, 150 mg/m2 per day, and (C) 21 days in a 28-day cycle, 100 mg/m2 per day. The use of the female item 62, wherein the sample is a tumor biopsy sample 〇64·^, the use of a 62, wherein the postal protein uses Western ink ':, ,; 仏疋, immunohistochemistry techniques or Detection of the MGMT protein enzymatic assay. Use of the unit dosage form of the formula 1 or 2, or a combination thereof, for the preparation of a medicament for treating a patient having colorectal cancer and/or colon cancer = in a sample obtained from the patient When the MGMT protein content or enzyme activity detected in the medium is low or medium compared with normal lymphocytes: the music is based on a protocol selected from the group consisting of (a) 14 days in the 21-day cycle. I〇〇mg/m2 per day; (b) 7 days in the 14-day cycle, 15 calls per day 2, and (C) 21 days in a 28-day cycle, 100 mg/m2 per day. 6 6. If you want to use item 6 5, use cold glycoside ^ /, the sample is a tumor biopsy sample 67. - The unit dosage form of claim (4) or a combination thereof is manufactured for treatment of esophageal cancer The drug of the patient, wherein the sample obtained by the patient is <measures that the MGMT gene tether is administered according to a protocol selected from the group consisting of: (4) the day of the 21-day cycle, 1 GGmg/m2 per day; (b) 7 days in a 14-day cycle, 150 mg/m per day, and 121049.doc -13-200808803 (c) 21 days in a 28-day cycle, 100 mg/m2 per day. 68. The use of claim 67, wherein the sample is a tumor biopsy sample. 69. The use of claim 67, wherein the MGMT gene is detected using methylation specific PCR. 70. Use of the unit dosage form of claim 1 or 2, or a combination thereof, for the manufacture of a medicament for treating a patient having esophageal cancer, wherein no sample is detected in the sample obtained from the patient In the case of MGMT protein, the drug is administered according to a regimen selected from the group consisting of: (a) 14 days in a 21-day cycle, 1 mg/m2 per day; (b) 7 days in a 14-day cycle, 15 mg/m2 per day; and (c) 21 days in the 28-day cycle, 1 mg/m2 per day. The use of Shiming for item 70, wherein the sample is a tumor biopsy sample 〇 72. The use of claim 7 wherein the MGM protein is Western blot immunoassay, immunohistochemistry or protein Enzymatic assay for detection. 73. Use of the unit dosage form of claim i or 2, or a combination thereof, for the treatment of a drug having a patient suffering from esophageal cancer, wherein in a sample obtained from the heart The amount of MGMT protein detected or enzyme: when the sex is low or medium compared to normal lymphocytes, the drug is administered according to a regimen selected from the group consisting of: (a) 14 days in the 21-day cycle 10 〇mg/m2 per day; (b) 7 days in a 14-day cycle, 150 mg/m2 per day; and 121049.doc -14-200808803 (c) 21 days in a 28-day cycle, 100 mg/m2 per day. 74. The use of claim 73, wherein the sample is a tumor biopsy sample of 0, and ' comprises a unit dosage form as claimed in claim 1. 76. The kit of claim 74, further comprising the unit dosage of claim 2, wherein the unit dosage form comprising claim 2 is contained. 7 8 · If the request is 7 5: a set of any one of the evenings, wherein the set further comprises a unit comprising about 5 mg, 20 or 100 called temozolo 79. The kit is assembled as a foam pack as claimed in any of the items 7 S 7 7 rk / , /5-77. 80. The set of claim 78, 81. The set of claim 79, 82. The set of claim 8 ,, wherein the set is a blister pack. Wherein the unit dosage form is a capsule. Wherein the unit dosage form is a capsule. 121049.doc -15- 200808803 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the representative figure is simple: 8. If the case has a chemical formula, please reveal the best display. Chemical formula of the inventive feature: , (none) 121049.doc