Cancer treatment

Abstract

To provide a method for treating advanced urothelial carcinoma in high-risk patients.SOLUTION: Administering to a subject in need thereof, in particular a subject with cancer, an amount of erdafitinib such that the serum phosphate concentration is in the range from 5. 5mg / dL to less than 5. 5mg / dL, including 5. 7mg / dL, or in the range from 5. 5mg / dL to less than or equal to 5. 5mg / dL, including 5. 9mg / dL, wherein the age of said subject in need, in particular the age of said subject with cancer, is 75 years or older.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention limits potential toxicities, such as nail toxicity, while providing a high probability of reaction. The present invention provides a cancer treatment using erdafitinib.

[0002] The present invention provides a method for administering erdafitinib to maximize erdafitinib exposure while limiting potential toxicity. The present invention provides a method for treating cancer with phytinib.

[0003] The present invention provides a high objective response rate, particularly an objective response rate of at least 40%, particularly objective response rate of at least 40% in chemotherapy-naive cancer patients, At least a 40% objective response rate in cancer patients with disease progression after chemotherapy, prior At least 40% objective in cancer patients with disease progression after two or more lines of chemotherapy To provide a cancer treatment with erdafitinib having a high response rate.

[0004] The present invention has a short time to response, specifically a median time to response of less than 2 months. The present invention provides a cancer treatment using erdafitinib.

[0005] The present invention provides a method for the treatment of high-risk patients with ergopachymyocarditis, particularly those at high risk for advanced urothelial carcinoma. A method for treating cancer with phytinib is provided. [Brief explanation of the drawings]

[0006] [Figure 1]

[0023] Figure 1 shows the study scheme for a phase 2, multicenter, open-label study to evaluate the efficacy and safety of erdafitinib in subjects with metastatic or surgically unresectable urothelial carcinoma harboring selected FGFR (fibroblast growth factor receptor) gene alterations (FGFR translocations or mutations). [Figure 2]Figure 1 shows a waterfall plot of the maximum percentage reduction from baseline in the sum of target lesion diameters among patients treated with the 8 mg continuous erdafitinib regimen (regimen 3 of the phase 2 study (Figure 1)). M, FGFR mutation; T, FGFR translocation. DETAILED DESCRIPTION OF THE INVENTION

[0007] The present invention limits potential toxicity while also providing a therapeutic benefit already in the first cycle of treatment (e.g., specifically is set for the first 28 days of treatment with daily continuous dosing or the first 21 days of treatment) and further treatment cycles (e.g., 2 cycles with continuous daily dosing). Maximize erdafitinib exposure during the treatment period (set at 8 days / cycle or 21 days / cycle), Treatment of cancer with erdafitinib is provided.

[0008] The present invention maximizes erdafitinib exposure and targets subjects in need of erdafitinib. Standard serum phosphate range, specifically 5.5 mg / dL to 7 mg / dL, inclusive Range of less than 5.5 mg / dL or range of 5.5 mg / dL to 9 mg / dL or less, including 5.5 mg / dL Treatment of cancer with erdafitinib, which rapidly reaches the target area and suppresses phosphate toxicity provide.

[0009] Erdafitinib or N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl) -N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl ]Ethane-1,2-diamine inhibits pan-fibroblast growth factor receptors (FGFR1, 2, 3, 4) It is a tyrosine kinase inhibitor.

[0010] The chemical structure of erdafitinib is: [ka] is.

[0011] Serum phosphate concentrations are a predictor of FGFR target engagement by erdafitinib. Serum phosphate concentration may represent an on-target pharmacodynamic marker indicative of target end-onset agonism. However, serum phosphate concentrations may increase with engagement. Hyperphosphatemia should be monitored to minimize, avoid, or control .

[0012] When serum phosphate levels were 5.5 mg / dL or higher, a higher proportion of patients received Eldafi It was found to respond to tinib treatment.

[0013] In one embodiment, the proportion of patients experiencing an objective response rate is at least Also 15%, 20%, 25%, 30%, 35%, 40%, or 45% , 50%, 55%, 60%, 65% or more than 65%.

[0014] In one embodiment, exposure to erdafitinib may be at least 10 days, depending on the type of cancer. At least 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 4 Those that produce an objective response rate of 5%, 50%, 55%, 60%, 65% or greater than 65% is.

[0015] In one embodiment, the serum phosphate concentration of the cancer patient is 5 or lower upon exposure to erdafitinib. .5mg / dL or higher, specifically 5.5mg / dL to 7mg / Range of less than 5.5 mg / dL or range of 5.5 mg / dL to 9 mg / dL or less, including 5.5 mg / dL and, depending on the type of cancer, at least 15%, or 20%, or 25%, or 30% , or 35%, or 40%, or 45%, 50%, 55%, 60%, 65% or more than 65% gives an objective response rate of

[0016] In one embodiment, the method of treating cancer described herein or the method of treating cancer described herein or for the manufacture of a medicament for the treatment of cancer as described herein. The erdafitinib for use has at least 15%, or 20%, or 25%, or 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 6 It gives an objective response rate of more than 5%.

[0017] In one embodiment, the cancer is urothelial carcinoma, metastatic or surgically unresectable urothelial carcinoma, Specifically, urothelial carcinoma with selected FGFR gene alterations, metastatic or surgically resected The method of treating a cancer described herein is a non-cancer-resistant urothelial cancer, or or the use of the method for the manufacture of a medicament for the treatment of cancer as described herein. Erdafitinib for use in It is about 40%, about 41%, about 42%, about 43%, and about 44%. It is about 45%, about 46%, about 47%, about 48%, and about 49%. Specifically, the objective response rate is in the range of 40% to 50%, or ~45% range, or 42% to 45% range.

[0018] In one embodiment, urothelial carcinoma, metastatic or surgically unresectable urothelial carcinoma, particularly urothelial carcinoma with selected FGFR gene alterations, metastatic or surgically unresectable In patients with urothelial carcinoma, erdaphycitinib is administered according to the dosing regimen disclosed herein. The objective response rate upon exposure to nib is at least 40%, specifically approximately 40%. , about 41%, about 42%, about 43%, about 44%, about 45% , about 46%, about 47%, about 48%, about 49%, about 50% Specifically, the objective response rate is in the range of 40% to 50%, or 40% to 45%, or is in the range of 42% to 45%.

[0019] In one embodiment, the method of treating cancer described herein or the method of treating cancer described herein or for the manufacture of a medicament for the treatment of cancer as described herein. Erdafitinib for use should be administered for at least 4 months, or at least 5 months, or Provide a median response duration of at least 6 months, or at least 7 months.

[0020] In one embodiment, the cancer is urothelial carcinoma, metastatic or surgically unresectable urothelial carcinoma, Specifically, urothelial carcinoma with selected FGFR gene alterations, metastatic or surgically resected The method of treating a cancer described herein is a non-cancer-resistant urothelial cancer, or or the use of the method for the manufacture of a medicament for the treatment of cancer as described herein. Erdafitinib for use in at least 4 months, or at least 5 months, or provide a median duration of response of at least 6 months, or at least 7 months, or is about 4 months, about 5 months, about 6 months, or about 7 months. The median duration of response ranged from 4 to 7 months.

[0021] In one embodiment, urothelial carcinoma, metastatic or surgically unresectable urothelial carcinoma, particularly urothelial carcinoma with selected FGFR gene alterations, metastatic or surgically unresectable In patients with urothelial carcinoma, erdaphycitinib is administered according to the dosing regimen disclosed herein. The median duration of response upon exposure to nib was at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or about 4 months, or The median duration of response is approximately 5 months, approximately 6 months, or approximately 7 months. , ranging from 4 to 7 months.

[0022] In one embodiment, the method of treating cancer described herein or the method of treating cancer described herein or for the manufacture of a medicament for the treatment of cancer as described herein. Erdafitinib for use should be administered for at least 4 months, or at least 5 months, or provides a median progression-free survival of at least 6 months, or at least 7 months.

[0023] In one embodiment, the cancer is urothelial carcinoma, metastatic or surgically unresectable urothelial carcinoma, Specifically, urothelial carcinoma with selected FGFR gene alterations, metastatic or surgically resected The method of treating a cancer described herein is a non-cancer-resistant urothelial cancer, or or the use of the method for the manufacture of a medicament for the treatment of cancer as described herein. Erdafitinib for use in at least 4 months, or at least 5 months, or provide a median progression-free survival of at least 6 months, or at least 7 months. Or about 4 months, or about 5 months, or about 6 months, or about 7 months. Typically, median progression-free survival ranges from 4 to 7 months.

[0024] In one embodiment, urothelial carcinoma, metastatic or surgically unresectable urothelial carcinoma, particularly urothelial carcinoma with selected FGFR gene alterations, metastatic or surgically unresectable In patients with urothelial carcinoma, erdaphycitinib is administered according to the dosing regimen disclosed herein. The median progression-free survival with exposure to nib was at least 4 months or at least 5 months. months, or at least six months, or at least seven months, or about four months or or about 5 months, about 6 months, or about 7 months. The median duration ranged from 4 to 7 months.

[0025] The methods of treating cancer described herein or the medicines for treating cancer described herein. Use of Erda for the manufacture of a medicament or for the treatment of cancer as described herein. The median time to response to fulvestib is very short. The median time to treatment was less than 2 months, specifically less than 1.5 months, specifically 1.4 months. It is nearby.

[0026] In one embodiment, the cancer is urothelial carcinoma, metastatic or surgically unresectable urothelial carcinoma, Specifically, urothelial carcinoma with selected FGFR gene alterations, metastatic or surgically resected The method of treating a cancer described herein is a non-cancer-resistant urothelial cancer, or or the use of the method for the manufacture of a medicament for the treatment of cancer as described herein. Erdafitinib for use in patients with rheumatoid arthritis has been shown to be effective for less than 2 months, specifically less than 1.5 months. The median duration is given as 1.4 months.

[0027] In one embodiment, urothelial carcinoma, metastatic or surgically unresectable urothelial carcinoma, particularly urothelial carcinoma with selected FGFR gene alterations, metastatic or surgically unresectable In patients with urothelial carcinoma, erdaphycitinib is administered according to the dosing regimen disclosed herein. The median time to response upon exposure to nib was less than 2 months, specifically less than 1.5 months. Specifically, it is around 1.4 months.

[0028] Surprisingly, the treatment of cancer described herein, in particular urothelial cancer, metastatic or surgical Unresectable urothelial carcinoma, specifically urothelial carcinoma with selected FGFR gene alterations Response to treatment of metastatic or surgically unresectable urothelial carcinoma is important in patients, e.g., those not previously treated with chemotherapy. Patients who have not received chemotherapy and are not suitable for cisplatin, and those who have received one prior line of chemotherapy Patients with disease progression after chemotherapy or those with disease progression after two or more lines of chemotherapy It was found that the effect was independent of the number of lines of prior therapy a patient had received. Therefore, response to treatment varies among patients with different numbers of prior lines of therapy, e.g., chemotherapy-naïve patients. Patients who have not received chemotherapy and are not suitable for cisplatin, and those who have received one prior line of chemotherapy Patients with disease progression after chemotherapy or those with disease progression after two or more lines of chemotherapy In one embodiment, the treatment is similar for patients who have had prior lines of chemotherapy, e.g. For example, patients with disease progression after one prior line of chemotherapy or two or more prior lines of chemotherapy Response to cancer treatment by patients with disease progression after chemotherapy is comparable to that in chemotherapy-naive patients. It's not worse than the combination.

[0029] Serum phosphate concentrations above 7 mg / dL, specifically above 9 mg / dL, are a sign of transient eruption. This may be a reason for discontinuing erdafitinib treatment or adjusting the erdafitinib dose (reduction in the dose). It was found that:

[0030] In one embodiment, temporary erdafitinib discontinuation is considered when serum phosphate levels return to 5. This represents discontinuation of erdafitinib administration until the serum cholesterol level reaches <5 mg / dL.

[0031] In one embodiment, temporary erdafitinib discontinuation is initiated when serum phosphate levels return to 7 m This represents the discontinuation of erdafitinib administration until the serum erythrocyte proliferation rate reaches <100 kJ / dL.

[0032] Effective and safe treatment with erdafitinib is indicated for patients with serum phosphate levels above 5.5 mg / kg. 5.5mg / dL to less than 7mg / dL, including 5.5mg / dL Erda is administered at a therapeutically effective dose in the range of 5.5 mg / dL to 9 mg / dL. It was found that administering fulvinib was effective.

[0033] Serum phosphate concentrations can be measured using, for example, ab65622 Phosphate Assay Kit. Measurement can be performed using commercially available kits such as Colorimetric (Abcam).

[0034] Daily, preferably once daily continuously (unless the context indicates otherwise, daily throughout the treatment) Administration of 8 mg of erdafitinib (without interruption or intermittent administration) resulted in no potential drug-related adverse events. Minimizing the need for treatment interruptions or dose reductions due to adverse events while Subjects requiring nib administration, specifically cancer patients, have a serum phosphate concentration of 5.5 mg / dL or higher. It was found that the probability of reaching or exceeding

[0035] Continuous daily administration of 8 mg of erdafitinib, preferably once daily, resulted in a 5.5 mg / dL serum phosphate concentration during the first cycle of erdafitinib treatment (e.g., It has been found that the 28-day or first 21-day setting can be achieved daily. erdafitinib administration by continuous administration of 8 mg erdafitinib once daily In patients in need, specifically cancer patients, adequately receive erdafitinib treatment during the first cycle. Early (e.g., day 14 ± 2 of treatment) should be considered to achieve a serum phosphate concentration of 5.5 mg / dL. Increased likelihood of reaching or exceeding the threshold for treatment discontinuation due to potential drug-related adverse events or minimize the need for dose reduction while maximizing effective treatment. was done.

[0036] In one embodiment, the blood of a subject in need of erdafitinib treatment, particularly a cancer patient, is The supernatant phosphate concentration is monitored.

[0037] In one embodiment, the blood of a subject in need of erdafitinib treatment, particularly a cancer patient, is Subjects in need of erdafitinib treatment, specifically cancer patients, whose serum phosphate levels are monitored. Early developmental toxicity associated with FGFR inhibitors in general and erdafitinib specifically, as demonstrated by Sex is monitored.

[0038] In one embodiment, the early stage associated with FGFR inhibitors generally or specifically with erdafitinib Phase toxicities included grade 3 or greater xerostomia or stomatitis / mucositis, dry skin, dry Nail toxicity (or Grade 2 if lasting longer than 1 week) or ocular toxicity of Grade 2 or higher Early developmental toxicity may occur after treatment discontinuation or This may be a reason for a dose reduction, which is at the discretion of the physician and may depend on the patient's condition. do.

[0039] In one embodiment, early developmental toxicity or FGFR inhibitors generally as described herein. Early developmental toxicity, or erdafitinib-specific toxicity, is usually grade 3 or higher. stomatitis / mucositis, dry skin, dry eyes, nail toxicity or specific ocular toxicity (keratitis or central serous retinopathy, also known as retinopathy, retinal detachment, retinal edema, retinal pigment epithelium) or FGFR inhibitors in general or specifically FGFR inhibitors in general are associated with other significant toxicities thought to be associated with erdafitinib or clinically significant toxicity thought to be specifically related to erdafitinib. Early developmental toxicity may be a reason to discontinue treatment or reduce the dose. and may depend on the patient's condition.

[0040] The present invention provides a method for treating cancer, comprising administering to a subject in need thereof, particularly a cancer patient, a blood Phosphate concentration is between 5.5mg / dL and less than 7mg / dL, including 5.5mg / dL In one embodiment, the method comprises administering an amount of erdafitinib in a range of In this study, the dose of erdafitinib was 8 mg, specifically 8 mg administered continuously daily. The present invention relates to a method for treating cancer, which is provided for a subject in need thereof, particularly a cancer patient. In addition, serum phosphate concentrations increased during the first cycle of erdafitinib treatment (treatment cycle duration was For example, the serum phosphate concentration is set for the first 28 days of administration or the first 21 days of administration. The frequency is on or around the 28th day of administration, or on or around the 21st day, or on or around the 14th day. 5.5 mg / dL, including 5.5 mg / dL This includes administering erdafitinib at a dose that achieves a blood glucose level in the range of 1.5 to 7 mg / dL. In one embodiment, the amount of erdafitinib is 8 mg, specifically 1 mg per day. It is 8 mg administered continuously daily.

[0041] The present invention provides a method for treating cancer, comprising administering to a subject in need thereof, particularly a cancer patient, a blood Phosphate concentration is 5.5mg / dL to 9mg / dL, including 5.5mg / dL. In one embodiment, the method comprises administering an amount of erdafitinib in a range of In this study, the dose of erdafitinib was 8 mg, specifically 8 mg administered continuously daily. The present invention relates to a method for treating cancer, which is provided for a subject in need thereof, particularly a cancer patient. In addition, serum phosphate concentrations increased during the first cycle of erdafitinib treatment (treatment cycle duration was For example, the serum phosphate concentration is set for the first 28 days of administration or the first 21 days of administration. The frequency is on or around the 28th day of administration, or on or around the 21st day, or on or around the 14th day. 5.5 mg / dL, including 5.5 mg / dL This includes administering erdafitinib at a dose that achieves a blood glucose level in the range of 1000 to 900 mg / dL. In one embodiment, the amount of erdafitinib is 8 mg, specifically 1 mg per day. It is 8 mg administered continuously daily.

[0042] The present invention relates to a method for producing a medicament for the treatment of cancer, the method comprising administering to a subject a serum phosphate concentration of 5.5 or less. El in an amount ranging from 5.5 mg / dL to less than 7 mg / dL, inclusive The present invention relates to the use of dafitinib. The serum phosphate concentration was measured during the first cycle of erdafitinib administration (treatment cycle duration, e.g., For example, the serum phosphate concentration is set at 28 days or 21 days after administration. On or around the 28th day of administration, or on or around the 21st day, or on or around the 14th day (evaluated before and after) One embodiment relates to the use of erdafitinib in amounts that reach the sub-mg / dL range. In this dosage form, the amount of erdafitinib is 8 mg, specifically 8 mg administered continuously daily. mg.

[0043] The present invention relates to a method for producing a medicament for the treatment of cancer, the method comprising administering to a subject a serum phosphate concentration of 5.5 or less. The amount of el is in the range of 5.5 mg / dL to 9 mg / dL, including mg / dL. The present invention relates to the use of dafitinib. The serum phosphate concentration was measured during the first cycle of erdafitinib administration (treatment cycle duration, e.g., For example, the serum phosphate concentration is set at 28 days or 21 days after administration. On or around the 28th day of administration, or on or around the 21st day, or on or around the 14th day (evaluated before and after) One embodiment relates to the use of erdafitinib in amounts that reach the sub-500 mg / dL range. In this dosage form, the amount of erdafitinib is 8 mg, specifically 8 mg administered continuously daily. mg.

[0044] The present invention relates to erdafitinib for use in the treatment of cancer, wherein serum phosphate The concentration is in the range of 5.5mg / dL to less than 7mg / dL, including 5.5mg / dL The present invention relates to erdafitinib administered in such an amount. Erdafitinib for the treatment of rheumatoid arthritis, Cycle (treatment cycle duration may be, for example, the first 28 days of administration or the first 21 days of administration) The serum phosphate concentration was measured on or around the 28th day of administration, or on or just after the 21st day. 5.5 mg within the period (evaluated on or around day 14 or on or around day 14) Administered in an amount that will reach a range of 5.5 mg / dL to less than 7 mg / dL, including 1 / dL. In one embodiment, the amount of erdafitinib is 8 mg , specifically 8 mg administered continuously daily.

[0045] The present invention relates to erdafitinib for use in the treatment of cancer, wherein serum phosphate The concentration is in the range of 5.5mg / dL to 9mg / dL, including 5.5mg / dL. The present invention relates to erdafitinib administered in such an amount. Erdafitinib for the treatment of rheumatoid arthritis, Cycle (treatment cycle duration may be, for example, the first 28 days of administration or the first 21 days of administration) The serum phosphate concentration was measured on or around the 28th day of administration, or on or just after the 21st day. 5.5 mg within the period (evaluated on or around day 14 or on or around day 14) The dose should be administered so that the range is 5.5 mg / dL to 9 mg / dL or less, including 1 / dL. In one embodiment, the amount of erdafitinib is 8 mg , specifically 8 mg administered continuously daily.

[0046] The present invention provides a method of treating cancer, comprising administering to a subject in need thereof, particularly a cancer patient, g of erdafitinib administered daily, specifically once daily, continuously. Dose adjustments are based on serum phosphate concentrations and the observed or absent toxicity. It can be implemented in accordance with the following.

[0047] The present invention relates to the use of erdafitinib for the manufacture of a medicament for the treatment of cancer. The drug contains erdafitinib in an amount of 8 mg, and the drug is administered daily, specifically once a day. The dosage adjustment is based on serum phosphate concentration. and can be performed based on the observed or absent toxicity.

[0048] The present invention provides erdafitinib for use in the treatment of cancer, in an amount of 8 mg. This relates to erdafitinib administered continuously daily, specifically once daily. This should be based on serum phosphate levels and the observed or absent toxicity. can.

[0049] During treatment with erdafitinib at a continuous 8 mg dose daily, preferably once daily, Serum phosphate levels may be monitored. If serum phosphate levels are less than 5.5 mg / dL, In this case, the dose of erdafitinib can be increased and administered daily, preferably once daily. In one embodiment, blood tests are performed to determine whether to titrate. Serum phosphate concentrations were measured on treatment days during the first cycle of erdafitinib treatment, specifically on erdafitinib. It is measured on day 14±2 of dafitinib administration, more specifically on day 14.

[0050] During treatment with erdafitinib at a continuous 8 mg dose daily, preferably once daily, Serum phosphate levels may be monitored. If serum phosphate levels are less than 7 mg / dL or is in the range of 7mg / dL to 9mg / dL, including 7mg / dL, or If the blood pressure is below 1000kJ / dL, the dose of erdafitinib can be increased, preferably daily. In one embodiment, the dose can be titrated to 9 mg once daily or continuously. Serum phosphate concentrations to be determined on the treatment day during the first cycle of erdafitinib treatment Specifically, it was measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14. do.

[0051] The present invention provides a method of treating cancer, comprising administering to a subject in need thereof, particularly a cancer patient, g of erdafitinib administered daily, specifically once daily, In one embodiment, the method comprises titrating the serum phosphate concentration. Serum phosphate concentrations were measured during the first cycle of erdafitinib treatment to determine whether on the treatment day, specifically on day 14 ± 2 of erdafitinib administration, more specifically on day 14. To be measured.

[0052] The present invention relates to a method for the treatment of cancer in a cancer patient using erdafitinib. The use of the present invention, wherein the medicament contains erdafitinib in an amount of 8 mg, and the medicament is administered daily. Typically, it is intended for continuous administration once daily, and serum phosphate levels in cancer patients are monitored. In one embodiment, the serum Phosphate concentrations were measured on treatment days during the first cycle of erdafitinib treatment, specifically on erdafitinib. It is measured on day 14±2 of the administration of phytinib, more specifically on day 14.

[0053] The present invention provides erdafitinib for use in the treatment of cancer in a cancer patient. , administered daily at a dose of 8 mg, specifically once daily, to improve serum phosphate levels in cancer patients. In one embodiment, the dose of erdafitinib is monitored to determine whether or not to titrate. Serum phosphate concentrations to be determined on the treatment day during the first cycle of erdafitinib treatment Specifically, it was measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14. do.

[0054] The present invention provides a method of treating cancer, comprising administering to a subject in need thereof, particularly a cancer patient, g of erdafitinib administered daily, specifically once daily, Monitoring serum phosphate levels is recommended. If serum phosphate levels are less than 5.5 mg / dL, If administered daily, the daily amount of erdafitinib administered continuously, preferably once daily, is 9 mg / dL, and the serum phosphate concentration is increased to 5 mg / dL, including 5.5 mg / dL. If the range is between 0.5 mg / dL and 0.7 mg / dL or less, the subject will be placed on continuous treatment with 8 mg per day. If serum phosphate levels are 7 mg / dL or higher, treatment should be temporarily discontinued. Specifically, erdafitinib treatment was not effective until serum phosphate levels returned to <7 mg / dL. The daily dose is discontinued or adjusted to less than 8 mg until , treatment is temporarily suspended until serum phosphate levels are below 5.5 mg / dL. In one embodiment, serum phosphate levels are measured in the first cycle of erdafitinib treatment. Treatment days during the course, specifically day 14 ± 2 of erdafitinib administration, more specifically day 1 In one embodiment, serum phosphate levels are measured specifically on day 14 ± 4. 2 days, more specifically, 7 mg / dL or more on the 14th day, specifically 7 mg / dL and up Treatment is initiated if serum phosphate levels are in the range of 5.5 mg / dL to 9 mg / dL or less. Erdafitinib treatment was temporarily discontinued until the blood pressure reached < 1000 mg / dL daily. , specifically resumed at a continuous dose of 8 mg once daily.

[0055] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0056] The present invention provides a method of treating cancer, comprising administering to a subject in need thereof, particularly a cancer patient, g of erdafitinib administered daily, specifically once daily, Monitoring serum phosphate levels, if serum phosphate levels are less than 7 mg / dL In this case, the daily dose of erdafitinib administered continuously, preferably once daily, is 9 mg / kg. g, inclusive of 7 mg / dL. If the serum phosphate level is in the range of 1 to 9 mg / dL, use a phosphate binder such as sevelamer. A daily dose of erdafitinib administered continuously, preferably during In one embodiment, the once-daily dose is increased to 9 mg, e.g., sevelamer. Combination therapy with phosphate binders is initiated. If serum phosphate levels rise above 9 mg / dL, In this case, treatment should be temporarily interrupted. Specifically, erdafitinib treatment should be discontinued after serum phosphate concentrations The drug is discontinued until the serum phosphate is again less than 7 mg / dL. If the dose is less than 2 weeks, the daily dose should be adjusted to the same or a lower daily dose. In the event of a persistent serum phosphate concentration of 0 mg / dL or greater, treatment should be permanently discontinued and specific In one embodiment, serum phosphate The concentration of erdafitinib was measured on the treatment day during the first cycle of erdafitinib treatment, specifically on the day of erdafitinib treatment. In one embodiment, the measurement is performed on day 14 ± 2 days after administration of the antibody, more specifically on day 14. If serum phosphate is >9 mg / dL, treatment begins with serum phosphate >7 mg / dL. Erdafitinib treatment was temporarily discontinued until the blood pressure reached <100 mg / kg, and then erdafitinib treatment was resumed daily. In one embodiment, the dose is resumed at 8 mg once daily. Serum phosphate concentrations during tinib administration may be controlled according to Table 4.

[0057] The present invention provides a method of treating cancer, comprising administering to a subject in need thereof, particularly a cancer patient, g of erdafitinib administered daily, specifically once daily, Monitoring serum phosphate levels and FGFR inhibitors in general or specifically erdafitinib and monitoring serum phosphate concentrations, including monitoring early developmental toxicity exhibited by the subject, associated with If the concentration is less than 5.5 mg / dL and no early developmental toxicity is observed, then the drug should be administered continuously. The daily dose of erdafitinib given, preferably once daily, is increased to 9 mg. , and the method relates to a serum phosphate concentration of 5.5 mg / dL to 7. If the dose is in the range of less than 8 mg / dL and no early developmental toxicity is demonstrated, the subject should be If serum phosphate levels are 7 mg / dL or higher, Treatment was temporarily interrupted, specifically, erdafitinib treatment was discontinued until serum phosphate concentrations The dose is discontinued until the blood pressure is again below 7 mg / dL, or the continuous daily dose is reduced to less than 8 mg. Specifically, treatment is initiated when serum phosphate levels are below 5.5 mg / dL. In one embodiment, serum phosphate levels are measured using Erda. Treatment day during the first cycle of erdafitinib treatment, specifically day 14 of erdafitinib administration ±2 days, more particularly on day 14. In one embodiment, serum phosphate concentrations If serum phosphate is 7 mg / dL or higher, treatment is initiated until serum phosphate is reduced to less than 5.5 mg / dL. Erdafitinib treatment was then temporarily suspended until Resume with one continuous dose of 8 mg.

[0058] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0059] The present invention provides a method of treating cancer, comprising administering to a subject in need thereof, particularly a cancer patient, g of erdafitinib administered daily, specifically once daily, Monitoring serum phosphate levels and FGFR inhibitors in general or specifically erdafitinib and monitoring for early developmental toxicity exhibited by the subject related to serum phosphate concentrations. If the concentration is less than 7 mg / dL and no early developmental toxicity is observed, The daily dose of erdafitinib administered, preferably once daily, is increased to 9 mg. Serum phosphate concentration is 7mg / dL to 9mg / dL or more, including 7mg / dL. If the range is below that and no early developmental toxicity is demonstrated, erdafitinib administered continuously while combination therapy with an anticoagulant is optionally initiated. The daily dose, preferably a once-daily dose, is increased to 9 mg. If serum phosphate concentration is above 9 mg / d, combination therapy with a phosphate binder such as sevelamer is initiated. If the blood pressure rises above 1000kJ, treatment should be temporarily interrupted. In particular, erdafitinib treatment should be discontinued. , discontinued until serum phosphate levels are again below 7 mg / dL, and / dL, the daily successive doses are adjusted to the same or lower daily dose. In one embodiment, the serum phosphate concentration is measured during the first cycle of erdafitinib treatment. Treatment day, specifically day 14 ± 2 of erdafitinib administration, more specifically day 14 In one embodiment, if the serum phosphate concentration is greater than 9 mg / dL, treatment is initiated. The drug was temporarily discontinued until serum phosphate levels were below 7 mg / dL, and then Rudafitinib treatment will be resumed daily, specifically at a continuous dose of 8 mg once daily.

[0060] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 4. It can be managed as follows.

[0061] The present invention provides a method of treating cancer, comprising administering to a subject in need thereof, particularly a cancer patient, g of erdafitinib administered daily, specifically once daily, This involves monitoring serum phosphate levels and is specifically a continuous 8 mg once daily regimen. While receiving treatment with erdafitinib, the subject's serum phosphate concentration is 5.5 mg In one embodiment, if the blood glucose level is less than 1 / dL, 9 mg is administered to the subject. , serum phosphate concentrations were measured on the treatment day during the first cycle of erdafitinib treatment, specifically It is measured on day 14 ± 2 days after erdafitinib administration, more specifically on day 14.

[0062] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0063] The present invention provides a method of treating cancer, comprising administering to a subject in need thereof, particularly a cancer patient, g of erdafitinib daily, specifically once daily, Specifically, while receiving continuous erdafitinib treatment at 8 mg once daily, If the subject's serum phosphate concentration is less than 7 mg / dL or if the serum phosphate concentration is more than 7 mg / dL, If the blood glucose level is in the range of 7mg / dL to 9mg / dL, including g / dL, 9mg will be administered to the subject. The method relates to a method in which serum phosphate concentration is 7 mg / dL to 9 mg / dL, inclusive. If the serum phosphate level is in the range of 0.1 mg / dL or less, combination therapy with phosphate binders such as sevelamer may be initiated. In one embodiment, combination therapy with a phosphate binder, such as sevelamer, is initiated. In one embodiment, the serum phosphate concentration is measured at day 14 of erdafitinib administration. It is measured on the 2nd day, specifically the 14th day.

[0064] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 4. It can be managed as follows.

[0065] The present invention provides a method of treating cancer, comprising administering to a subject in need thereof, particularly a cancer patient, g of erdafitinib daily, specifically once daily, Specifically, while receiving continuous erdafitinib treatment at 8 mg once daily, The subjects' serum phosphate concentrations are less than 5.5 mg / dL and no early developmental toxicity is observed. In one embodiment, 9 mg of serum phosphorus is administered to the subject if serum phosphorus is not present. The acid salt concentration was measured on the treatment day during the first cycle of erdafitinib treatment, specifically on the day of erdafitinib treatment. It is measured on day 14 ± 2 days after administration of tinib, more specifically on day 14.

[0066] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0067] The present invention provides a method of treating cancer, comprising administering to a subject in need thereof, particularly a cancer patient, g of erdafitinib daily, specifically once daily, Specifically, while receiving continuous erdafitinib treatment at 8 mg once daily, If the patient's serum phosphate concentration is less than 7 mg / dL or if the serum phosphate concentration is more than 7 mg / dL, The range is 7mg / dL to 9mg / dL, including g / dL, and early developmental toxicity is not observed. Unless otherwise indicated, 9 mg is administered to cancer patients. The range is 7mg / dL to 9mg / dL, including 7mg / dL, and early developmental toxicity If no such treatment is indicated, combination therapy with a phosphate binder, such as sevelamer, may be initiated. In one embodiment, combination therapy with a phosphate binder, such as sevelamer, is initiated. In some embodiments, serum phosphate levels are measured during the first cycle of erdafitinib treatment. Specifically, measurement was performed on day 14 ± 2 of erdafitinib administration, more specifically on day 14 will be done.

[0068] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 4. It can be managed as follows.

[0069] The present invention relates to a method for the treatment of cancer in a cancer patient using erdafitinib. The use of the present invention, wherein the medicament contains erdafitinib in an amount of 8 mg, and the medicament is administered daily. Typically, it is intended for continuous administration once daily, and serum phosphate levels in cancer patients are monitored. If serum phosphate is less than 5.5 mg / dL, The amount of erdafitinib in the drug product for each consecutive administration is increased to 9 mg. Serum phosphate concentration is less than 5mg / dL to 7mg / dL, including 5mg / dL. If the serum phosphate is below the 8 mg daily limit, the subject will remain on continuous treatment. If the concentration is 7 mg / dL or higher, treatment should be temporarily suspended, specifically with Eldaf. Ignitib therapy is discontinued until serum phosphate levels are again <7 mg / dL, or The daily continuous dose is adjusted to less than 8 mg, and the treatment is specifically In one embodiment, the serum phosphate concentration is temporarily discontinued until the serum phosphate concentration is less than 5.5 mg / dL. In this study, serum phosphate concentrations were measured on the treatment day during the first cycle of erdafitinib treatment, specifically It is measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14. In embodiments, if the serum phosphate concentration is 7 mg / dL or greater, treatment is Temporarily discontinued until the iodine-containing iodine concentration was less than 5.5 mg / dL, and then discontinued. Tinib treatment will be resumed daily, specifically at a continuous dose of 8 mg once daily.

[0070] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0071] The present invention relates to a method for the treatment of cancer in a cancer patient using erdafitinib. The use of the present invention, wherein the medicament contains erdafitinib in an amount of 8 mg, and the medicament is administered daily. Typically, it is intended for continuous administration once daily, and serum phosphate levels in cancer patients are monitored. If serum phosphate is less than 7 mg / dL, then daily, specifically once a day The amount of erdafitinib in the drug product for continuous administration is increased to 9 mg. Serum phosphate concentration is 7mg / dL to 9mg / dL or less, including 7mg / dL. If the range is within the above range, combination therapy with a phosphate binder, such as sevelamer, is optionally initiated. of erdafitinib in pharmaceutical products for continuous daily administration, specifically once daily, for the duration of the study. The amount is increased to 9 mg. In one embodiment, a phosphate binder, such as sevelamer, is administered. If serum phosphate levels rise above 9 mg / dL, treatment should be discontinued. Specifically, erdafitinib treatment was discontinued until serum phosphate concentrations were again below 7 mg / mL. Once serum phosphate is below 7 mg / dL, continuous daily administration is discontinued. In one embodiment, the serum phosphate level is adjusted to the same or a lower daily dose. The concentration of erdafitinib was measured on the treatment day during the first cycle of erdafitinib treatment, specifically on the day of erdafitinib treatment. In one embodiment, the measurement is performed on day 14 ± 2 days after administration of the antibody, more specifically on day 14. If serum phosphate is >9 mg / dL, treatment begins with serum phosphate >7 mg / dL. Erdafitinib treatment was temporarily discontinued until the blood pressure reached <100 mg / kg, and then erdafitinib treatment was resumed daily. Typically, the dose is resumed at 8 mg once daily.

[0072] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 4. It can be managed as follows.

[0073] The present invention relates to a method for the treatment of cancer in a cancer patient using erdafitinib. The use of the present invention, wherein the medicament contains erdafitinib in an amount of 8 mg, and the medicament is administered daily. Typically, it is intended for continuous administration once daily, and serum phosphate levels in cancer patients are monitored. and is generally associated with FGFR inhibitors or specifically with erdafitinib, as indicated by cancer patients. Early developmental toxicity associated with phosphate-lowering drugs was monitored and evaluated if serum phosphate levels were less than 5.5 mg / dL. and if no early developmental toxicity is demonstrated, then daily, specifically once daily, continuous administration The amount of erdafitinib in the drug product for this purpose is increased to 9 mg. phosphate concentration is between 5.5 mg / dL and less than 7 mg / dL, inclusive of 5.5 mg / dL; If no early developmental toxicity is demonstrated, the subject will remain on continuous treatment at 8 mg once daily. If serum phosphate levels are 7 mg / dL or higher, treatment should be temporarily interrupted and Specifically, erdafitinib treatment should be continued until serum phosphate levels are again <7 mg / dL. The daily continuous dose is adjusted to less than 8 mg, specifically, Treatment is temporarily suspended until serum phosphate levels are below 5.5 mg / dL. In one embodiment, the serum phosphate concentration is measured after the first cycle of erdafitinib treatment. Treatment day during the study, specifically day 14 ± 2 days of erdafitinib administration, more specifically day 14 In one embodiment, if the serum phosphate concentration is 7 mg / dL or higher, , treatment is temporarily suspended until serum phosphate levels are less than 5.5 mg / dL, and Erdafitinib treatment was then resumed daily, specifically at a continuous dose of 8 mg once daily. can be.

[0074] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0075] The present invention relates to a method for the treatment of cancer in a cancer patient using erdafitinib. The use of the present invention, wherein the medicament contains erdafitinib in an amount of 8 mg, and the medicament is administered daily. Typically, it is intended for continuous administration once daily, and serum phosphate levels in cancer patients are monitored. and is generally associated with FGFR inhibitors or specifically with erdafitinib, as indicated by cancer patients. Early developmental toxicity associated with phosphate-dependent steroid use was monitored and evaluated if serum phosphate levels were less than 7 mg / dL and If no early developmental toxicity is observed, then daily administration, specifically once daily, is recommended. The amount of erdafitinib in the drug is increased to 9 mg. Salt concentration is 7mg / dL to 9mg / dL or less, including 7mg / dL, and early onset If no toxicity is observed, combination therapy with phosphate binders, such as sevelamer, is an option. Eldaf in medicines for continuous daily administration, specifically once a day, while starting In one embodiment, the amount of rifametinib is increased to 9 mg. Combination therapy with an adsorbent is initiated. If serum phosphate levels rise above 9 mg / dL, Treatment was temporarily interrupted, specifically, erdafitinib treatment was discontinued until serum phosphate concentrations It is discontinued until serum phosphate is again below 7 mg / dL; Successive daily doses are adjusted to the same or lower daily dose. Serum phosphate concentrations were measured on the treatment day during the first cycle of erdafitinib treatment, specifically on the erdafitinib The measurement is performed on day 14 ± 2 days, more specifically on day 14, of administration of rudafitinib. In this condition, if the serum phosphate concentration is greater than 9 mg / dL, treatment is initiated. Erdafitinib treatment was temporarily discontinued until the serum creatinine concentration was less than 7 mg / dL, and then , and resumed daily, specifically at a continuous 8 mg once daily.

[0076] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 4. It can be managed as follows.

[0077] The present invention relates to a method for the treatment of cancer in a cancer patient using erdafitinib. The use of the present invention, wherein the medicament contains erdafitinib in an amount of 9 mg, and the medicament is administered daily. Specifically, it is intended for continuous administration once a day, and specifically, for continuous administration once a day. The patient's serum phosphate concentration during treatment with 8 mg of erdafitinib If the blood glucose level is less than 5.5 mg / dL, the pharmaceutical agent is administered to the cancer patient. In embodiments, serum phosphate concentrations are measured during the first cycle of erdafitinib treatment. The treatment day, specifically, the 14th day ± 2 days after erdafitinib administration, more specifically, the 14th day It is determined.

[0078] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0079] The present invention relates to a method for the treatment of cancer in a cancer patient using erdafitinib. The use of the present invention, wherein the medicament contains erdafitinib in an amount of 9 mg, and the medicament is administered daily. Specifically, it is intended for continuous administration once a day, and specifically, for continuous administration once a day. The patient's serum phosphate concentration during treatment with 8 mg of erdafitinib If serum phosphate concentration is less than 7 mg / dL or if serum phosphate concentration is more than 7 mg / dL, including 7 mg / dL If the serum cholesterol level is in the range of 0.05 to 9 mg / dL, the drug is administered to cancer patients. Serum phosphate concentration is in the range of 7mg / dL to 9mg / dL, including 7mg / dL. In one embodiment, combination therapy with a phosphate binder, such as sevelamer, may be initiated. In one embodiment, combination therapy with a phosphate binder, such as sevelamer, is initiated. In this study, serum phosphate concentrations were measured on the treatment day during the first cycle of erdafitinib treatment, specifically is measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14.

[0080] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 4. It can be managed as follows.

[0081] The present invention relates to a method for the treatment of cancer in a cancer patient using erdafitinib. The use of the present invention, wherein the medicament contains erdafitinib in an amount of 9 mg, and the medicament is administered daily. Specifically, it is intended for continuous administration once a day, and specifically, for continuous administration once a day. The patient's serum phosphate concentration during treatment with 8 mg of erdafitinib If the IL-10 level is less than 5.5 mg / dL and no early developmental toxicity is demonstrated, the drug is In one embodiment, the serum phosphate concentration is measured by administering Erda to a patient. Treatment day during the first cycle of erdafitinib treatment, specifically day 14 of erdafitinib administration ±2 days, more specifically measured on day 14.

[0082] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0083] The present invention relates to a method for the treatment of cancer in a cancer patient using erdafitinib. The use of the present invention, wherein the medicament contains erdafitinib in an amount of 9 mg, and the medicament is administered daily. Specifically, it is intended for continuous administration once a day, and specifically, for continuous administration once a day. The patient's serum phosphate concentration during treatment with 8 mg of erdafitinib If serum phosphate concentration is less than 7 mg / dL or if serum phosphate concentration is more than 7 mg / dL, including 7 mg / dL If the concentration is in the range of 0.5 to 9 mg / dL and no early developmental toxicity is observed, The present invention relates to the use of a steroid drug administered to a cancer patient, the steroid drug being administered to a cancer patient when the serum phosphate concentration is 7 or more times higher than 7 mg / dL, inclusive. If the range is between 100 mg / dL and 9 mg / dL or less and no early developmental toxicity is observed, Combination therapy with a phosphate binder, such as sevelamer, may be initiated. In one embodiment, combination therapy with a phosphate binder, such as sevelamer, is initiated. The phosphate concentration was measured on the treatment day during the first cycle of erdafitinib treatment, specifically on erdafitinib. The measurement is made on day 14±2 of administration of rituximab, more specifically on day 14.

[0084] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 4. It can be managed as follows.

[0085] The present invention provides erdafitinib for use in the treatment of cancer in a cancer patient. , administered daily at a dose of 8 mg, specifically once daily, to improve serum phosphate levels in cancer patients. should be monitored and administered daily if serum phosphate levels are below 5.5 mg / dL, preferably The dose of erdafitinib administered continuously once daily will be increased to 9 mg. Regarding ritinib: Serum phosphate concentration is 5.5 mg / dL or higher, including 5.5 mg / dL. If the range is below 7 mg / dL, the subject will remain on continuous treatment at 8 mg once daily. If serum phosphate levels are 7 mg / dL or higher, treatment should be temporarily interrupted and specific In patients with rheumatoid arthritis, erdafitinib treatment should be discontinued until serum phosphate levels are again <7 mg / dL. The daily continuous dose is discontinued or adjusted to less than 8 mg. Specifically, the treatment is , specifically, is temporarily discontinued until serum phosphate levels are below 5.5 mg / dL. In one embodiment, the serum phosphate concentration is measured during the first cycle of erdafitinib treatment. Treatment day, specifically day 14 ± 2 of erdafitinib administration, more specifically day 14 In one embodiment, if the serum phosphate concentration is 7 mg / dL or greater, treatment is initiated. Therapy was temporarily suspended until serum phosphate levels were below 5.5 mg / dL, and then After this, erdafitinib treatment will be resumed daily, specifically at a continuous dose of 8 mg once daily. .

[0086] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0087] The present invention provides erdafitinib for use in the treatment of cancer in a cancer patient. , administered daily at a dose of 8 mg, specifically once daily, to improve serum phosphate levels in cancer patients. should be monitored and if serum phosphate levels are less than 7 mg / dL or If your blood sugar level is in the range of 7mg / dL to 9mg / dL, including 7mg / dL, it is recommended to take it daily. The dose of erdafitinib administered continuously once daily is increased to 9 mg. Regarding dafitinib, serum phosphate levels are between 7 mg / dL and 9 mg / dL, including 7 mg / dL. If the serum phosphate level is in the range of 0.5 to 1.5 g / dL, combination therapy with a phosphate binder, such as sevelamer, may be initiated. In one embodiment, combination therapy with a phosphate binder, such as sevelamer, may be initiated. If serum phosphate levels rise above 9 mg / dL, treatment should be temporarily discontinued and Specifically, erdafitinib treatment should be continued until serum phosphate levels are again <7 mg / dL. Once serum phosphate is below 7 mg / dL, the daily continuous dose is discontinued at the same In one embodiment, the serum phosphate concentration is adjusted to a daily dose of ergocalcinosis or a lower daily dose. Treatment day during the first cycle of erdafitinib treatment, specifically day 14 of erdafitinib administration ±2 days, more particularly on day 14. In one embodiment, serum phosphate concentrations If serum phosphate is >9 mg / dL, treatment should be continued until serum phosphate is <7 mg / dL. Erdafitinib treatment was temporarily discontinued, and thereafter, erdafitinib treatment was resumed daily, specifically once daily. Restarted at 8 mg continuously.

[0088] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 4. It can be managed as follows.

[0089] The present invention provides erdafitinib for use in the treatment of cancer in a cancer patient. , administered daily at a dose of 8 mg, specifically once daily, to improve serum phosphate levels in cancer patients. The study was conducted to monitor and evaluate the efficacy of FGFR inhibitors in general or specifically erdafitinib in cancer patients. Early developmental toxicity associated with phosphate-lowering drugs was monitored and evaluated if serum phosphate levels were less than 5.5 mg / dL. and if no early developmental toxicity is observed, it may be administered continuously daily, preferably once a day. The amount of erdafitinib administered is increased to 9 mg. The acid salt concentration is between 5.5 mg / dL and less than 7 mg / dL, inclusive of 5.5 mg / dL, and If no early developmental toxicity is demonstrated, the subject will remain on continuous treatment at 8 mg once daily. If serum phosphate levels are 7 mg / dL or higher, treatment should be temporarily discontinued and specific Generally, erdafitinib treatment should be continued until serum phosphate levels are again below 7 mg / dL. The daily continuous dose is discontinued or adjusted to less than 8 mg, specifically, is temporarily discontinued until serum phosphate levels are below 5.5 mg / dL. In one embodiment, the serum phosphate concentration is measured during the first cycle of erdafitinib treatment. treatment day, specifically day 14 ± 2 days of erdafitinib administration, more specifically day 14 In one embodiment, if the serum phosphate concentration is 7 mg / dL or greater, Treatment is temporarily suspended until serum phosphate levels are below 5.5 mg / dL, and then After this, erdafitinib treatment was resumed daily, specifically at a continuous dose of 8 mg once daily. do.

[0090] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0091] The present invention provides erdafitinib for use in the treatment of cancer in a cancer patient. , administered daily at a dose of 8 mg, specifically once daily, to improve serum phosphate levels in cancer patients. is monitored and indicated by cancer patients to FGFR inhibitors in general or to erdafitinib Specific associated early developmental toxicity was monitored and was not observed if serum phosphate concentrations were less than 7 mg / dL. or serum phosphate concentration is 7mg / dL to 9mg / dL or less, including 7mg / dL the amount of erdafitinib administered continuously daily, preferably once daily, when the range is For erdafitinib, the dose is increased to 9 mg. Serum phosphate levels are increased to 7 mg / d. In cases where the range is 7mg / dL to 9mg / dL including L, for example, sevelamer In one embodiment, combination therapy with a phosphorus binder, such as sevelamer, may be initiated. Combination therapy with an adsorbent is initiated. If serum phosphate levels rise above 9 mg / dL, Treatment was temporarily interrupted, specifically, erdafitinib treatment was discontinued until serum phosphate concentrations It is discontinued until serum phosphate is again below 7 mg / dL; Successive daily doses are adjusted to the same or lower daily dose. Serum phosphate concentrations were measured on the treatment day during the first cycle of erdafitinib treatment, specifically on the erdafitinib The measurement is performed on day 14 ± 2 days, more specifically on day 14, of administration of rudafitinib. In this condition, if the serum phosphate concentration is greater than 9 mg / dL, treatment is initiated. Erdafitinib treatment was temporarily discontinued until the serum creatinine concentration was less than 7 mg / dL, and then , and resumed daily, specifically at a continuous 8 mg once daily.

[0092] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 4. It can be managed as follows.

[0093] The present invention provides erdafitinib for use in the treatment of cancer in a cancer patient, the administration of which is daily , specifically while receiving continuous erdafitinib treatment at 8 mg once daily. If the patient's serum phosphate concentration is less than 5.5 mg / dL, the patient should be given 9 mg of phosphate daily. In one embodiment, the present invention relates to erdafitinib administered continuously once daily. Serum phosphate concentrations were measured on the treatment day during the first cycle of erdafitinib treatment, specifically on the erdafitinib It is measured on day 14 ± 2 of rudafitinib administration, more specifically on day 14.

[0094] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0095] The present invention provides erdafitinib for use in the treatment of cancer in a cancer patient, the administration of which is daily , specifically while receiving continuous erdafitinib treatment at 8 mg once daily. If the patient's serum phosphate concentration is less than 7 mg / dL or If the range is between 7mg / dL and 9mg / dL, including mg / dL, 9mg should be used every Specifically, it relates to erdafitinib administered continuously once daily. If your blood pressure is in the range of 7mg / dL to 9mg / dL, including 7mg / dL, for example: Combination therapy with a phosphate binder such as sevelamer may be initiated. Combination therapy with a phosphate binder, such as Velamar, is initiated. In one embodiment, serum phosphate The concentration of erdafitinib was measured on the treatment day during the first cycle of erdafitinib treatment, specifically on the day of erdafitinib treatment. The measurement is performed on day 14 ± 2 days after administration of the antibody, more specifically on day 14.

[0096] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 4. It can be managed as follows.

[0097] The present invention provides erdafitinib for use in the treatment of cancer in a cancer patient, the administration of which is daily , specifically while receiving continuous erdafitinib treatment at 8 mg once daily. The patient's serum phosphate concentration is less than 5.5 mg / dL and no early developmental toxicity is observed. If not, Erdafiti is administered daily in an amount of 9 mg, specifically once daily continuously. In one embodiment, serum phosphate levels are measured at the first day of erdafitinib treatment. Treatment days during one cycle, specifically day 14 of erdafitinib administration ± 2 days, more specifically is measured on the 14th day.

[0098] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0099] The present invention provides erdafitinib for use in the treatment of cancer in a cancer patient, the administration of which is daily , specifically while receiving continuous erdafitinib treatment at 8 mg once daily. If the patient's serum phosphate concentration is less than 7 mg / dL or mg / dL, and early developmental toxicity is in the range of 7 mg / dL to 9 mg / dL or less. If not indicated at all, Erda is administered daily in an amount of 9 mg, specifically once daily continuously. Regarding phytinib: Serum phosphate levels are between 7 mg / dL and 9 mg / dL, including 7 mg / dL. / dL or less and no early developmental toxicity is observed, e.g., sevelamer, etc. In one embodiment, combination therapy with a phosphate binder such as sevelamer may be initiated. Concomitant therapy with phosphate binders is initiated. In one embodiment, serum phosphate levels are elevated. Treatment days during the first cycle of rudafitinib treatment, specifically the 14th day of rudafitinib administration The measurement is taken on day ±2, more specifically on day 14.

[0100] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 4. It can be managed as follows.

[0101] In one embodiment of the present invention, the dose of erdafitinib is increased to 8 mg daily to 9 mg daily. Serum phosphate concentrations (to determine whether erdafitinib plasma The concentration and steady-state concentration of serum phosphate are assessed.

[0102] In one embodiment of the present invention, the dose of erdafitinib is increased from 8 mg daily to 9 mg daily. Serum phosphate concentrations were assessed at the first stage of erdafitinib treatment to determine whether the Treatment day during one cycle, specifically, approximately day 14 of erdafitinib treatment ± 2 days, specifically Specifically, it was the 14th day of erdafitinib treatment (14th day of cycle 1 of erdafitinib treatment). In one embodiment, one cycle is 21 days. One cycle is 28 days.

[0103] The daily amounts of erdafitinib referred to herein may be administered in one pharmaceutical composition or in two or more The pharmaceutical agent referred to herein can be administered by a pharmaceutical composition of the formula (I). In one embodiment, an 8 mg dose of E. coli is administered in a 20 mg dose. Rudafitinib is available in two formulations, each containing 4 mg of erdafitinib. In one embodiment, a 9 mg dose of Eldafi Erdafitinib is available in three formulations: three tablets containing 3 mg of erdafitinib each. It can be administered as

[0104] The present invention provides a method of treating cancer, comprising: a) 8 mg of erdafitinib daily to subjects in need thereof, specifically cancer patients, Ideally, administer once daily continuously; b) Subjects' serum phosphate concentrations were measured on the treatment day during the first cycle of erdafitinib treatment, specifically should be measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14; c-1) If serum phosphate concentration is less than 5.5 mg / dL, erdafitinib should be administered within 9 days. mg daily, specifically once daily continuously; c-2) Serum phosphate concentration is 5.5mg / dL to 7mg / dL, including 5.5mg / dL If your blood pressure is below 1 L, erdafitinib should be administered at a dose of 8 mg daily, specifically once daily. further administration in succession; c-3) If serum phosphate concentration is 7 mg / dL or higher, erdafitinib treatment is recommended. The serum phosphate concentration was temporarily discontinued until it was less than 5.5 mg / dL, and then Dafitinib treatment should be resumed daily, specifically at a continuous dose of 8 mg once daily. The present invention relates to a method comprising:

[0105] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0106] The present invention provides a method of treating cancer, comprising: a) 8 mg of erdafitinib daily to subjects in need thereof, specifically cancer patients, Ideally, administer once daily continuously; b) Subjects' serum phosphate concentrations were measured on the treatment day during the first cycle of erdafitinib treatment, specifically should be measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14; c-1) Serum phosphate concentration is less than 7 mg / dL or serum phosphate concentration is more than 7 mg / dL If the blood pressure is in the range of 7 mg / dL to 9 mg / dL or less, including g / dL, erdafitinib is administered continuously daily, specifically once daily, in an amount of 9 mg; and serum phosphate levels are If the range is 7mg / dL to 9mg / dL, including 7mg / dL, for example, Concomitant therapy with phosphate binders such as Lamar should be initiated as an option; c-2) If serum phosphate concentration is greater than 9 mg / dL, erdafitinib treatment is Temporarily discontinued until phosphate levels were below 7 mg / dL, and then Eldafi Tinib treatment should be resumed daily, specifically at a continuous dose of 8 mg once daily. The present invention relates to a method comprising:

[0107] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 4. It can be managed as follows.

[0108] The present invention provides a method of treating cancer, comprising: a) 8 mg of erdafitinib daily to subjects in need thereof, specifically cancer patients, Ideally, administer once daily continuously; b) Subjects' serum phosphate concentrations were measured on the treatment day during the first cycle of erdafitinib treatment, specifically should be measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14; c-1) Serum phosphate concentration is less than 5.5 mg / dL and no early developmental toxicity is observed. If this is not possible, erdafitinib should be administered at a dose of 9 mg daily, specifically once daily continuously. To be done; c-2) Serum phosphate concentration is 5.5mg / dL to 7mg / dL, including 5.5mg / dL If the clinical efficacy is in the range of less than 8 L and no early developmental toxicity is demonstrated, erdafitinib mg daily, specifically once daily continuously; c-3) Serum phosphate concentration is 7 mg / dL or higher and no early developmental toxicity is observed. If not, erdafitinib treatment should be discontinued until serum phosphate levels are reduced to <5.5 mg / dL. Erdafitinib treatment was temporarily discontinued, and then resumed daily, specifically once daily. The drug should be restarted at a continuous dose of 8 mg. The present invention relates to a method comprising:

[0109] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0110] The present invention provides a method of treating cancer, comprising: a) 8 mg of erdafitinib daily to subjects in need thereof, specifically cancer patients, Ideally, administer once daily continuously; b) Subjects' serum phosphate concentrations were measured on the treatment day during the first cycle of erdafitinib treatment, specifically should be measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14; c-1) Serum phosphate concentration is less than 7 mg / dL and no early developmental toxicity is observed. If the serum phosphate level is 7mg / dL to 9mg / dL or less, including 7mg / dL If the dose is in the range of 9 mg / kg and no early developmental toxicity is demonstrated, erdafitinib should be administered at a dose of 9 mg / kg. and the serum phosphate concentration is 7 mg / d In cases where the range is 7mg / dL to 9mg / dL including L, for example, sevelamer Concomitant therapy with an anticoagulant should be initiated as an option; c-2) Serum phosphate concentration is greater than 9 mg / dL and no early developmental toxicity is observed. If so, erdafitinib treatment should be temporarily discontinued until serum phosphate levels are reduced to <7 mg / dL. and thereafter, erdafitinib treatment was discontinued daily, specifically once daily continuously. The dose should be resumed at 8 mg. The present invention relates to a method comprising:

[0111] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 4. It can be managed as follows.

[0112] The present invention relates to a method for the treatment of cancer in a cancer patient using erdafitinib. The use of a) The medication contains erdafitinib in an amount of 8 mg, and the medication is administered daily, specifically once a day. is for one continuous administration; b) Patient serum phosphate concentrations were measured on the treatment day during the first cycle of erdafitinib treatment, specifically Typically measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14; c-1) If serum phosphate concentration is less than 5.5 mg / dL, daily, specifically once a day the amount of erdafitinib in said pharmaceutical product for each consecutive administration is increased to 9 mg; c-2) Serum phosphate concentration is 5.5mg / dL to 7mg / dL, including 5.5mg / dL If the range is less than 1 L, the patient should be placed on continuous treatment with 8 mg daily, specifically once daily. stay; c-3) If serum phosphate concentration is 7 mg / dL or higher, erdafitinib treatment is recommended. The serum phosphate concentration was temporarily discontinued until it was less than 5.5 mg / dL, and then Dafitinib treatment is resumed daily, specifically at a continuous dose of 8 mg once daily. Regarding.

[0113] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0114] The present invention relates to a method for the treatment of cancer in a cancer patient using erdafitinib. The use of a) The medication contains erdafitinib in an amount of 8 mg, and the medication is administered daily, specifically once a day. is for one continuous administration; b) Patient serum phosphate concentrations were measured on the treatment day during the first cycle of erdafitinib treatment, specifically Typically measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14; c-1) Serum phosphate concentration is less than 7 mg / dL or serum phosphate concentration is more than 7 mg / dL If your blood sugar level is in the range of 7mg / dL to 9mg / dL or less, including g / dL, then The amount of erdafitinib in the drug product for continuous once-daily administration was increased to 9 mg. and serum phosphate concentration is in the range of 7mg / dL to 9mg / dL, including 7mg / dL If the range is within the above range, combination therapy with a phosphate binder, such as sevelamer, is optionally initiated; c-2) If serum phosphate concentration is greater than 9 mg / dL, erdafitinib treatment is Temporarily discontinued until phosphate levels were below 7 mg / dL, and then Eldafi Tinib treatment is resumed daily, specifically at a continuous dose of 8 mg once daily. .

[0115] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 4. It can be managed as follows.

[0116] The present invention relates to a method for the treatment of cancer in a cancer patient using erdafitinib. The use of a) The medication contains erdafitinib in an amount of 8 mg, and the medication is administered daily, specifically once a day. is for one continuous administration; b) Patient serum phosphate concentrations were measured on the treatment day during the first cycle of erdafitinib treatment, specifically Typically measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14; c-1) Serum phosphate concentration is less than 5.5 mg / dL and no early developmental toxicity is observed. If not, daily administration of erdafichia in medicines for continuous administration, specifically once a day The nib amount was increased to 9mg; c-2) Serum phosphate concentration is 5.5mg / dL to 7mg / dL, including 5.5mg / dL If the dose is in the range of less than 1 L and no early developmental toxicity is demonstrated, the patient may be treated with 8 mg daily. Specifically, treatment should be limited to one continuous treatment per day; c-3) Serum phosphate concentration is 7 mg / dL or higher and no early developmental toxicity is observed. If not, erdafitinib treatment should be discontinued until serum phosphate levels are reduced to <5.5 mg / dL. Erdafitinib treatment was temporarily discontinued, and thereafter, erdafitinib treatment was resumed daily, specifically once daily. Regarding use, resumed at 8 mg continuously.

[0117] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0118] The present invention relates to a method for the treatment of cancer in a cancer patient using erdafitinib. The use of a) The medication contains erdafitinib in an amount of 8 mg, and the medication is administered daily, specifically once a day. is for one continuous administration; b) Patient serum phosphate concentrations were measured on the treatment day during the first cycle of erdafitinib treatment, specifically Typically measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14; c-1) Serum phosphate concentration is less than 7 mg / dL and no early developmental toxicity is observed. If the serum phosphate level is 7mg / dL to 9mg / dL or less, including 7mg / dL If the dose is within the range of 0.1 mg / kg / day and no early developmental toxicity is observed, then daily, specifically once daily, The amount of erdafitinib in the drug product for continuous administration was increased to 9 mg; and serum levels were When the phosphate concentration is in the range of 7mg / dL to 9mg / dL, including 7mg / dL Combination therapy with phosphate binders, such as sevelamer, is optionally initiated; c-2) Serum phosphate concentration is greater than 9 mg / dL and no early developmental toxicity is observed. If so, erdafitinib treatment should be temporarily discontinued until serum phosphate levels are reduced to <7 mg / dL. and thereafter, erdafitinib treatment was discontinued daily, specifically once daily continuously. Use will be resumed at 8mg.

[0119] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 4. It can be managed as follows.

[0120] The present invention provides erdafitinib for use in the treatment of cancer in a cancer patient. , a) Erdafitinib is administered continuously daily, specifically once daily, in an amount of 8 mg; b) Patient serum phosphate concentrations were measured on the treatment day during the first cycle of erdafitinib treatment, specifically Typically measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14; c-1) If serum phosphate concentration is less than 5.5 mg / dL, erdafitinib should be administered within 9 days. mg administered daily, specifically once daily continuously; c-2) Serum phosphate concentration is 5.5mg / dL to 7mg / dL, including 5.5mg / dL If your blood pressure is below 1 L, erdafitinib should be administered at a dose of 8 mg daily, specifically once daily. further administered sequentially; c-3) If serum phosphate concentration is 7 mg / dL or higher, erdafitinib treatment is recommended. The serum phosphate concentration was temporarily discontinued until it was less than 5.5 mg / dL, and then Dafitinib treatment will be resumed daily, specifically at a continuous dose of 8 mg once daily. Regarding phytinib.

[0121] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0122] The present invention provides erdafitinib for use in the treatment of cancer in a cancer patient. , a) Erdafitinib is administered continuously daily, specifically once daily, in an amount of 8 mg; b) Patient serum phosphate concentrations were measured on the treatment day during the first cycle of erdafitinib treatment, specifically Typically measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14; c-1) Serum phosphate concentration is less than 7 mg / dL or serum phosphate concentration is more than 7 mg / dL If the blood pressure is in the range of 7 mg / dL to 9 mg / dL or less, including g / dL, erdafitinib is administered continuously daily, specifically once daily, in an amount of 9 mg; and serum phosphate levels are If the range is 7mg / dL to 9mg / dL, including 7mg / dL, for example, Combination therapy with phosphate binders such as Lamar is optionally initiated; c-2) If serum phosphate concentration is greater than 9 mg / dL, erdafitinib treatment is Temporarily discontinued until phosphate levels were below 7 mg / dL, and then Eldafi Tinib treatment is resumed daily, specifically at 8 mg once daily. Regarding the nib.

[0123] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 4. It can be managed as follows.

[0124] The present invention provides erdafitinib for use in the treatment of cancer in a cancer patient. , a) Erdafitinib is administered continuously daily, specifically once daily, in an amount of 8 mg; b) Patient serum phosphate concentrations were measured on the treatment day during the first cycle of erdafitinib treatment, specifically Typically measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14; c-1) Serum phosphate concentration is less than 5.5 mg / dL and no early developmental toxicity is observed. If this is not possible, erdafitinib should be administered at a dose of 9 mg daily, specifically once daily continuously. be; c-2) Serum phosphate concentration is 5.5mg / dL to 7mg / dL, including 5.5mg / dL If the clinical efficacy is in the range of less than 8 L and no early developmental toxicity is demonstrated, erdafitinib mg daily, specifically once daily continuously; c-3) Serum phosphate concentration is 7 mg / dL or higher and no early developmental toxicity is observed. If not, erdafitinib treatment should be discontinued until serum phosphate levels are reduced to <5.5 mg / dL. Erdafitinib treatment was temporarily discontinued, and thereafter, erdafitinib treatment was resumed daily, specifically once daily. Regarding erdafitinib, which was resumed at 8 mg continuously.

[0125] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 3. It can be managed as follows.

[0126] The present invention provides erdafitinib for use in the treatment of cancer in a cancer patient. , a) Erdafitinib is administered continuously daily, specifically once daily, in an amount of 8 mg; b) the patient's serum phosphate concentration on the day of treatment during the first cycle of erdafitinib treatment; Specifically, it was measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14. ; c-1) Serum phosphate concentration is less than 7 mg / dL and no early developmental toxicity is observed. If the serum phosphate level is 7mg / dL to 9mg / dL or less, including 7mg / dL If the dose is in the range of 9 mg / kg and no early developmental toxicity is demonstrated, erdafitinib should be administered at a dose of 9 mg / kg. and the serum phosphate concentration is 7 mg / d In cases where the range is 7mg / dL to 9mg / dL including L, for example, sevelamer Combination therapy with an adsorbent is optionally initiated; c-2) Serum phosphate concentration is greater than 9 mg / dL and no early developmental toxicity is observed. If so, erdafitinib treatment should be temporarily discontinued until serum phosphate levels are reduced to <7 mg / dL. and thereafter, erdafitinib treatment was discontinued daily, specifically once daily continuously. Regarding erdafitinib, it will be resumed at a dose of 8mg.

[0127] In one embodiment, the serum phosphate concentration during further erdafitinib administration is determined according to Table 4. It can be managed as follows.

[0128] The methods of treatment and use described herein rely on phosphate concentration as a pharmacodynamic marker. It should be understood that these may be modified or discontinued based on toxicity. In embodiments, treatment or use is altered or discontinued as described in Table 1.

[0129] [Table 1]

[0130] If erdafitinib is discontinued, specifically for more than 1 week continuously due to drug-related toxicity, If discontinued, erdafitinib may be resumed at the same dose level or at the first lower dose level after recovery from toxicity. In one embodiment, the erdafitinib dose may be reintroduced at any of the dose reduction stages. The reduction steps are as described in Table 2. The second dose reduction is the second dose reduction for drug-related toxicity. After the occurrence of the above, the following steps may be carried out, specifically as described in Table 2.

[0131] [Table 2]

[0132] When treatment with erdafitinib or its administration should be discontinued, e.g., erdafitinib but acceptable (non-hematologic toxicity is grade 1 or less or return to baseline) If the patient must be withheld for longer than 28 days due to a drug-related adverse event that does not resolve promptly, If a patient is benefiting from treatment, it is up to the physician to decide whether to continue treatment. If physicians cannot demonstrate that continued treatment with erdafitinib is in the patient's best interest, It should be understood that the dose of erdafitinib is reduced and that the If the underlying adverse event completely resolves, the dose can be adjusted if the patient is benefiting from treatment. If necessary, the dose can be re-escalated to the next higher level. Increasing the dose may prove to be in the patient's best interest.

[0133] Patients with any grade (grade 1-4) toxicity should receive symptomatic treatment as needed. It should be understood that must be provided.

[0134] In one embodiment, treatment with erdafitinib is discontinued as described herein. If serum phosphate is monitored until it returns to the indicated stage, the assessment of serum phosphate should be , conducted at least weekly.

[0135] In one embodiment, treatment with erdafitinib is in combination with treatment of hyperphosphatemia as described herein. If discontinued due to illness, the discontinuation is for about 7 days, specifically 7 days.

[0136] Serum phosphate concentrations were measured on the treatment day, specifically during the first cycle of erdafitinib treatment. Specifically, it is measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14. Pharmacodynamic markers to determine whether to escalate the starting dose of erdafitinib from 8 mg Phosphate levels, if measured as a phosphate buffer, may be further monitored during erdafitinib treatment. It should be understood that in one embodiment, the clinical management of serum phosphate levels is based on the data in Table 3. Performed as shown.

[0137] [Table 3]

[0138] In one embodiment, clinical management of serum phosphate concentrations is performed as set forth in Table 4. do.

[0139] [Table 4]

[0140] Restriction of daily phosphate intake may be required to manage elevated phosphates. You should understand that there is something.

[0141] To manage elevated phosphate, patients may be prescribed phosphate-binding drugs such as sevelamer phosphate. It should be understood that it may be necessary to take medications in combination.

[0142] The tumor response assessments reported herein are Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was carried out in accordance with

[0143] The present invention provides documents relating to erdafitinib formulations and dosing regimens described herein. It also relates to packaging containing such information, for example a patient leaflet.

[0144] In one embodiment, the cancer referred to herein is a cancer mediated by FGFR kinases. It's cancer.

[0145] In one embodiment, the cancer is bladder cancer.

[0146] In one embodiment, the cancer is hepatocellular carcinoma.

[0147] In one embodiment, the cancer is squamous cell carcinoma.

[0148] In one embodiment, the cancer is squamous cell NSCLC (non-small cell lung cancer), particularly selected It is squamous cell NSCLC (non-small cell lung cancer) with FGFR gene alterations, specifically This study aimed to identify patients with squamous NSCLC (non-small cell lung cancer) with selected FGFR gene alterations after relapse of standard treatment. The aim of this study is to treat cancer in patients with pulmonary carcinoma (pulmonary thrombocytopenic leukemia).

[0149] In one embodiment, the cancer is hepatocellular carcinoma with FGF19 amplification or overexpression.

[0150] In one embodiment, the cancer is cholangiocarcinoma, particularly advanced or metastatic cholangiocarcinoma.

[0151] In one embodiment, the cancer is urothelial carcinoma.

[0152] In one embodiment, the cancer is metastatic or surgically unresectable urothelial carcinoma.

[0153] In one embodiment, the cancer is an advanced urothelial carcinoma with a selected FGFR gene alteration. Specifically, selected FGFR genes that have progressed during or after one prior treatment Cancer treatment for patients with advanced urothelial carcinoma with genetic alterations.

[0154] In one embodiment, the cancer is lung cancer, specifically non-small cell lung cancer.

[0155] In one embodiment, the cancer is adenoid cystic carcinoma, mucoepidermoid carcinoma, follicular thyroid carcinoma, breast cancer, Ewing's disease Sarcoma, small round cell tumor of bone, synovial sarcoma, glioblastoma multiforme, pilocytic astrocytoma, lung cancer, clear The cell types are selected from renal cell carcinoma, bladder cancer, prostate cancer, ovarian cancer, and colon cancer.

[0156] In one embodiment, the cancer is multiple myeloma, specifically t(4;14) translocation-positive multiple myeloma. It is myeloma.

[0157] In one embodiment, the cancer is non-muscle invasive bladder cancer, specifically cancers with FGFR genomic alterations (e.g., For example, non-muscle invasive bladder cancer with multiple myeloma (e.g., translocations, fusions and / or mutations).

[0158] In one embodiment, the cancer is esophageal cancer or head and neck cancer.

[0159] In one embodiment, the cancer is gastric cancer.

[0160] In one embodiment, the cancer referred to herein is characterized by an FGFR genomic alteration (e.g., a translocation , fusions and / or mutations), particularly erdafitinib-sensitive FGFR Cancers with genomic alterations (e.g., translocations, fusions, and / or mutations), such as FGFR genomic alterations Bladder cancer with genomic alterations (e.g., translocations, fusions, and / or mutations) or FGFR genomic alterations Urothelial carcinomas with alterations (e.g., translocations, fusions, and / or mutations) or FGFR genomic Metastatic or surgically resected tumors with genomic alterations (e.g., translocations, fusions, and / or mutations) Unresectable urothelial carcinoma, or FGFR genomic alterations (e.g., translocations, fusions, and / or mutations) Cholangiocarcinoma with FGFR genomic alterations (e.g., translocations, fusions, and / or mutations) Patients with advanced or metastatic bile duct cancer.

[0161] In one embodiment, the cancer referred to herein is a cancer characterized by the following fusion FGFR3:TACC3 v1;FGFR3:TACC3 v3;FGFR3:TACC3 intron;FGFR 3:BAIAP2L1;FGFR2:AFF3;FGFR2:BICC1;FGFR2: CASP7;FGFR2:CCDC6 and FGFR2:OFD1 It is a cancer that causes

[0162] In one embodiment, the cancer referred to herein is a cancer characterized by FGFR3-TACC3 fusion or translocation Cancers with FGFR3-TACC3 translocations, such as bladder cancers with FGFR3-TACC3 translocations, ACC3 translocation-containing urothelial carcinoma or metastatic or metastatic urothelial carcinoma with FGFR3-TACC3 translocation Most cases are surgically unresectable urothelial carcinoma.

[0163] In one embodiment, the cancer referred to herein is characterized by the following FGFR3 gene mutations: FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, FGFR 3 Y373C.

[0164] In one embodiment, the cancer referred to herein is characterized by the following FGFR3 gene mutations: FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, FGFR 3 Bladder cancer, urothelial carcinoma, or metastatic or Surgically unresectable urothelial carcinoma.

[0165] In one embodiment, a subject in need of treatment for a cancer referred to herein, particularly a cancer The use or method for treating cancer in a patient may comprise administering to said patient a therapeutically effective amount of a compound selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, Patients with systemic changes who have received at least one line of prior systemic chemotherapy or neoadjuvant chemotherapy failure of infusion or adjuvant chemotherapy within 12 months or Metastatic or surgically unresectable urothelial carcinoma for which cisplatin is not suitable, but for which chemotherapy has not been performed The present invention is directed to the use for or treatment of a patient having

[0166] In one embodiment, a subject in need of treatment for a cancer referred to herein, particularly a cancer The use for treating cancer in a patient or the method of treating cancer may comprise administering to a subject a luminal cluster I subtype urinary The present invention relates to use for or treatment of patients with urothelial carcinoma.

[0167] In one embodiment, erdafitinib is administered as a pharmaceutically acceptable salt.

[0168] In a preferred embodiment, erdafitinib (base) is administered.

[0169] In one embodiment, erdafitinib is administered in an amount equivalent to 8 mg base equivalent or 9 mg salt equivalent. It is administered as a pharmaceutically acceptable salt in an amount corresponding to the base equivalent.

[0170] Salts can be prepared, for example, by reacting erdafitinib with a suitable acid in a suitable solvent. It can be manufactured.

[0171] Acid addition salts can be formed with both inorganic and organic acids. Examples of acid addition salts include: Acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, Leic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfone Acid, methanesulfonic acid (mesylate), ethanesulfonic acid, naphthalenesulfonic acid, valerian acid, acetic acid, propionic acid, butanoic acid, malonic acid, glucuronic acid and lactobionic acid Another group of acid addition salts includes salts formed with acids selected from the group consisting of acetic acid, Acid, adipic acid, ascorbic acid, aspartic acid, citric acid, DL-lactic acid, fumaric acid, Gluconic acid, glucuronic acid, hippuric acid, hydrochloric acid, glutamic acid, DL-malic acid, meta Examples include salts formed with benzophenone sulfonic acid, sebacic acid, stearic acid, succinic acid and tartaric acid. can be done.

[0172] In one embodiment, erdafitinib is administered in the form of a solvate. As used herein, the term "solvate" refers to a physical association of erdafitinib with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, solvates may be formed, for example, when one or more solvent molecules are present in the crystal lattice of the crystalline solid. The term "solvate" refers to a solvate that is both solution-phase and isolated. It is intended to encompass both non-solvents that can form solvates. Non-limiting examples include water, isopropanol, ethanol, methanol, DMSO, and acetic acid. ethyl acetate, ethanolamine, and the like.

[0173] Solvates are well known in pharmaceutical chemistry. Solvates can occur during the preparation process of a substance (e.g. , in relation to its purification), preservation of the material (e.g., its stability) and ease of handling the material. can be important for the synthesis of hydroxybenzoates, and are often formed as part of the isolation or purification steps of chemical synthesis. Those skilled in the art will recognize by standard and long-established techniques that hydrates or other solvates are the desired compounds. Whether formed by the isolation or purification conditions used to prepare a given compound Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g., single crystal X-ray crystallography or X-ray powder diffraction) and solid Single-body NMR (SS-NMR, also known as magic angle spinning NMR or MAS-NMR) Such techniques include NMR, IR, HPLC and MS, as well as other techniques that require skilled personnel. Alternatively, those skilled in the art may wish to identify specific solvates. Solvates may be intentionally formed using crystallization conditions that include the amount of solvent required for the product. The formation of solvates can then be confirmed using standard methods described above. Any complexes (e.g., inclusion complexes with compounds such as cyclodextrins or clathrates) can be Also included are slates or complexes with metals.

[0174] In one embodiment, a treatment cycle as used herein is a 28-day cycle.

[0175] In one embodiment, as used herein, a patient, particularly a cancer patient or an erudafici The subject in need of nib treatment is a human.

[0176] In one aspect of the present invention, a cancer patient or subject in need thereof as defined above or In the embodiment described in the above, the cancer patient or subject in need thereof is a high-risk patient. , specifically metastatic or surgically unresectable urothelial carcinoma, specifically selected FGFR Metastatic or surgically unresectable urinary tract tumors with genetic alterations (FGFR translocations or mutations) High-risk patients with skin cancer, specifically those with FGFR gene alterations as defined above. Patients were classified as follows: age 75 years or older; ECOG PS of 2; and ≥10 g / dL hemoglobin; visceral metastases, specifically those in the liver, lung, and / or bone; and a B of 2 or 3 In one embodiment, the patient meets one or more of the following risk factors for hemoglobinuria: Robin concentrations are measured in whole blood. In one embodiment, high-risk patients are aged 75 In one embodiment, high-risk patients are those with visceral metastases, particularly liver, lung, and In one embodiment, high-risk patients are those with: Criteria: age 75 years or older; ECOG PS of 2; hemoglobin <10 g / dL; visceral translocation metastases, specifically those of the liver, lungs, and / or bones; and Bellmunt risk of 2 or 3 In one embodiment, high-risk patients are those who meet at least two of the following criteria: Patients aged 75 years or older with visceral metastases, specifically those in the liver, lungs, and / or bones be.

[0177] In one embodiment, the high-risk patient is 75 years of age or older and is at high risk for the treatment of a variety of conditions including the inflammatory bowel disease described herein. The objective response rate upon exposure to erdafitinib according to the dosing regimen was at least 40% Specifically, it is about 40%, about 41%, about 42%, and about 43%. , about 44%, about 45%, about 46%, about 47%, about 48% Specifically, the objective response rate is in the range of 40% to 50%. It is an enclosure.

[0178] In one embodiment, the high-risk patient is 75 years of age or older and is at high risk for the treatment of a variety of conditions including the inflammatory bowel disease described herein. The median duration of response when exposed to erdafitinib according to the dosing regimen was at least 8 years. months, or at least 9 months, or at least 10 months, or at least 11 months, or at least At least about 12 months, or at least about 13 months.

[0179] In one embodiment, the high-risk patient is 75 years of age or older and is at high risk for the treatment of a variety of conditions including the inflammatory bowel disease described herein. Progression-free survival after exposure to erdafitinib according to the dosing regimen was at least 5 years. It is the moon.

[0180] In one embodiment, the high-risk patient is 75 years of age or older and is at high risk for the treatment of a variety of conditions including the inflammatory bowel disease described herein. Overall survival during exposure to erdafitinib according to the dosing regimen was at least 13 months or at least 14 months.

[0181] In one embodiment, high-risk patients are those with visceral metastases, particularly liver, lung and / or bone metastases. and a patient having the above condition who is receiving erdafitinib according to the dosing regimen disclosed herein. The objective response rate at exposure is at least 30%, specifically about 30%, and is about 3 1%, about 32%, about 33%, about 34%, about 35%, about 3 6%, approximately 37%, and approximately 38%. Specifically, the objective response rate is 30% to It's in the 35% range.

[0182] In one embodiment, high-risk patients are those with visceral metastases, particularly liver, lung and / or bone metastases. and a patient having the above condition who is receiving erdafitinib according to the dosing regimen disclosed herein. The median duration of response at the time of exposure is at least 5 months or at least 5.5 months.

[0183] In one embodiment, high-risk patients are those with visceral metastases, particularly liver, lung and / or bone metastases. and a patient having the above condition who is receiving erdafitinib according to the dosing regimen disclosed herein. progression-free survival at the time of exposure is at least 4 months or at least 5 months.

[0184] In one embodiment, high-risk patients are those with visceral metastases, particularly liver, lung and / or bone metastases. and a patient having the above condition who is receiving erdafitinib according to the dosing regimen disclosed herein. Overall survival at the time of exposure is at least 10 months, or at least 11 months, or at least The period is also 12 months, or at least 13 months.

[0185] Accordingly, the present invention provides a method for the treatment of cancer in a subject in need thereof, particularly The present invention relates to a method for treating cancer, comprising administering a therapeutically effective amount of erdafitinib to a cancer patient, and Generally, cancer patients are high-risk patients, specifically those with metastatic or surgically unresectable urothelial carcinoma, Specifically, metastatic disease with selected FGFR gene alterations (FGFR translocations or mutations) or surgically unresectable urothelial carcinoma, specifically those with FGFR gene alterations as defined above In one embodiment, the therapeutically effective amount of erdafitinib is administered daily. In one embodiment, the dose is 8 mg, specifically administered once daily, more specifically continuously. In this case, the therapeutically effective amount of erdafitinib is administered daily, specifically once daily, more specifically The daily dose of erdafitinib is 9 mg continuously. The daily dose of erdafitinib is 1 pharmaceutical composition or 2 In one embodiment, erdafitinib is administered as one or more pharmaceutical compositions. The 8 mg dose of erdafitinib is comprised of two pharmaceutical compositions, specifically 4 mg each of erdafitinib. or as two pharmaceutical compositions, one of which contains 3 mg of Eldaf It is administered as two tablets, one containing erdafitinib and one containing 5 mg erdafitinib. In one embodiment, the 9 mg dose of erdafitinib is a three-drug The composition, specifically, as three tablets each containing 3 mg of erdafitinib, or two pharmaceutical compositions, one containing 4 mg of erdafitinib and one containing 5 mg of erdafitinib; In one embodiment, the drug may be administered as two tablets containing erdafitinib. In one embodiment, the patient is 75 years of age or older. In one embodiment, the patient has visceral metastases. In one embodiment, the patient is 75 years of age or older and has visceral metastases.

[0186] In one embodiment, the present invention provides a method for treating high-risk patients, particularly those with metastatic or surgically unresectable disease. urothelial carcinoma, specifically selected FGFR gene alterations (FGFR translocations or mutations) ) metastatic or surgically unresectable urothelial carcinoma, particularly those having FGF as defined above Manufacture of a drug for the treatment of cancer in high-risk patients with R gene alterations Use of rudafitinib. In one embodiment, rudafitinib is administered in an amount of 8 mg. daily, specifically once a day, more specifically continuously, or In one embodiment, erdafitinib is administered in an amount of 9 mg daily, specifically 1 mg daily. It is or will be administered once, more particularly continuously. The daily amount of the drug may be administered as one pharmaceutical composition or as two or more pharmaceutical compositions. A pharmaceutical product as referred to herein may be one pharmaceutical composition or two or more pharmaceutical compositions. In one embodiment, an 8 mg dose of erdafitinib may comprise two pharmaceutical agents. The composition, specifically as two tablets each containing 4 mg of erdafitinib, or two pharmaceutical compositions, one containing 3 mg of erdafitinib and one containing 5 mg of erdafitinib; In one embodiment, the erdafitinib may be administered as two tablets containing erdafitinib. The 9 mg dose of erdafitinib was administered in three pharmaceutical compositions, specifically 3 mg each. or as two pharmaceutical compositions, specifically one containing erdafitinib Two tablets, one containing 4 mg of erdafitinib and one containing 5 mg of erdafitinib In one embodiment, the patient is 75 years of age or older. In one embodiment, the patient has visceral metastases. In one embodiment, the patient is Patients are 75 years of age or older and have visceral metastases.

[0187] In one embodiment, the present invention provides a method for treating high-risk patients, particularly those with metastatic or surgically unresectable disease. urothelial carcinoma, specifically selected FGFR gene alterations (FGFR translocations or mutations) ) metastatic or surgically unresectable urothelial carcinoma, particularly those having FGF as defined above Eldafi for use in the treatment of cancer in high-risk patients with R gene alterations In one embodiment, erdafitinib is administered daily in an amount of 8 mg, specifically In some embodiments, the drug is or will be administered once daily, more particularly continuously. In the form of erdafitinib, erdafitinib is administered daily in an amount of 9 mg, specifically once daily, more specifically The daily dose of erdafitinib is or will be administered continuously. The compounds may be administered as one pharmaceutical composition or as two or more pharmaceutical compositions. In embodiments, the 8 mg dose of erdafitinib is administered in two pharmaceutical compositions, specifically: As two tablets each containing 4 mg of erdafitinib, or as two pharmaceutical compositions, Specifically, one containing 3 mg of erdafitinib and one containing 5 mg of erdafitinib In one embodiment, erdafitinib can be administered as two tablets containing The 9 mg dose of each of the three pharmaceutical compositions, specifically 3 mg of erdafitinib or as two pharmaceutical compositions, one of which contains 4 mg of Eldafi It is administered as two tablets, one containing erdafitinib and the other containing 5 mg erdafitinib. In one embodiment, the patient is 75 years of age or older. In one embodiment, the patient has visceral metastases. In one embodiment, the patient is 75 years of age or older. , with visceral metastases.

[0188] As used herein in connection with a numerical value, the term "about" has its ordinary meaning in connection with the numerical value. Where appropriate, the word "about" is intended to mean a numerical value ±10%, or ±5%, or It can be replaced by ±2%, or ±1%.

[0189] All documents cited herein are incorporated by reference in their entirety. [Example]

[0190] Ongoing Phase 2 multicenter, open-label study (NCT02365597) The phase 2 multicenter, open-label study evaluated selected FGFR genetic alterations (FGFR translocations or apoptosis). ERD in subjects with metastatic or surgically unresectable urothelial carcinoma with a mutated ERDA gene This study is being conducted to evaluate the efficacy and safety of fitinib.

[0191] This study will be conducted in the screening phase (molecular screening and Study screening within 30 days of first administration), including the treatment and post-treatment follow-up periods The treatment period includes the period from the first administration to the end-of-treatment visit. The follow-up period includes the period from the time of subject death to the time of subject death. or withdraw consent, or be lost to follow-up, or until the end of the study, whichever comes first. It will be long.

[0192] The study treatment will be administered in 28-day cycles. Prior to interim analysis 1, there were two treatment regimens. Patients were randomly assigned to one of two regimens: Regimen 1 (10 mg once daily intermittently (7 days / 7 days)); Regimen 2 (6 mg once daily) Patients were randomized 1:1 to receive 28-day cycles of chemotherapy (10 consecutive doses). Pharmacokinetic and pharmacodynamic modeling relating ritinib dosing regimens to serum phosphate concentrations Based on the results of this study, the protocol was amended to include a starting dose of 8 mg / day continuous dosing (registration). On day 14, the target serum phosphate concentration was not reached at that time (serum phosphate (patients with thiamin monophosphate levels less than 5.5 mg / dL) and no treatment-related adverse events were observed. In patients who did not respond to treatment, the dose was titrated up to 9 mg / day. Dose reduction based on ) was anticipated in the protocol.

[0193] See Figure 1 for the Phase 2 study scheme.

[0194] patient Enrolled patients met the Response Evaluation Criteria Have measurable urothelial carcinoma according to the NIH in Solid Tumors version 1.1 He was an adult.

[0195] Patients will receive a custom assay from formalin-fixed, paraffin-embedded tumor samples. at least one FGFR2 / FGFR3 mutation according to central laboratory testing of RNA It was required to have a mutation or fusion.

[0196] Patients must be on or after at least one line of prior systemic chemotherapy or for less than 12 months had progressed after neoadjuvant or adjuvant chemotherapy.

[0197] Chemotherapy-naive patients who were cisplatin-ineligible based on protocol criteria were accepted. The inappropriateness of cisplatin was due to: 1) a 24-hour urine test of 60 mL / min / 1.73 m 2 2) Glomerular filtration rate less than the value calculated by Cockcroft-Gault; or 3) Grade 2 Peripheral neuropathy (Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) onal Cancer Institute.CTCAE v4.0.NCI,NIH ,DHHS.May 29,2009.NIH publication#09-747 The criteria were based on renal dysfunction, defined as:

[0198] Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 required It was.

[0199] There was no limit to the number of prior lines of therapy.

[0200] Prior immunotherapy (e.g., treatment with PD-L1 / PD-1 inhibitors) was accepted. .

[0201] Patients must have adequate bone marrow, liver, and kidney (creatinine clearance ≥ 40 mL / min) function. It was required that they have the ability.

[0202] Phosphate levels persistently above the upper limit of normal despite medical management, poorly controlled Patients with significant cardiovascular disease, brain metastases, known hepatitis B or C, or known HIV Excluded.

[0203] endpoint The primary endpoint of this ongoing study is the efficacy of the selected regimen (regimen 3). ) is the objective response rate.

[0204] Secondary endpoints included progression-free survival (PFS), duration of response (DoR), These include overall survival, safety, predictive biomarker assessment and pharmacokinetics.

[0205] evaluation Patients were randomly assigned to receive a steroid test within 30 days of screening, once every 6 weeks for the first 3 months, and once every 9 months for the next 9 months. Radiographs were performed once every 12 weeks for 1 month, then once every 4–6 months until disease progression. Imaging was used to assess efficacy.

[0206] Tumor response was assessed using RECIST version 1.1 (Eisenhauer EA et al. l., Eur J Cancer, 2009, 45(2), 228-247) Assessed by the investigator.

[0207] Safety will be assessed by the investigator through medical review of AE reports and vital sign measurements. values, physical examination, laboratory tests, ECOG performance status, and results of other safety assessments were evaluated serially based on

[0208] result Baseline characteristics and efficacy data were collected from May 7, 2015 to June 10, 2017. 170 patients were enrolled and considered evaluable according to RECIST 1.1 The data are presented in terms of participants (Table 5).

[0209] Safety data are collected from safety endpoints, defined as patients who received at least one dose of study treatment. Regarding the analysis population (N=207, enrolled between May 7, 2015 and December 5, 2017) As of December 5, 2017, the median treatment duration was 4.2 months. , patients received a median of five cycles of erdafitinib.

[0210] During the screening period, 21% of patients had FGFR mutations or fusions that met the inclusion criteria. Had.

[0211] Across dosing regimens, 89% had received at least one line of prior systemic chemotherapy It progressed after treatment.

[0212] [Table 5]

[0213] Across all dosing regimens, the confirmed objective response rate was 35% (95% CI, 28% to 43%). ), with the highest rates being seen with continuous erdafitinib at 8 mg / day, especially in Regimen 3. The confirmed disease control rate was 76% among all patients. The majority of patients treated with erdafitinib at 8 mg / day continuously had low tumor burden. (44 / 59 [75%] had a reduction in the sum of target lesion diameters; Figure 2). The median survival time was 5.1 months, and in regimen 3, the median survival time was 5.1 months with continuous eltrombopag at 8 mg / day. It was longest among patients treated with dafitinib (Table 6).

[0214] The median duration of response in the 8 mg / day continuous erdafitinib group (regimen 3) was 5.4 months, with many responses ongoing (Table 6).

[0215] [Table 6]

[0216] Time to response In the subset of 59 patients on Regimen 3, the median time to response was 1.41 months, with a range of 1.1 to 5.5 months.

[0217] Across all dosing regimens, 94% (n=195) of patients reported TRAEs. Most of the cases were grade 1 or 2 (Table 7).

[0218] 33% (n=69) of patients reported grade 3 TRAEs, and 0.5% (n=1) Patients reported grade 4 TRAEs but no treatment-related deaths.

[0219] AEs were manageable.

[0220] Recommendations for prevention of major AEs associated with erdafitinib treatment: A low-phosphate diet is recommended for all patients to reduce the risk of hyperphosphatemia. (dietary phosphate intake of 600-800 mg per day). An alcohol-free, emollient, moisturizing cream to reduce the risk of skin reactions Avoid unnecessary exposure to sunlight, soaps, perfumed products and hot baths. It was recommended that To reduce the risk of nail reactions, it is recommended that patients keep their hands and feet clean and their nails trimmed. It was recommended.

[0221] management Hyperphosphatemia (>5.5 mg / dL) can be treated with phosphate binders if medically indicated. It was managed. Dry skin can be treated with additional topical emollients such as ammonium lactate, salicylic acid, or zinc oxide creams. It was managed with ointment. Nail effects were managed with topical nail strengtheners. In severe cases, antibiotics or silver nitrate were used. was done.

[0222] TRAEs associated with the FGFR inhibitor class were typically grade 1 or 2 Across all treatment regimens, two patients reported retinopathy (grade 2 [n=1] and Grade 3 [n=1]).

[0223] Across all dosing regimens, 22 (11%) patients discontinued medication as a result of TRAEs The most common TRAEs leading to treatment discontinuation were asthenia, dry mouth, and palmar-plantar fever. It was red dysesthesias syndrome.

[0224] [Table 7]

[0225] The analysis was conducted to investigate efficacy among high-risk patients using a continuous 8 mg / day (as described herein) The regimen was pharmacodynamically guided to increase serum phosphate to 9 mg / day. 3) The study was conducted on 99NCT02365597 patients who received the dosage regimen. Participants were enrolled in NCT02365597 by December 21, 2017, and data were collected. The cutoff date for analysis was March 15, 2018. High-risk patients were those with: standard: - Age 75 years or older; - ECOG performance status of 2 ;Oken M, Creech R, Tormey D, et al.Toxicity and response criteria of the Eastern Co. operative Oncology Group.Am J Clin Oncol .1982;5:649-655) - hemoglobin less than 10 g / dL; - visceral metastases to the liver, lungs and / or bones; - Two or three Bellmunt risk factors (Bellmunt J, Chouei ri TK, Fougeray R, et al: Prognostic factor s in patients with advanced transitional cell carcinoma of the urothelial tract treatment failure with plat inum-containing regimens.J Clin Oncol 28 :1850-1855,2010) It is defined as a patient who meets one or more of the following criteria.

[0226] Objective response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival Results for overall survival (OS) were based on high-risk patients (≥75 years of age) as defined above. Age; ECOG PS of 2; hemoglobin less than 10 g / dL; visceral metastases and 2 or 3 The Bellmunt risk factors were used to analyze selected baseline variables. .

[0227] Results: Efficacy results (Table 8) showed that investigator-assessed ORR was consistent across all patients. 40% in the primary analysis and 36% in all subgroups except for ECOG PS of 2 The ORR in the high-risk subgroup ranged from 14.3% to 53.3%. ORR was significantly higher in two high-risk subgroups: those aged 75 years or older and those <10 g / dL. Among subjects with hemoglobin < 50%, the mean was 50% or higher.

[0228] DOR was 13.4 months in patients aged 75 years or older with COG PS 2 and The subgroup without visceral disease had a DOR of 2.8 months and 4.6 months, respectively. The majority of subgroups were in the 5.5 to 6 month range, except for the 1 group.

[0229] Median PFS was significantly higher in the subgroups with ECOG PS 2 and Bellmunt risk factors 2-3. >5 months across all subgroups except for loops. The median PFS was 5.52 months.

[0230] OS data are immature but generally exceed one year in most subgroups. Follows trends in PFS with median. High risk based on age, hemoglobin level and visceral metastases In the subgroup, median OS was 13.8 months compared with the primary analysis of all patients. The median S was met or exceeded.

[0231] [Table 8]

[0232] The results of the safety study are shown in Table 9. Grade 3 / 4 serious adverse events by subgroup There was no difference in the incidence rate, ranging from 26.7% to 36.4%, except for ECOG PS of 2. was included within.

[0233] Dose modifications were generally similar across the various subgroups. Among the high-risk groups: Patients aged 75 years or older and those with an ECOG PS of 2 received the highest rates of dose reduction and and had interruptions.

[0234] Treatment discontinuation rates due to adverse events were significantly associated with ECOG PS 2 and Bellmunt risk factors. Approximately 2-3% of the patients across subgroups were non-Hodgkin lymphoma patients (57.1% and 36.4%, respectively). The rate was 20%.

[0235] There were seven deaths attributable to treatment-emergent adverse events. Six of these deaths occurred in the setting of documented disease progression with visceral metastases. One death The myocardial infarction was not considered treatment-related because it occurred in a patient with impaired cardiac function. Ta.

[0236] Observations suggest that erdafitinib is effective in high-risk patients in general and in FG as a whole population in particular. To provide comparable efficacy in high-risk patients with FR-altered advanced urothelial carcinoma supports.

[0237] Limited by small sample size and immature OS data, chemotherapy Common high-risk criteria (older age, lower hemoglobin levels) associated with adverse outcomes in patients with urothelial carcinoma Robin, visceral disease, multiple Bellmunt risk factors) can be treated with erdafitinib The data did not affect ORR in treated patients.

[0238] ECOG PS 2 indicates a trend toward visceral metastasis and Bellmunt risk factors 2-3. adverse PFS and OS effects in patients treated with erdafitinib, with This was the only statistically significant risk factor associated with ergocerebellar hyperplasia in this group of patients. This may be associated with a high discontinuation rate of fitinib.

[0239] Overall, the safety profile of erdafitinib is characterized by the presence of high-risk features. was not affected.

[0240] [Table 9]

[0241] Table 10 shows the results of continuous dosing of 8 mg / day in two age groups (<75 years and ≥75 years). Dosing regimen (pharmacodynamically guided and serum phosphate as described herein) The distribution of risk factors in 99 patients receiving regimen 3) was increased to 9 mg / day. This report is based on the results of a randomized controlled trial conducted by the National Cancer Institute (NCT02365597).

[0242] [Table 10]

[0243] The final analysis for NCT02365597 will be 12 months after the last subject is enrolled. The study was performed according to the protocol. Erdafitinib (protocol-defined target serum phosphate If the salt concentration is not reached and no significant treatment-related adverse events (TRAEs) occur , increased to 9 mg / day, erdafitinib 8 mg / day in 28-day cycles) The median follow-up for the 101 patients treated with CT was approximately 24 months. The sustained ORR was 40%. The median DOR was 5.98 months. 31% of responders had a DOR of more than 1 year. Median PFS was 5.52 months, but OS was The median survival time was 11.3 months. The 12-month and 24-month survival rates were 49% and 50%, respectively. The median treatment duration was 5.4 months. The profile was consistent with the primary analysis. No new TRAEs were observed. Central serous retinopathy (CSR) events occurred in 27% of patients ( 85% (23 / 27) were grade 1 or 2 The dose was reduced in 13 patients, discontinued in 8, and discontinued in 3. At the data cutoff date, 63% (17 / 27) had resolved. Ongoing CSR 60% (6 / 10) of events were grade 1. No treatment-related deaths occurred. .

Claims

1. A method of treating cancer, comprising administering to a subject in need thereof, particularly a cancer patient, serum phosphate The concentration is in the range of 5.5 mg / dL to less than 7 mg / dL, inclusive of 5.5 mg / dL. or in the range of 5.5 mg / dL to 9 mg / dL inclusive. The method comprises administering erdafitinib in an amount such that the age, specific wherein the cancer patient is 75 years of age or older.

2. A method of treating cancer, comprising administering to a subject in need thereof, particularly a cancer patient, serum phosphate The concentration is in the range of 5.5 mg / dL to less than 7 mg / dL, inclusive of 5.5 mg / dL. or in the range of 5.5 mg / dL to 9 mg / dL inclusive. and administering to said subject in need thereof an amount of erdafitinib such that said amount of erdafitinib is in a range of from 0.01 to 0.01% of said subject's ECOG PS. , specifically, the cancer patient's ECOG PS is 2.

3. A method of treating cancer, comprising administering to a subject in need thereof, particularly a cancer patient, serum phosphate The concentration is in the range of 5.5 mg / dL to less than 7 mg / dL, inclusive of 5.5 mg / dL. or in the range of 5.5 mg / dL to 9 mg / dL inclusive. and administering to said subject in need thereof an amount of erdafitinib, wherein the cancer patient has a hemoglobin concentration of less than 10 g / dL.

4. A method of treating cancer, comprising administering to a subject in need thereof, particularly a cancer patient, serum phosphate The concentration is in the range of 5.5 mg / dL to less than 7 mg / dL, inclusive of 5.5 mg / dL. or in the range of 5.5 mg / dL to 9 mg / dL inclusive. The method comprises administering to the subject in need thereof, particularly to the subject in need thereof, an amount of erdafitinib such as The method, wherein the cancer patient has visceral metastases.

5. A method of treating cancer, comprising administering to a subject in need thereof, particularly a cancer patient, serum phosphate The concentration is in the range of 5.5 mg / dL to less than 7 mg / dL, inclusive of 5.5 mg / dL. or in the range of 5.5 mg / dL to 9 mg / dL inclusive. The method comprises administering to the subject in need thereof, particularly to the subject in need thereof, an amount of erdafitinib such as The cancer patient has two or three Bellmunt risk factors.

6. The concentration of serum phosphate is between 5.5 mg / dL and 7 mg / dL, inclusive. The method according to any one of claims 1 to 5, wherein the range is less than L.

7. A blood test for the manufacture of a medicament for the treatment of cancer in cancer patients aged 75 years or older. Phosphate concentration is between 5.5 mg / dL and less than 7 mg / dL, including 5.5 mg / dL. or in the range of 5.5 mg / dL to 9 mg / dL inclusive Use of erdafitinib at doses within the range.

8. and a method for producing a medicament for treating cancer in a cancer patient having an ECOG PS of 2. Serum phosphate concentration is between 5.5 mg / dL and 7 mg / dL, including 5.5 mg / dL. or between 5.5 mg / dL and 9 mg / dL inclusive Use of erdafitinib in an amount ranging from

9. Pharmaceutical product for the treatment of cancer in cancer patients with hemoglobin levels less than 10 g / dL The serum phosphate concentration for producing in the range of 5.5 mg / dL to less than 7 mg / dL, or in the range of 5.5 mg / dL to Use of erdafitinib in an amount that is in the range of 0.9 mg / dL or less.

10. A method for the preparation of a medicament for the treatment of cancer in cancer patients with visceral metastases, comprising administering to said patient a serum phosphorus Acid salt concentration is in the range of 5.5 mg / dL to less than 7 mg / dL, including 5.5 mg / dL or in the range of 5.5 mg / dL to 9 mg / dL inclusive. Use of erdafitinib at doses that

11. Medicament for the treatment of cancer in cancer patients with 2 or 3 Bellmunt risk factors For manufacturing the product, the serum phosphate concentration is 5.5 mg / dL, including 5.5 mg / dL. in the range of 1.5 to less than 7 mg / dL or 5.5 mg / dL inclusive Use of erdafitinib in amounts ranging up to 9 mg / dL.

12. The concentration of serum phosphate is between 5.5 mg / dL and 7 mg / dL, inclusive. The use according to any one of claims 7 to 11, wherein the range is less than L.

13. Erdafitinib for use in the treatment of cancer in cancer patients 75 years of age or older and serum phosphate concentration is between 5.5 mg / dL and 7 mg / dL, inclusive. range of less than 5.5 mg / dL or between 5.5 mg / dL and 9 mg / dL, inclusive Erdafitinib administered in an amount that is in the range of 0.1L or less.

14. Erdafitin for use in the treatment of cancer in cancer patients with an ECOG PS of 2 and the serum phosphate concentration is between 5.5 mg / dL and 7 mg / dL, inclusive. g / dL or in the range of 5.5 mg / dL to 9 mg, inclusive / dL or less.

15. For use in the treatment of cancer in cancer patients with hemoglobin levels less than 10 g / dL and the serum phosphate concentration is 5.5 mg / dL or less, including 5.5 mg / dL. 5.5 mg / dL to less than 7 mg / dL or 5.5 mg / dL inclusive Erdafitinib administered in an amount such that the blood cholesterol level ranges from 0.01 mg / dL to 0.05 mg / dL or less.

16. Erdafitinib for use in the treatment of cancer in cancer patients with visceral metastases. Serum phosphate concentration is between 5.5 mg / dL and 7 mg / dL, including 5.5 mg / dL. or between 5.5 mg / dL and 9 mg / dL inclusive Erdafitinib is administered in an amount ranging from 0.1 to 1.

0.

17. For use in treating cancer in cancer patients with 2 or 3 Bellmut risk factors and the serum phosphate concentration is 5.5 mg / dL or less, including 5.5 mg / dL. 5.5 mg / dL to less than 7 mg / dL or 5.5 mg / dL inclusive Erdafitinib administered in an amount such that the blood cholesterol level ranges from 0.01 mg / dL to 0.05 mg / dL or less.

18. The concentration of serum phosphate is between 5.5 mg / dL and 7 mg / dL, inclusive. The use of any one of claims 13 to 17, wherein the range is less than L Nib.

19. A method of treating cancer comprising administering 8 mg of Erda to a subject in need thereof, particularly a cancer patient. and administering rituximab daily, specifically once daily, to the patient in need thereof. The age of the elephant, particularly the age of the cancer patient, is 75 years or older.

20. A method of treating cancer comprising administering 8 mg of Erda to a subject in need thereof, particularly a cancer patient. and administering rituximab daily, specifically once daily, to the patient in need thereof. The ECOG PS of the elephant, particularly the ECOG PS of said cancer patient, is 2.

21. A method of treating cancer comprising administering 8 mg of Erda to a subject in need thereof, particularly a cancer patient. and administering rituximab daily, specifically once daily, to the patient in need thereof. The hemoglobin concentration of the elephant, specifically the hemoglobin concentration of the cancer patient, is less than 10 g / dL. That's the method.

22. A method of treating cancer comprising administering 8 mg of Erda to a subject in need thereof, particularly a cancer patient. and administering rituximab daily, specifically once daily, to the patient in need thereof. The method of claim 1, wherein the patient, in particular the cancer patient, has visceral metastases.

23. A method of treating cancer comprising administering 8 mg of Erda to a subject in need thereof, particularly a cancer patient. and administering rituximab daily, specifically once daily, to the patient in need thereof. The method of claim 1, wherein the patient, particularly the cancer patient, has two or three Bellmunt risk factors.

24. EL for manufacturing a medicine for the treatment of cancer in cancer patients aged 75 years or older 1. Use of erdafitinib, wherein the medicament contains erdafitinib in an amount of 8 mg, The pharmaceutical is intended for continuous daily administration, specifically once daily use.

25. and a method for producing a medicament for treating cancer in a cancer patient having an ECOG PS of 2. Use of erdafitinib, wherein the medicament contains erdafitinib in an amount of 8 mg. , wherein the pharmaceutical product is for continuous daily administration, particularly once a day.

26. Pharmaceutical product for the treatment of cancer in cancer patients with hemoglobin levels less than 10 g / dL 1. Use of erdafitinib for the manufacture of a pharmaceutical composition comprising erdafitinib in an amount of 8 mg. and the medicament is for continuous daily administration, particularly once a day. Therefore, use.

27. Eldafi for the manufacture of a medicament for the treatment of cancer in cancer patients with visceral metastases erdafitinib in an amount of 8 mg, The product is for continuous daily administration, specifically once a day, for use.

28. Medicament for the treatment of cancer in cancer patients with 2 or 3 Bellmunt risk factors 1. Use of erdafitinib for the manufacture of a pharmaceutical product, wherein the pharmaceutical product is erdafitinib in an amount of 8 mg. The pharmaceutical contains dafitinib, and the pharmaceutical is for continuous daily administration, particularly once a day. It is something that is used.

29. Erdafichi for use in the treatment of cancer in cancer patients aged 75 years or older nibs, erdafichi administered daily, specifically once daily, in an amount of 8 mg; Nib.

30. Eldaf for use in the treatment of cancer in cancer patients with ECOG PS of 2 eldaf, which is imipramine, administered daily in an amount of 8 mg, specifically once daily continuously; Itinib.

31. Use in the treatment of cancer in cancer patients with hemoglobin levels below 10 g / dL. Erdafitinib for the treatment of rheumatoid arthritis, administered daily, specifically once daily, in an amount of 8 mg. Erdafitinib is given.

32. Erdafitinib for use in the treatment of cancer in cancer patients with visceral metastases Erdafitinib is administered at a dose of 8 mg daily, specifically once a day continuously.

33. Use in the treatment of cancer in cancer patients with 2 or 3 Bellmut risk factors. Erdafitinib for the treatment of rheumatoid arthritis, administered daily, specifically once daily, in an amount of 8 mg. Erdafitinib is given.

34. The cancer is urothelial carcinoma, bladder cancer, hepatocellular carcinoma, squamous cell carcinoma, or lung cancer.

29. The method or use according to any one of 2 or 19 to 28.

35. 35. The method of claim 34, wherein the cancer is metastatic or surgically unresectable urothelial carcinoma. Or use.

36. 35. The method or use of claim 34, wherein the cancer is advanced or metastatic cholangiocarcinoma.

37. 1. A method of treating cancer, comprising: a) administering 8 mg of erdafitinib daily to a subject in need thereof, specifically a cancer patient; Typically, once daily continuous administration; b) measuring the subject's serum phosphate concentration on the treatment day during the first cycle of erdafitinib treatment, Specifically, it should be measured on the 14th day ± 2 days after erdafitinib administration, more specifically on the 14th day. and; c-1) if the serum phosphate concentration is less than 5.5 mg / dL, erdafitinib , administered daily, specifically once daily, in an amount of 9 mg; c-2) The serum phosphate concentration is 5.5 mg / dL to 7 mg / dL, inclusive. / dL, erdafitinib is administered daily in an amount of 8 mg, specifically 1 day one further continuous administration; c-3) When the serum phosphate concentration is 7 mg / dL or more, the erdafitinib treatment Therapy is temporarily discontinued until serum phosphate levels are below 5.5 mg / dL, and then After this, erdafitinib treatment is resumed daily, specifically at 8 mg once daily. thing Including, The subject in need, specifically the cancer patient, meets the following criteria: age 75 years or older; COG PS; hemoglobin less than 10 g / dL; visceral metastases, specifically liver, lung and / or or bone; and patients who meet one or more of two or three Bellmunt risk factors There is a way.

38. Use of erdafitinib for the manufacture of a medicament for the treatment of cancer in a cancer patient. So, a) the pharmaceutical product contains erdafitinib in an amount of 8 mg, and the pharmaceutical product is administered daily in a specific is for continuous administration once daily; b) the patient's serum phosphate concentration on the day of treatment during the first cycle of erdafitinib treatment; Specifically, it was measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14. ； c-1) If the serum phosphate concentration is less than 5.5 mg / dL, daily, specifically 1 The amount of erdafitinib in the drug product for continuous once-daily administration is increased to 9 mg. Re; c-2) The serum phosphate concentration is 5.5 mg / dL to 7 mg / dL, inclusive. / dL, the patient should be treated with 8 mg daily, specifically once daily continuous Remain in treatment; c-3) When the serum phosphate concentration is 7 mg / dL or more, the erdafitinib treatment Therapy is temporarily discontinued until serum phosphate levels are below 5.5 mg / dL, and then Erdafitinib treatment was then resumed daily, specifically at a continuous dose of 8 mg once daily. The cancer patients met the following criteria: age 75 years or older; ECOG PS of 2; and <10 g / dL. hemoglobin; visceral metastases, particularly those in the liver, lungs, and / or bones; and 2 or 3 The patient meets one or more of the Bellmunt risk factors.

39. 1. Erdafitinib for use in the treatment of cancer in a cancer patient, comprising: a) administered daily, specifically once daily, in an amount of 8 mg; b) the patient's serum phosphate concentration on the day of treatment during the first cycle of erdafitinib treatment; Specifically, it was measured on day 14 ± 2 of erdafitinib administration, more specifically on day 14. ； c-1) if the serum phosphate concentration is less than 5.5 mg / dL, erdafitinib , administered daily in an amount of 9 mg, specifically once daily continuously; c-2) The serum phosphate concentration is 5.5 mg / dL to 7 mg / dL, inclusive. / dL, erdafitinib is administered daily in an amount of 8 mg, specifically 1 day one further consecutive dose; c-3) When the serum phosphate concentration is 7 mg / dL or more, the erdafitinib treatment Therapy is temporarily discontinued until serum phosphate levels are below 5.5 mg / dL, and then Erdafitinib treatment was then resumed daily, specifically at a continuous dose of 8 mg once daily. The cancer patients met the following criteria: age 75 years or older; ECOG PS of 2; and <10 g / dL. hemoglobin; visceral metastases, particularly those in the liver, lungs, and / or bones; and 2 or 3 Erdafitinib, patients who meet one or more of the Bellmunt risk factors.

40. Selected FGFR gene alterations (FGFR translocations) in patients aged 75 years or older for use in the treatment of metastatic or surgically unresectable urothelial carcinoma with urothelial cell carcinoma (urothelial cell carcinoma with urothelial cell carcinoma mutations) Erdafitinib for the treatment of rheumatoid arthritis, administered daily, specifically once daily, in an amount of 8 mg. and the daily amount of erdafitinib is administered in two pharmaceutical compositions, specifically 4 mg / kg each. as two tablets containing 1 mg of erdafitinib or as two pharmaceutical compositions, specifically two, one containing 3 mg of erdafitinib and one containing 5 mg of erdafitinib; Erdafitinib, given as a tablet.

41. Selected FGFR gene alterations (FGFR translocations) in patients aged 75 years or older for use in the treatment of metastatic or surgically unresectable urothelial carcinoma with urothelial cell carcinoma (urothelial cell carcinoma with urothelial cell carcinoma mutations) Erdafitinib for the treatment of rheumatoid arthritis, administered daily, specifically once daily, in an amount of 9 mg. and the daily amount of erdafitinib is administered in three pharmaceutical compositions, specifically in three as three tablets containing 1 mg of erdafitinib, or as two pharmaceutical compositions, specifically 1 two, one containing 4 mg of erdafitinib and one containing 5 mg of erdafitinib; Erdafitinib, given as a tablet.

42. Selected FGFR gene alterations (FGFR translocations or apoptosis) in patients with visceral metastases For use in the treatment of metastatic or surgically unresectable urothelial carcinoma with a mutated urothelial cell carcinoma (urothelial carcinoma) Erdafitinib of 8 mg administered daily, specifically once daily continuously. The daily amount of erdafitinib is 4 mg each of two pharmaceutical compositions. as two tablets containing erdafitinib, or as two pharmaceutical compositions, specifically one containing 3 mg erdafitinib and two tablets, one containing 5 mg erdafitinib Erdafitinib, administered as

43. Selected FGFR gene alterations (FGFR translocations or apoptosis) in patients with visceral metastases For use in the treatment of metastatic or surgically unresectable urothelial carcinoma with a mutated urothelial cell carcinoma (urothelial carcinoma) erdafitinib, administered daily, specifically once daily, in an amount of 9 mg. The daily amount of erdafitinib is 3 mg each of three pharmaceutical compositions. as three tablets containing erdafitinib, or as two pharmaceutical compositions, one of which is 4 mg erdafitinib and two tablets, one containing 5 mg erdafitinib Erdafitinib, administered as

44. Selected FGFR genes in patients aged 75 years or older with visceral metastases Metastatic or surgically unresectable urothelium with genetic alterations (FGFR translocations or mutations) Erdafitinib for use in the treatment of cancer, specifically administered in an amount of 8 mg daily. and the daily dose of erdafitinib is administered once daily continuously to Specifically, as two tablets each containing 4 mg of erdafitinib, or as a combination of two pharmaceutical Pharmaceutical compositions, specifically one containing 3 mg of erdafitinib and one containing 5 mg of erdafitinib. Erdafitinib, given as two tablets containing dafitinib.

45. Selected FGFR genes in patients aged 75 years or older with visceral metastases Metastatic or surgically unresectable urothelium with genetic alterations (FGFR translocations or mutations) Erdafitinib for use in the treatment of cancer, specifically administered in an amount of 9 mg daily. is administered once daily continuously, and said daily amount of erdafitinib is Specifically, as three tablets each containing 3 mg of erdafitinib, or as a combination of two pharmaceutical Pharmaceutical compositions, specifically one containing 4 mg of erdafitinib and one containing 5 mg of erdafitinib. Erdafitinib, given as two tablets containing dafitinib.

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