TW201839399A - Cancer treatment - Google Patents

Abstract

The present invention provides a method for treating cancer with eratinib.

Description

   Cancer treatment   

The present invention provides for the treatment of cancer with erdafitinib, which has a high response potential while limiting potential toxicity (such as nail toxicity).

The invention provides for the treatment of cancer with eratinib, which maximizes eratinib exposure while limiting potential toxicity.

The present invention provides for the treatment of cancer with erdatinib, which has a high objective response rate, specifically at least 40%, and has an objective response rate of at least 40% in patients without chemotherapy (chemo-naïve) cancer. Have an objective response rate of at least 40% in cancer patients with disease progression after previous first-line chemotherapy, and at least 40% of objective response rates in cancer patients with disease progression after previous second-line or more chemotherapy.

The invention provides treatment of cancer with eratinib, with a short-term response, specifically with a median response time of less than 2 months.

Figure 1 shows a phase 2 multicenter open-label study to assess erdatinib on metastatic or surgically unresectable urinary tract with genetic alterations (FGFR translocations or mutations) of selected FGFR (fibroblast growth factor receptor) Study protocol for efficacy and safety in patients with skin cancer.

Figure 2 shows a waterfall plot of the maximum percentage reduction in the sum of target lesion diameters for patients treated with an 8 mg continuous eratinib regimen (Scheme 3 (Figure 1) in Phase 2 study). M, FGFR mutation; T, FGFR translocation.

The invention provides for the treatment of cancer with eratinib, which has been in the first cycle of treatment and in additional cycles of treatment (eg, set at 28 days / cycle or 21 days / cycle, specifically with daily continuous doses) Maximize eratinib exposure (eg, set on the first 28 days of treatment or the first 21 days of treatment, specifically with daily continuous doses), while limiting potential toxicity.

The present invention provides the use of eratinib for the treatment of cancer, which maximizes eratinib exposure and quickly places subjects in need of eratinib within the target serum phosphate range, specifically from 5.5mg / dL to <7mg / dL and including 5.5mg / dL, or ranging from 5.5mg / dL to 9 mg / dL and includes 5.5 mg / dL to keep phosphate-based toxicity under control.

Erdatinib or N- (3,5-dimethoxyphenyl) -N '-(1-methylethyl) -N- [3- (1-methyl-1H-pyrazole-4- (Quinyl) quinoxaline-6-yl] ethane-1,2-diamine-based pan-fibroblast growth factor receptor (FGFR 1, 2, 3, 4) tyrosine kinase inhibitor.

Department of Chemical Structure of Erdatinib

Serum phosphate levels may represent target pharmacodynamic markers pointing to FGFR targets with erdatinib participation. Serum phosphate levels increase with target involvement. However, serum phosphate levels need to be monitored to minimize or avoid or control acute and long-term hyperphosphatemia.

It has been found that when serum phosphate levels At 5.5 mg / dL, a higher proportion of patients responded to eratinib treatment.

In embodiments, depending on the type of cancer, the proportion of patients showing an objective response rate is at least 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, 50%, 55%, 60%, 65% or more.

In an embodiment, depending on the type of cancer, exposure to erdatinib is such that it provides at least 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, 50%, 55%, 60%, 65%, or more than 65% objective response rate.

In embodiments, depending on the type of cancer, the serum phosphate level of a cancer patient is 5.5mg / dL, specifically, ranging from 5.5mg / dL to <7mg / dL and including 5.5mg / dL, or ranging from 5.5mg / dL to 9mg / dL and including 5.5mg / dL, provide at least 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, 50%, 55%, 60%, 65%, or more than 65% objective response rate.

In embodiments, a method of treating a cancer as described herein, or the use of a medicament for the manufacture of a medicament for treating a cancer as described herein, or using erdatinib for treating a cancer as described herein provides at least 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, 50%, 55%, 60%, 65%, or more than 65% objective response rate.

In an embodiment, such as a method of treating a cancer as described herein, or the use of a medicament for the manufacture of a medicament for treating a cancer as described herein, or erdatinib for the treatment of a cancer as described herein ( Among them, the cancer is urothelial carcinoma, metastatic or surgically unresectable urothelial carcinoma, specifically urothelial carcinoma, metastatic or surgically unresectable urothelial carcinoma with selected FGFR genetic alterations) providing at least 40% of The objective response rate is specifically about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, and about 48%. The objective response rate is about 49% and about 50%. Specifically, the objective response rate ranges from 40% to 50%, or ranges from 40% to 45%, or ranges from 42% to 45%,

In embodiments, for patients with urothelial cancer, metastatic or surgically unresectable urothelial cancer (specifically with selected FGFR genetically altered urothelial cancer, metastatic or surgically unresectable urothelial cancer) Patients, according to the dosing regimen disclosed herein, the objective response rate after exposure to eratinib is at least 40%, specifically about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, and about 50%. Specifically, the objective response rate ranges from 40% to 50%, or ranges from 40% to 45%, or ranges from 42% to 45%.

In embodiments, a method of treating a cancer as described herein, or the use of a medicament for the manufacture of a medicament for treating a cancer as described herein, or using erdatinib for treating a cancer as described herein provides at least Median response duration of 4 months, or at least 5 months, or at least 6 months, or at least 7 months.

In embodiments, a method of treating a cancer as described herein, or the use of a medicament for the manufacture of a medicament for treating a cancer as described herein, or using erdatinib for the treatment of a cancer as described herein (wherein The cancer is urothelial cancer, metastatic or surgically unresectable urothelial cancer, specifically urinary epithelial cancer with selected FGFR genetic alterations, metastatic or surgically unresectable urothelial cancer) provided for at least 4 months, Or at least 5 months, or 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 of median response duration. Specifically, the median response duration ranged between 4 and 7 months.

In an embodiment, for patients with urothelial cancer, metastatic or surgically unresectable urothelial cancer (specifically, urothelial cancer, metastatic or surgically unresectable urothelial cancer with a genetic alteration of FGFR selected) Patients, according to the dosing regimen disclosed herein, have a median response duration after exposure to eratinib of at least 4 months, or at least 5 months, or 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. Specifically, the median response duration ranged between 4 and 7 months.

In embodiments, a method of treating a cancer as described herein, or the use of a medicament for the manufacture of a medicament for treating a cancer as described herein, or using erdatinib for treating a cancer as described herein provides at least The median progression-free survival was 4 months, or at least 5 months, or at least 6 months, or at least 7 months.

In embodiments, a method of treating a cancer as described herein, or the use of a medicament for the manufacture of a medicament for treating a cancer as described herein, or using erdatinib for the treatment of a cancer as described herein (wherein The cancer is urothelial cancer, metastatic or surgically unresectable urothelial cancer, specifically urinary epithelial cancer with selected FGFR genetic alterations, metastatic or surgically unresectable urothelial cancer) provided for at least 4 months, Or a median progression-free survival of at least 5 months, or 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. Specifically, the median progression-free survival ranged between 4 and 7 months.

In an embodiment, for patients with urothelial cancer, metastatic or surgically unresectable urothelial cancer (specifically, urothelial cancer, metastatic or surgically unresectable urothelial cancer with a genetic alteration of FGFR selected) Patients, with a dosing regimen as disclosed herein, have a median progression-free survival after exposure to erdatinib of at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or It is about 4 months, or about 5 months, or about 6 months, or about 7 months. Specifically, the median progression-free survival ranged between 4 and 7 months.

The method of treating a cancer as described herein, or the use of a medicament for the manufacture of a medicament for treating a cancer as described herein, or the use of erdatinib for the treatment of a cancer as described herein has a median time short. In an embodiment, the corresponding median time is less than 2 months, specifically less than 1.5 months, and specifically about 1.4 months.

In embodiments, a method of treating a cancer as described herein, or the use of a medicament for the manufacture of a medicament for treating a cancer as described herein, or using erdatinib for the treatment of a cancer as described herein (wherein The cancer is urothelial cancer, metastatic or surgically unresectable urothelial cancer, specifically urothelial cancer, metastatic or surgically unresectable urothelial cancer with a genetic alteration of FGFR selected) provided for less than 2 months, The median response time was less than 1.5 months, specifically about 1.4 months.

In embodiments, patients with urothelial cancer, metastatic or surgically unresectable urothelial cancer (specifically, urothelial cancer, metastatic or surgically unresectable urothelial cancer with a genetic alteration of FGFR selected) According to the dosing regimen disclosed herein, the median time to response after exposure to eratinib is less than 2 months, specifically less than 1.5 months, and specifically about 1.4 months.

Surprisingly, it has been found to treat cancers as described herein (specifically for the treatment of urothelial cancer, metastatic or surgically unresectable urothelial cancer, specifically urothelial cancer, metastatic with selected FGFR genetic alterations) Or surgically unresectable urothelial cancer) with patients (e.g., patients who have not received chemotherapy, specifically patients who did not qualify for cisplatin for the first time, patients with disease progression after previous first-line chemotherapy, The number of patients with disease progression after multi-line chemotherapy) had no prior line treatment. In an embodiment, the response to treatment is similar for patients who have received a different number of previous line treatments, for example, patients who have not received chemotherapy, specifically patients who have not received cisplatin for the first time, have a disease after previous first line chemotherapy Patients who have progressed or who have disease progression after previous second or more lines of chemotherapy. In embodiments, the response to cancer treatment by a patient having previous line of chemotherapy (e.g., a patient having disease progression after a previous first line of chemotherapy, or a patient having disease progression after a previous second or more lines of chemotherapy) is no better than an untreated Poor in chemotherapy patients.

Already discovered A serum phosphate level of 7 mg / dL (specifically> 9 mg / dL) may justify a temporary interruption of eratinib treatment or an eratinib dose adjustment (dose reduction).

In an embodiment, a temporary interruption of eratinib represents an interruption in the administration of eratinib until the serum phosphate level is again <5.5 mg / dL.

In an embodiment, a temporary interruption of eratinib represents an interruption in the administration of eratinib until the serum phosphate level is again <7 mg / dL.

It has been found that an effective and safe treatment with eratinib is administered at a therapeutically effective dose, with serum phosphate levels ranging from 5.5 mg / dL to <7 mg / dL and including 5.5 mg / dL, or ranging from 5.5mg / dL to 9 mg / dL and includes 5.5 mg / dL.

Serum phosphate levels can be measured using commercially available kits, such as, for example, the ab65622 phosphate assay kit (colorimetric) (Abcam).

It has been found that, on a continuous basis (unless the context indicates different, daily, no interruption of treatment, no intermittent administration), a dose of 8 mg of eratinib per day, preferably once daily, is needed for eratinib Subjects given, particularly cancer patients, have the potential to reach or cross 5.5 mg / dL increased serum phosphate levels while minimizing the need for treatment interruption or dose reduction for potential drug-related adverse events.

It has been found that, on a continuous basis, 8 mg of eratinib per day, preferably once daily, can reach a serum phosphate level of 5.5 mg / dL (set to, Such as the first 28 days or the first 21 days). It has been found that on a continuous basis, 8 mg of eratinib per day, preferably once daily, has potential for eratinib in subjects requiring eratinib administration, particularly cancer patients. In the first cycle of treatment increase (eg, 14 days ± 2 days of treatment), the serum phosphate level of 5.5 mg / dL is reached or increased early enough to maximize effective treatment while minimizing potential drug-related The need for treatment interruption or dose reduction for adverse events.

In an embodiment, the serum phosphate levels of a subject in need of eratinib treatment, particularly a cancer patient, are monitored.

In an embodiment, the serum phosphate level of a subject in need of ertintinib treatment, particularly a cancer patient, is monitored, and the amount of Early-onset toxicity that is often associated with FGFR inhibitors or specifically ertinib.

In embodiments, the early-onset toxicity typically associated with a FGFR inhibitor or specifically with eratinib comprises grade 3 or higher xerostomia or stomatitis / mucositis, dry skin, dry eyes, nail toxicity (or Grade 2 if lasting more than 1 week) or Grade 2 or higher eye toxicity (keratitis, central serous retinopathy / retinal pigment epithelium detachment). Early-onset toxicity can justify interrupted treatment or reduced doses. It depends on the judgment of the physician, and it depends on the patient's disease state.

In an embodiment, early-onset toxicity, or early-onset toxicity typically associated with a FGFR inhibitor or specifically eratinib as described herein, means clinically significant toxicity that is considered clinically significant Usually associated with FGFR inhibitors or specifically with eratinib, generally considered to be grade 3 or higher, this clinically significant toxicity consists of one or more of the following: stomatitis / mucositis, dry skin, dry eyes , Nail toxicity or particularly eye toxicity (keratitis, or retinopathy, also described as central serous retinopathy, retinal detachment, retinal edema, retinal pigment epithelium detachment, choroidal retinopathy), or regarding what is generally considered to be associated with FGFR inhibition Agents or other significant toxicities associated with eratinib. Early-onset toxicity can justify interrupted treatment or reduced doses. It depends on the judgment of the physician, and it depends on the patient's disease state.

The present invention relates to a method for treating cancer, which method comprises administering to a subject in need thereof, particularly a cancer patient, an amount of eratinib such that the level of serum phosphate ranges from 5.5 mg / dL to < 7 mg / dL and includes 5.5 mg / dL. In an embodiment, the amount of eratinib administered is 8 mg on a continuous basis, specifically 8 mg per day. The present invention relates to a method for treating cancer, the method comprising administering to a subject in need thereof, particularly a cancer patient, an amount of ertintinib such that, within the first cycle of eratinib administration ( The duration of the treatment cycle is set, for example, on the first 28 days of administration or on the first 21 days of administration, and on the 28th day of administration or on the approximately 28th day, or on the 21st day or approximately the 21st day of administration Or, serum phosphate water was evaluated on or about day 14 of administration) Serum phosphate levels reached from 5.5 mg / dL to <7 mg / dL and included a range of 5.5 mg / dL. In an embodiment, the amount of eratinib administered is 8 mg on a continuous basis, specifically 8 mg per day.

The present invention relates to a method for treating cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, an amount of edatinib such that the level of serum phosphate ranges from 5.5 mg / dL to 9 mg / dL and includes 5.5 mg / dL. In an embodiment, the amount of eratinib administered is 8 mg on a continuous basis, specifically 8 mg per day. The present invention relates to a method for treating cancer, which method comprises administering to a subject in need thereof, particularly a cancer patient, an amount of eratinib, such that during the first cycle of eratinib administration (treatment The cycle duration is set, for example, on the first 28 days of administration or on the first 21 days of administration, and on the 28th day of administration or on approximately 28th day, or on the 21st day of administration or approximately 21st day, Or on the 14th day of administration or on the 14th day of assessment of serum phosphate water), the level of serum phosphate reaches from 5.5mg / dL to 9 mg / dL and includes a range of 5.5 mg / dL. In an embodiment, the amount of eratinib administered is 8 mg on a continuous basis, specifically 8 mg per day.

The present invention relates to the use of eratinib in the manufacture of a medicament for treating cancer in an amount such that the level of serum phosphate ranges from 5.5 mg / dL to <7 mg / dL and includes 5.5 mg / dL. The present invention relates to the use of eratinib in the manufacture of a medicament for treating cancer in an amount such that the first cycle of eratinib administration (the duration of the treatment cycle is set to, for example, Serum phosphate is assessed on the first 21 days of administration, and on the 28th or approximately 28th day of administration, or on the 21st or approximately 21st day of administration, or on the 14th or approximately 14th day of administration In saline), serum phosphate levels reach a range from 5.5 mg / dL to <7 mg / dL and include 5.5 mg / dL. In an embodiment, the amount of eratinib administered is 8 mg on a continuous basis, specifically 8 mg per day.

The present invention relates to the use of erdatinib in the manufacture of a medicament for treating cancer in an amount such that the level of serum phosphate ranges from 5.5 mg / dL to 9 mg / dL and includes 5.5 mg / dL. The present invention relates to the use of eratinib in the manufacture of a medicament for treating cancer in an amount such that the first cycle of eratinib administration (the duration of the treatment cycle is set to, for example, the first 28 days of administration or Serum phosphate is assessed on the first 21 days of administration, and on the 28th or approximately 28th day of administration, or on the 21st or approximately 21st day of administration, or on the 14th or approximately 14th day of administration Saline), the level of serum phosphate reaches from 5.5mg / dL to 9 mg / dL and includes a range of 5.5 mg / dL. In an embodiment, the amount of eratinib administered is 8 mg on a continuous basis, specifically 8 mg per day.

The present invention relates to the use of eratinib in the treatment of cancer, wherein eratinib is administered in an amount such that the level of serum phosphate ranges from 5.5 mg / dL to <7 mg / dL and includes 5.5 mg / dL. The present invention relates to the use of eratinib in the treatment of cancer, wherein eratinib is administered in an amount such that the first cycle of eratinib administration (the duration of the treatment cycle is set to, for example, the first 28 days of administration) Or the first 21 days of administration, and the serum is assessed on the 28th or approximately 28th day of administration, or on the 21st or approximately 21st day of administration, or on the 14th or approximately 14th day of administration Phosphate water), serum phosphate levels reach a range from 5.5 mg / dL to <7 mg / dL and include 5.5 mg / dL. In an embodiment, the amount of eratinib administered is 8 mg on a continuous basis, specifically 8 mg per day.

The present invention relates to the use of erdatinib for the treatment of cancer, wherein erdatinib is administered in an amount such that the level of serum phosphate ranges from 5.5 mg / dL to 9 mg / dL and includes 5.5 mg / dL. The present invention relates to the use of eratinib in the treatment of cancer, wherein eratinib is administered in an amount such that the first cycle of eratinib administration (the duration of the treatment cycle is set to, for example, the first 28 days of administration) Or the first 21 days of administration, and the serum is assessed on the 28th or approximately 28th day of administration, or on the 21st or approximately 21st day of administration, or on the 14th or approximately 14th day of administration Phosphate water), the level of serum phosphate reaches from 5.5mg / dL to 9 mg / dL and includes a range of 5.5 mg / dL. In an embodiment, the amount of eratinib administered is 8 mg on a continuous basis, specifically 8 mg per day.

The present invention relates to a method for treating cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, 8 mg of eratinib per day, specifically once per day, on a continuous basis. Dosage adjustments can be made based on serum phosphate levels and observed with or without toxicity.

The present invention relates to the use of erdatinib in the manufacture of a medicament for treating cancer, wherein the medicament comprises erdatinib in an amount of 8 mg, and wherein the medicament is administered daily on a continuous basis, specifically, Once a day. Dosage adjustments can be made based on serum phosphate levels and observed with or without toxicity.

The present invention relates to the use of eratinib for the treatment of cancer, wherein eratinib is administered daily in an amount of 8 mg, specifically once daily, on a continuous basis. Dosage adjustments can be made based on serum phosphate levels and observed with or without toxicity.

On a continuous basis, serum phosphate levels can be monitored during the treatment of eratinib at a daily dose of 8 mg, preferably once daily. If the level of serum phosphate is <5.5mg / dL, the dose of eratinib can be increased. On a continuous basis, it can be increased to 9mg daily, preferably once daily. In an embodiment, on the treatment day during the first cycle of eratinib treatment (specifically 14 days ± 2 days of eratinib administration, more specifically day 14), the measurement is used to determine whether the Serum phosphate levels.

On a continuous basis, serum phosphate levels can be monitored during the treatment of eratinib at a daily dose of 8 mg, preferably once daily. If serum phosphate levels are <7mg / dL, or range from 7mg / dL to 9mg / dL and includes 7mg / dL, or 9mg / dL, can increase the dose of eratinib, on a continuous basis, can be increased to 9mg daily, preferably once a day. In an embodiment, on the treatment day during the first cycle of eratinib treatment (specifically 14 days ± 2 days of eratinib administration, more specifically day 14), the measurement is used to determine whether the Serum phosphate levels.

The present invention relates to a method for treating cancer, which method comprises administering to a subject in need thereof, particularly a cancer patient, 8 mg of ertintinib daily, specifically once daily, on a continuous basis, The method includes monitoring a subject's serum phosphate level. In an embodiment, on the treatment day during the first cycle of eratinib treatment (specifically 14 days ± 2 days of eratinib administration, more specifically day 14), the measurement is used to determine whether the Serum phosphate levels.

The present invention relates to the use of erdatinib in the manufacture of a medicament for the treatment of cancer in cancer patients, wherein the medicament comprises erdatinib in an amount of 8 mg, wherein the medicament is Daily, and in which serum phosphate levels of cancer patients are monitored. In an embodiment, on the treatment day during the first cycle of eratinib treatment (specifically 14 days ± 2 days of eratinib administration, more specifically day 14), the measurement is used to determine whether the Serum phosphate levels.

The present invention relates to the use of erdatinib for the treatment of cancer in cancer patients, wherein erdatinib is given in an amount of 8 mg per day on a continuous basis, specifically once daily, and wherein the Serum phosphate levels. In an embodiment, on the treatment day during the first cycle of eratinib treatment (specifically 14 days ± 2 days of eratinib administration, more specifically day 14), the measurement is used to determine whether the Serum phosphate levels.

The present invention relates to a method for treating cancer, which method comprises administering 8 mg of edatinib to a subject in need thereof, in particular a cancer patient, on a continuous basis, specifically once daily, which The method includes monitoring the subject's serum phosphate level, and when the serum phosphate level is <5.5 mg / dL, the daily amount of eratinib (preferably daily) will be given on a continuous basis. (Amount) to 9 mg. When the serum phosphate levels ranged from 5.5 mg / dL to <7 mg / dL and included 5.5 mg / dL, the subject maintained continuous treatment at 8 mg daily. When serum phosphate levels At 7 mg / dL, temporarily interrupt the treatment, specifically interrupt the eratinib treatment until the serum phosphate level is again <7 mg / dL, or adjust the daily continuous dose to <8 mg, specifically temporarily interrupt the treatment, specifically Yes until serum phosphate level is <5.5 mg / dL. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14). In embodiments, when the serum phosphate level is 7mg / dL (specifically from 7mg / dL to 9 mg / dL and including 7 mg / dL), specifically on day 14 ± 2 days (more specifically on day 14), the treatment was temporarily interrupted until the serum phosphate level was <5.5 mg / dL, and then continuously Based on 8 mg daily (specifically once daily), ertintinib treatment was restarted.

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to a method for treating cancer, which method comprises administering 8 mg of edatinib to a subject in need thereof, in particular a cancer patient, on a continuous basis, specifically once daily, which The method includes monitoring the subject's serum phosphate level, and when the serum phosphate level is <7 mg / dL, the daily amount of eratinib (preferably once daily) will be given on a continuous basis. Amount) was increased to 9 mg. When serum phosphate levels range from 7mg / dL to At 9 mg / dL and including 7 mg / dL, increase the daily amount of eratinib (preferably once daily) given to 9 mg on a continuous basis, and begin to combine with phosphate as appropriate (Eg, for example, sevelamer). In an embodiment, concurrent treatment with a phosphate binding agent (such as, for example, Sevelamer) is initiated. When serum phosphate levels increase to> 9 mg / dL, treatment is temporarily discontinued, specifically ertinib treatment is discontinued until serum phosphate levels are again <7 mg / dL, and when serum phosphate levels are below 7 mg / dL At that time, the daily continuous dose is adjusted to the same or lower than the daily dose. With serum phosphate levels> 10 mg / dL for> 2 weeks, treatment is permanently discontinued, specifically ertinib treatment is discontinued. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14). In embodiments, when the serum phosphate level is> 9 mg / dL, the treatment is temporarily interrupted until the serum phosphate level is <7 mg / dL, and then erdatinib is restarted with 8 mg daily on a continuous basis Treatment, specifically once a day. In embodiments, during further administration of eratinib, serum phosphate levels may be managed according to Table 4.

The present invention relates to a method for treating cancer, which method comprises, on a continuous basis, administering to a subject in need thereof, particularly a cancer patient, 8 mg of eratinib daily (specifically once daily). The method includes monitoring a subject's serum phosphate level, and monitoring the early onset toxicity shown by the subject, which is usually associated with an FGFR inhibitor or specifically ertinib, and when the serum phosphate level is When <5.5 mg / dL and no early onset toxicity is shown, the daily amount of eratinib (preferably once daily) administered is increased to 9 mg on a continuous basis. When serum phosphate levels ranged from 5.5 mg / dL to <7 mg / dL and included 5.5 mg / dL and did not show early onset toxicity, the subject maintained continuous treatment at 8 mg daily. When serum phosphate levels At 7 mg / dL, temporarily interrupt the treatment, specifically interrupt the eratinib treatment until the serum phosphate level is again <7 mg / dL, or adjust the daily continuous dose to <8 mg, specifically temporarily interrupt the treatment, specifically Yes until serum phosphate level is <5.5 mg / dL. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14). In embodiments, when the serum phosphate level is At 7 mg / dL, the treatment was temporarily interrupted until the serum phosphate level was <5.5 mg / dL, and then ertinib treatment was restarted with 8 mg daily on a continuous basis, specifically once daily.

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to a method for treating cancer, which method comprises, on a continuous basis, administering to a subject in need thereof, particularly a cancer patient, 8 mg of eratinib daily (specifically once daily). The method includes monitoring a subject's serum phosphate level, and monitoring the early onset toxicity shown by the subject, which is usually associated with an FGFR inhibitor or specifically ertinib, and when the serum phosphate level is When <7 mg / dL and no early onset toxicity is shown, the daily amount of eratinib (preferably once daily) administered is increased to 9 mg on a continuous basis. When serum phosphate levels range from 7mg / dL to When 9 mg / dL and including 7 mg / dL does not show early-onset toxicity, the daily amount of edatinib (preferably once daily) administered is increased to 9 mg on a continuous basis, as appropriate Initiate concurrent treatment with phosphate binding agents such as, for example, Sevelamer. In an embodiment, concurrent treatment with a phosphate binding agent (such as, for example, Sevelamer) is initiated. When serum phosphate levels increase to> 9 mg / dL, treatment is temporarily discontinued, specifically ertinib treatment is discontinued until serum phosphate levels are again <7 mg / dL, and when serum phosphate levels are below 7 mg / dL At that time, the daily continuous dose is adjusted to the same or lower than the daily dose. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14). In embodiments, when the serum phosphate level is> 9 mg / dL, the treatment is temporarily interrupted until the serum phosphate level is <7 mg / dL, and then erdatinib is restarted with 8 mg daily on a continuous basis Treatment, specifically once a day.

In embodiments, during further administration of eratinib, serum phosphate levels may be managed according to Table 4.

The present invention relates to a method for treating cancer, which method comprises administering to a subject in need thereof (specifically, a cancer patient) 9 mg of eratinib per day, specifically once per day, on a continuous basis. The method includes monitoring a subject's serum phosphate level while on treatment with 8 mg eratinib per day and wherein when the subject's serum phosphate level is <5.5 mg / dL, on a continuous basis 9 mg was administered to the subject, specifically once daily. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14).

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to a method for treating cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, 9 mg of edatinib daily, particularly once daily, on a continuous basis, and When treated with 8 mg daily eratinib, when the subject's serum phosphate level is <7 mg / dL or when the serum phosphate level ranges from 7 mg / dL to At 9 mg / dL and including 7 mg / dL, 9 mg is administered to the subject on a continuous basis, specifically once daily. When serum phosphate levels range from 7mg / dL to At 9 mg / dL and including 7 mg / dL, simultaneous treatment with a phosphate binding agent such as, for example, Sevelamer can be initiated. In an embodiment, concurrent treatment with a phosphate binding agent (such as, for example, Sevelamer) is initiated. In an embodiment, the serum phosphate level is measured on day 14 ± 2 days, and more specifically on day 14 of eratinib administration.

In embodiments, during further administration of eratinib, serum phosphate levels may be managed according to Table 4.

The present invention relates to a method for treating cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, 9 mg of edatinib daily, particularly once daily, on a continuous basis, and When treating with 8 mg of eratinib per day, wherein when the subject has a serum phosphate level <5.5 mg / dL and does not show early onset toxicity, 9 mg is administered to the subject on a continuous basis, Specifically, once a day. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14).

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to a method for treating cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, 9 mg of edatinib daily, particularly once daily, on a continuous basis, and When treated with 8 mg eratinib per day, when the patient's serum phosphate level is <7 mg / dL or when the serum phosphate level ranges from 7 mg / dL to When 9 mg / dL includes 7 mg / dL and does not show early onset toxicity, 9 mg is administered to cancer patients on a continuous basis, specifically once daily. When serum phosphate levels range from 7mg / dL to When 9 mg / dL includes 7 mg / dL and does not show early-onset toxicity, concurrent treatment with a phosphate-binding agent such as, for example, Sevelamer can be initiated. In an embodiment, concurrent treatment with a phosphate binding agent (such as, for example, Sevelamer) is initiated. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14).

In embodiments, during further administration of eratinib, serum phosphate levels may be managed according to Table 4.

The present invention relates to the use of erdatinib in the manufacture of a medicament for treating cancer in a cancer patient, wherein the medicament comprises erdatinib in an amount of 8 mg, and wherein the drug is Daily (specifically once daily) administration, in which the serum phosphate level of cancer patients is monitored, and when the serum phosphate level is <5.5 mg / dL, daily (specifically once daily) will be given on a continuous basis The amount of eratinib in the drug increased to 9mg. When serum phosphate levels range from 5.5 mg / dL to <7 mg / dL and include 5.5 mg / dL, patients maintain continuous treatment at 8 mg daily. When serum phosphate levels At 7 mg / dL, temporarily interrupt the treatment, specifically interrupt the eratinib treatment until the serum phosphate level is again <7 mg / dL, or adjust the daily continuous dose to <8 mg, specifically temporarily interrupt the treatment, specifically Yes until serum phosphate level is <5.5 mg / dL. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14). In embodiments, when the serum phosphate level is At 7 mg / dL, the treatment was temporarily interrupted until the serum phosphate level was <5.5 mg / dL, and then ertinib treatment was restarted with 8 mg daily on a continuous basis, specifically once daily.

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to the use of erdatinib in the manufacture of a medicament for treating cancer in a cancer patient, wherein the medicament comprises erdatinib in an amount of 8 mg, and wherein the drug is Daily (specifically once daily) administration, in which the serum phosphate level of cancer patients is monitored, and when the serum phosphate level is <7 mg / dL, the daily (specifically once daily) administration will be given on a continuous basis The amount of eratinib in the drug increased to 9 mg. When serum phosphate levels range from 7mg / dL to At 9 mg / dL and including 7 mg / dL, increase the daily (specifically once daily) edatinib given to 9 mg on a continuous basis, and start with phosphate-binding agents such as Um) while treating. In an embodiment, concurrent treatment with a phosphate binding agent (such as, for example, Sevelamer) is initiated. When serum phosphate levels increase to> 9 mg / dL, treatment is temporarily discontinued, specifically ertinib treatment is discontinued until serum phosphate levels are again <7 mg / dL, and when serum phosphate levels are below 7 mg / dL At that time, the daily continuous dose is adjusted to the same or lower than the daily dose. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14). In embodiments, when the serum phosphate level is> 9 mg / dL, the treatment is temporarily interrupted until the serum phosphate level is <7 mg / dL, and then erdatinib is restarted with 8 mg daily on a continuous basis Treatment, specifically once a day.

In embodiments, during further administration of eratinib, serum phosphate levels may be managed according to Table 4.

The present invention relates to the use of erdatinib in the manufacture of a medicament for treating cancer in a cancer patient, wherein the medicament comprises erdatinib in an amount of 8 mg, and wherein the drug is Day (specifically once daily) administration, in which serum phosphate levels of cancer patients are monitored, and early onset toxicity shown by cancer patients, which is usually associated with FGFR inhibitors or specifically erdatinib, is monitored, and when When serum phosphate levels are <5.5 mg / dL and do not show early onset toxicity, the amount of edatinib in the drug administered daily (specifically once daily) is increased to 9 mg on a continuous basis. When serum phosphate levels ranged from 5.5 mg / dL to <7 mg / dL and included 5.5 mg / dL and did not show early-onset toxicity, the patient maintained continuous treatment at 8 mg daily. When serum phosphate levels At 7 mg / dL, temporarily interrupt the treatment, specifically interrupt the eratinib treatment until the serum phosphate level is again <7 mg / dL, or adjust the daily continuous dose to <8 mg, specifically temporarily interrupt the treatment, specifically Yes until serum phosphate level is <5.5 mg / dL. In an embodiment, the serum phosphate level is measured on the treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14). In embodiments, when the serum phosphate level is At 7 mg / dL, the treatment was temporarily interrupted until the serum phosphate level was <5.5 mg / dL, and then ertinib treatment was restarted with 8 mg daily on a continuous basis, specifically once daily.

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to the use of erdatinib in the manufacture of a medicament for treating cancer in a cancer patient, wherein the medicament comprises erdatinib in an amount of 8 mg, and wherein the drug is Day (specifically once daily) administration, in which serum phosphate levels of cancer patients are monitored, and early onset toxicity shown by cancer patients, which is usually associated with FGFR inhibitors or specifically erdatinib, is monitored, and when When serum phosphate levels are <7 mg / dL and do not show early onset toxicity, the amount of edatinib in the drug administered daily, specifically once daily, is increased to 9 mg on a continuous basis. When serum phosphate levels range from 7mg / dL to When 9 mg / dL includes 7 mg / dL and does not show early-onset toxicity, increase the daily (specifically once-daily) edatinib administered to 9 mg on a continuous basis, and start with phosphate-binding agents as appropriate (Eg, Sevelamer). In an embodiment, concurrent treatment with a phosphate binding agent (such as, for example, Sevelamer) is initiated. When serum phosphate levels increase to> 9 mg / dL, treatment is temporarily discontinued, specifically ertinib treatment is discontinued until serum phosphate levels are again <7 mg / dL, and when serum phosphate levels are below 7 mg / dL At that time, the daily continuous dose is adjusted to the same or lower than the daily dose. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14). In embodiments, when the serum phosphate level is> 9 mg / dL, the treatment is temporarily interrupted until the serum phosphate level is <7 mg / dL, and then erdatinib is restarted with 8 mg daily on a continuous basis Treatment, specifically once a day.

In embodiments, the serum phosphate level may be managed according to Table 4 during further ertinib administration.

The present invention relates to the use of erdatinib in the manufacture of a medicament for the treatment of cancer in cancer patients, wherein the medicament comprises a certain amount of erdatinib at 9 mg, and wherein the drug Administered daily (specifically once daily), and when treated with 8 mg of eratinib per day, when the patient's serum phosphate level was <5.5 mg / dL, the drug was administered on a continuous basis It is given to cancer patients, specifically once a day. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14).

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to the use of erdatinib in the manufacture of a medicament for the treatment of cancer in cancer patients, wherein the medicament comprises a certain amount of eratinib at 9 mg, and wherein the medicament is on a continuous basis Given daily (specifically once daily), and when treated with 8 mg eratinib per day, when the patient's serum phosphate level is <7 mg / dL or when the serum phosphate level ranges from 7 mg / dL to At 9 mg / dL and including 7 mg / dL, the drug is administered to cancer patients on a continuous basis, specifically once daily. When serum phosphate levels range from 7mg / dL to At 9 mg / dL and including 7 mg / dL, simultaneous treatment with a phosphate binding agent such as, for example, Sevelamer can be initiated. In an embodiment, concurrent treatment with a phosphate binding agent (such as, for example, Sevelamer) is initiated. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14).

In embodiments, during further administration of eratinib, serum phosphate levels may be managed according to Table 4.

The present invention relates to the use of erdatinib in the manufacture of a medicament for the treatment of cancer in cancer patients, wherein the medicament comprises a certain amount of eratinib at 9 mg, and wherein the medicament is on a continuous basis Given daily (specifically once daily), and when treated with 8 mg daily eratinib, when the patient's serum phosphate level was <5.5 mg / dL and did not show early onset toxicity, The drug is administered to cancer patients on a daily basis. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14).

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to the use of erdatinib in the manufacture of a medicament for the treatment of cancer in cancer patients, wherein the medicament comprises a certain amount of eratinib at 9 mg, and wherein the medicament is on a continuous basis Given daily (specifically once daily), and when treated with 8 mg eratinib per day, when the patient's serum phosphate level is <7 mg / dL or when the serum phosphate level ranges from 7 mg / dL to When 9 mg / dL includes 7 mg / dL and does not show early onset toxicity, the drug is administered to cancer patients on a continuous basis, specifically once daily. When serum phosphate levels range from 7mg / dL to When 9 mg / dL includes 7 mg / dL and does not show early-onset toxicity, concurrent treatment with a phosphate-binding agent such as, for example, Sevelamer can be initiated. In an embodiment, concurrent treatment with a phosphate binding agent (such as, for example, Sevelamer) is initiated. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14).

In embodiments, during further administration of eratinib, serum phosphate levels may be managed according to Table 4.

The present invention relates to the use of erdatinib for the treatment of cancer in cancer patients, wherein erdatinib is administered in an amount of 8 mg per day on a continuous basis, specifically once daily, in which serum in cancer patients is monitored Phosphate levels, and when serum phosphate levels are <5.5 mg / dL, the amount of edatinib administered daily (preferably once daily) is increased to 9 mg on a continuous basis. When serum phosphate levels range from 5.5 mg / dL to <7 mg / dL and include 5.5 mg / dL, patients maintain continuous treatment at 8 mg daily. When serum phosphate levels At 7 mg / dL, temporarily interrupt the treatment, specifically interrupt the eratinib treatment until the serum phosphate level is again <7 mg / dL, or adjust the daily continuous dose to <8 mg, specifically temporarily interrupt the treatment, specifically Yes until serum phosphate level is <5.5 mg / dL. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14). In embodiments, when the serum phosphate level is At 7 mg / dL, the treatment was temporarily interrupted until the serum phosphate level was <5.5 mg / dL, and then ertinib treatment was restarted with 8 mg daily on a continuous basis, specifically once daily.

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to the use of erdatinib for the treatment of cancer in cancer patients, wherein erdatinib is administered in an amount of 8 mg per day on a continuous basis, specifically once daily, in which serum in cancer patients is monitored Phosphate levels, and when serum phosphate levels are <7mg / dL or when serum phosphate levels range from 7mg / dL to At 9 mg / dL and including 7 mg / dL, the amount of edatinib administered daily (preferably once daily) is increased to 9 mg on a continuous basis. When serum phosphate levels range from 7mg / dL to At 9 mg / dL and including 7 mg / dL, simultaneous treatment with a phosphate binding agent such as, for example, Sevelamer can be initiated. In an embodiment, concurrent treatment with a phosphate binding agent (such as, for example, Sevelamer) is initiated. When serum phosphate levels increase to> 9 mg / dL, treatment is temporarily discontinued, specifically ertinib treatment is discontinued until serum phosphate levels are again <7 mg / dL, and when serum phosphate levels are below 7 mg / dL At that time, the daily continuous dose is adjusted to the same or lower than the daily dose. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14). In embodiments, when the serum phosphate level is> 9 mg / dL, the treatment is temporarily interrupted until the serum phosphate level is <7 mg / dL, and then erdatinib is restarted with 8 mg daily on a continuous basis Treatment, specifically once a day.

In embodiments, during further administration of eratinib, serum phosphate levels may be managed according to Table 4.

The present invention relates to the use of erdatinib for the treatment of cancer in cancer patients, wherein erdatinib is administered in an amount of 8 mg per day on a continuous basis, specifically once daily, wherein the serum in cancer patients is monitored Phosphate levels, and monitor early-onset toxicity typically associated with FGFR inhibitors or specifically erdatinib as shown by cancer patients, and when serum phosphate levels are <5.5 mg / dL and no early-onset toxicity is shown The amount of eratinib administered daily (preferably once daily) was increased to 9 mg on a continuous basis. When serum phosphate levels ranged from 5.5 mg / dL to <7 mg / dL and included 5.5 mg / dL and did not show early-onset toxicity, the patient maintained continuous treatment at 8 mg daily. When serum phosphate levels At 7 mg / dL, temporarily interrupt the treatment, specifically interrupt the eratinib treatment until the serum phosphate level is again <7 mg / dL, or adjust the daily continuous dose to <8 mg, specifically temporarily interrupt the treatment, specifically Yes until serum phosphate level is <5.5 mg / dL. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14). In embodiments, when the serum phosphate level is At 7 mg / dL, the treatment was temporarily interrupted until the serum phosphate level was <5.5 mg / dL, and then ertinib treatment was restarted with 8 mg daily on a continuous basis, specifically once daily.

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to the use of erdatinib for the treatment of cancer in cancer patients, wherein erdatinib is administered in an amount of 8 mg per day on a continuous basis, specifically once daily, wherein the serum in cancer patients is monitored Phosphate levels, and monitor early-onset toxicity typically associated with FGFR inhibitors or specifically erdatinib, as shown by cancer patients, and when serum phosphate levels are <7mg / dL or when serum phosphate levels Range from 7mg / dL to At 9 mg / dL and including 7 mg / dL, the amount of edatinib administered daily (preferably once daily) is increased to 9 mg on a continuous basis. When serum phosphate levels range from 7mg / dL to At 9 mg / dL and including 7 mg / dL, simultaneous treatment with a phosphate binding agent such as, for example, Sevelamer can be initiated. In an embodiment, concurrent treatment with a phosphate binding agent (such as, for example, Sevelamer) is initiated. When serum phosphate levels increase to> 9 mg / dL, treatment is temporarily discontinued, specifically ertinib treatment is discontinued until serum phosphate levels are again <7 mg / dL, and when serum phosphate levels are below 7 mg / dL At that time, the daily continuous dose is adjusted to the same or lower than the daily dose. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14). In embodiments, when the serum phosphate level is> 9 mg / dL, the treatment is temporarily interrupted until the serum phosphate level is <7 mg / dL, and then erdatinib is restarted with 8 mg daily on a continuous basis Treatment, specifically once a day.

In embodiments, during further administration of eratinib, serum phosphate levels may be managed according to Table 4.

The present invention relates to the use of erdatinib for the treatment of cancer in cancer patients, wherein erdatinib is given on a continuous basis in a certain amount of 9 mg per day, specifically once a day, when the patient's Serum phosphate levels were <5.5 mg / dL, and were treated with 8 mg eratinib per day on a continuous basis, specifically once daily. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14).

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to the use of erdatinib for the treatment of cancer in cancer patients, wherein erdatinib is given on a continuous basis in a certain amount of 9 mg per day, specifically once a day, when the patient's Serum phosphate levels are <7mg / dL or when serum phosphate levels range from 7mg / dL to At 9 mg / dL and including 7 mg / dL, it is treated with 8 mg of eratinib per day on a continuous basis, specifically once daily. When serum phosphate levels range from 7mg / dL to At 9 mg / dL and including 7 mg / dL, simultaneous treatment with a phosphate binding agent such as, for example, Sevelamer can be initiated. In an embodiment, concurrent treatment with a phosphate binding agent (such as, for example, Sevelamer) is initiated. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14).

In embodiments, during further administration of eratinib, serum phosphate levels may be managed according to Table 4.

The present invention relates to the use of erdatinib for the treatment of cancer in cancer patients, wherein erdatinib is given on a continuous basis in a certain amount of 9 mg per day, specifically once a day, when the patient's When serum phosphate levels were <5.5 mg / dL and did not show early-onset toxicity, they were treated with 8 mg of eratinib per day on a continuous basis, specifically once daily. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14).

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to the use of erdatinib for the treatment of cancer in cancer patients, wherein erdatinib is given on a continuous basis in a certain amount of 9 mg per day, specifically once a day, when the patient's Serum phosphate levels are <7mg / dL or when serum phosphate levels range from 7mg / dL to When 9 mg / dL and included 7 mg / dL and did not show early onset toxicity, treatment was performed with 8 mg of eratinib per day on a continuous basis, specifically once daily. When serum phosphate levels range from 7mg / dL to When 9 mg / dL includes 7 mg / dL and does not show early-onset toxicity, concurrent treatment with a phosphate-binding agent such as, for example, Sevelamer can be initiated. In an embodiment, concurrent treatment with a phosphate binding agent (such as, for example, Sevelamer) is initiated. In an embodiment, the serum phosphate level is measured on a treatment day during the first cycle of eratinib treatment (specifically day 14 ± 2 of eratinib administration, more specifically day 14).

In embodiments, during further administration of eratinib, serum phosphate levels may be managed according to Table 4.

In an embodiment of the invention, when the plasma concentration of eratinib and the steady state level of serum phosphate are reached, the serum phosphate level is assessed (to determine whether the amount of eratinib can be increased from 8 mg per day to daily 9mg).

In an embodiment of the present invention, the treatment day within the first cycle of eratinib treatment, specifically about 14 days ± 2 days of eratinib treatment, and specifically on the 14th day of eratinib treatment On day 14 (day 14 of cycle 1 of eratinib treatment), serum phosphate levels were assessed to determine if the amount of eratinib could be increased from 8 mg per day to 9 mg per day. In an embodiment, the cycle is 21 days. In an embodiment, the cycle is 28 days.

The daily amount of eratinib as described herein can be administered via one pharmaceutical composition or via more than one pharmaceutical composition. A medicament as mentioned herein may comprise one pharmaceutical composition or more than one pharmaceutical composition. In an embodiment, an 8-mg dose of eratinib can be administered as 2 formulations, specifically 2 tablets, each containing 4 mg of eratinib. In an embodiment, a 9 mg dose of eratinib can be administered as 3 formulations, specifically 3 tablets, each containing 3 mg of eratinib.

The present invention relates to a method for treating cancer, which method comprises a) administering 8 mg of edatinib to a subject in need thereof, in particular a cancer patient, on a continuous basis, specifically once daily. B) measurement of the subject's serum phosphate level on the treatment day during the first cycle of ertintinib treatment, specifically on day 14 ± 2 days after ertintinib administration, and more specifically on erdatinib administration Day 14 of cinitin; c-1) When the serum phosphate level is <5.5mg / dL, ertinib is given in a certain amount of 9mg daily on a continuous basis, specifically once daily; c- 2) When serum phosphate levels range from 5.5 mg / dL to <7 mg / dL and include 5.5 mg / dL, further erdatinib is given in an amount of 8 mg daily (specifically once daily) on a continuous basis C-3) When the serum phosphate level is At 7 mg / dL, ertintinib treatment was temporarily interrupted until the serum phosphate level was <5.5 mg / dL, and then eratinib treatment was restarted at 8 mg daily on a continuous basis, specifically once daily .

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to a method for treating cancer, which method comprises a) administering 8 mg of edatinib to a subject in need thereof, in particular a cancer patient, on a continuous basis, specifically once daily. B) measurement of the subject's serum phosphate level on the treatment day during the first cycle of ertintinib treatment, specifically on day 14 ± 2 days after ertintinib administration, and more specifically on erdatinib administration Day 14 of Tinib; c-1) when serum phosphate level is <7mg / dL or when serum phosphate level ranges from 7mg / dL to At 9 mg / dL and including 7 mg / dL, erdatinib is given on a continuous basis at a certain amount of 9 mg daily, specifically once daily; and when serum phosphate levels range from 7 mg / dL to At 9 mg / dL and including 7 mg / dL, simultaneous treatment with phosphate binding agents (such as Sevelamer) can be initiated; c-2) When serum phosphate levels are> 9 mg / dL, erdatinib Treatment was temporarily discontinued until the serum phosphate level was <7 mg / dL, and then eratinib treatment was restarted with 8 mg daily on a continuous basis, specifically once daily.

In embodiments, during further administration of eratinib, serum phosphate levels may be managed according to Table 4.

The present invention relates to a method for treating cancer, which method comprises a) administering 8 mg of edatinib to a subject in need thereof, in particular a cancer patient, on a continuous basis, specifically once daily. B) measuring the subject's serum phosphate level on the treatment day during the first cycle of ertintinib treatment, specifically on day 14 ± 2 days of ertinib administration, and more specifically on erdatinib administration Day 14 of catinib; c-1) When the serum phosphate level is <5.5mg / dL and does not show early onset toxicity, ertinib is given in a certain amount of 9mg daily on a continuous basis, specifically Once daily; c-2) When serum phosphate levels range from 5.5 mg / dL to <7 mg / dL and include 5.5 mg / dL and do not show early onset toxicity, further amounts of 8 mg per day on a continuous basis Give eratinib, specifically once daily; c-3) when serum phosphate levels are When 7 mg / dL does not show early onset toxicity, ertintinib treatment is temporarily discontinued until the serum phosphate level is <5.5 mg / dL, and then eratinib treatment is restarted with 8 mg daily on a continuous basis , Specifically once a day.

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to a method for treating cancer, which method comprises a) administering 8 mg of edatinib to a subject in need thereof, in particular a cancer patient, on a continuous basis, specifically once daily. B) measurement of the subject's serum phosphate level on the treatment day during the first cycle of ertintinib treatment, specifically on day 14 ± 2 days after ertintinib administration, and more specifically on erdatinib administration Day 14 of tinib; c-1) when serum phosphate levels are <7 mg / dL and no early onset toxicity is shown, or when serum phosphate levels range from 7 mg / dL to When 9 mg / dL includes 7 mg / dL and does not show early-onset toxicity, eratinib is given on a continuous basis at a daily amount of 9 mg, specifically once daily; and when serum phosphate levels range from 7 mg / dL to At 9 mg / dL and including 7 mg / dL, simultaneous treatment with phosphate binding agents (such as Sevelamer) can be initiated; c-2) When serum phosphate levels are> 9 mg / dL and no early onset toxicity is shown The ertintinib treatment was temporarily interrupted until the serum phosphate level was <7 mg / dL, and then the ertintinib treatment was restarted with 8 mg daily on a continuous basis, specifically once daily.

In embodiments, during further administration of eratinib, serum phosphate levels may be managed according to Table 4.

The present invention relates to the use of erdatinib in the manufacture of a medicament for treating cancer in a cancer patient, wherein a) the medicament comprises erdatinib in an amount of 8 mg, and wherein daily on a continuous basis Administer the drug, specifically once daily; b) measure the patient's serum phosphate level on the treatment day during the first cycle of eratinib treatment, specifically on the 14th day ± 2 days of erlotinib, more Specifically on day 14; c-1) When the serum phosphate level is <5.5 mg / dL, increase the amount of edatinib in the drug used for daily administration to 9 mg on a continuous basis, specifically Once daily; c-2) when the serum phosphate level ranges from 5.5mg / dL to <7mg / dL and includes 5.5mg / dL, the patient maintains continuous treatment at 8mg (specifically once daily); c-3 When serum phosphate levels are At 7 mg / dL, ertintinib treatment was temporarily interrupted until the serum phosphate level was <5.5 mg / dL, and then eratinib treatment was restarted at 8 mg daily on a continuous basis, specifically once daily .

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to the use of erdatinib in the manufacture of a medicament for the treatment of cancer in cancer patients, wherein a) the medicament comprises erdatinib in an amount of 8 mg, and wherein daily on a continuous basis Administer the drug, specifically once daily; b) measure the patient's serum phosphate level on the treatment day during the first cycle of eratinib treatment, specifically on the 14th day ± 2 days of erlotinib, more Specifically on day 14; c-1) when serum phosphate levels are <7mg / dL or when serum phosphate levels range from 7mg / dL to At 9 mg / dL and including 7 mg / dL, increase the amount of eratinib in the drug used for daily administration (specifically once daily) to 9 mg on a continuous basis; and when the serum phosphate level ranges from 7mg / dL to At 9 mg / dL and including 7 mg / dL, simultaneous treatment with phosphate binding agents (such as Sevelamer) can be initiated; c-2) When serum phosphate levels are> 9 mg / dL, erdatinib Treatment was temporarily discontinued until the serum phosphate level was <7 mg / dL, and then eratinib treatment was restarted with 8 mg daily on a continuous basis, specifically once daily.

In embodiments, during further administration of eratinib, serum phosphate levels may be managed according to Table 4.

The present invention relates to the use of erdatinib in the manufacture of a medicament for the treatment of cancer in cancer patients, wherein a) the medicament comprises erdatinib in an amount of 8 mg, and wherein daily on a continuous basis Administer the drug, specifically once daily; b) measure the patient's serum phosphate level on the treatment day during the first cycle of eratinib treatment, specifically on the 14th day ± 2 days of erlotinib, more Specifically on day 14; c-1) the amount of eratinib in the drug to be used for daily administration on a continuous basis when the serum phosphate level is <5.5 mg / dL and does not show early onset toxicity Increased to 9 mg, specifically once daily; c-2) the patient maintained daily when serum phosphate levels ranged from 5.5 mg / dL to <7 mg / dL and included 5.5 mg / dL and did not show early onset toxicity 8mg (specifically once daily) continuous treatment; c-3) when serum phosphate levels are When 7 mg / dL does not show early onset toxicity, ertintinib treatment is temporarily discontinued until the serum phosphate level is <5.5 mg / dL, and then eratinib treatment is restarted with 8 mg daily on a continuous basis , Specifically once a day.

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to the use of erdatinib in the manufacture of a medicament for the treatment of cancer in cancer patients, wherein a) the medicament comprises erdatinib in an amount of 8 mg, and wherein daily on a continuous basis Administer the drug, specifically once daily; b) measure the patient's serum phosphate level on the treatment day during the first cycle of eratinib treatment, specifically on the 14th day ± 2 days of eratinib, More specifically on day 14; c-1) when serum phosphate levels are <7 mg / dL and do not show early onset toxicity, or when serum phosphate levels range from 7 mg / dL to 9 mg / dL and including 7 mg / dL without showing early-onset toxicity, increase the amount of edatinib in the drug used for daily administration (specifically once daily) to 9 mg on a continuous basis; and when Serum phosphate levels range from 7mg / dL to At 9 mg / dL and including 7 mg / dL, simultaneous treatment with phosphate binding agents (such as Sevelamer) can be initiated; c-2) When serum phosphate levels are> 9 mg / dL and no early onset toxicity is shown The ertintinib treatment was temporarily interrupted until the serum phosphate level was <7 mg / dL, and then the ertintinib treatment was restarted with 8 mg daily on a continuous basis, specifically once daily.

In embodiments, during further administration of eratinib, serum phosphate levels may be managed according to Table 4.

The present invention relates to the use of erdatinib for the treatment of cancer in cancer patients, wherein a) erdatinib is administered in an amount of 8 mg per day on a continuous basis, specifically once daily; b) in erda Patients ’serum phosphate levels were measured during the first day of treatment with tenitin, specifically on the 14th day ± 2 days of ertinib, and more specifically on the 14th day; c-1) when serum phosphate levels When the dosage is <5.5mg / dL, erdatinib is given in a certain amount of 9mg daily on a continuous basis, specifically once daily; c-2) When the serum phosphate level ranges from 5.5mg / dL to <7mg / dL and including 5.5mg / dL, further erdatinib is given in an amount of 8mg per day (specifically once daily) on a continuous basis; c-3) when the serum phosphate level is At 7 mg / dL, ertintinib treatment was temporarily interrupted until the serum phosphate level was <5.5 mg / dL, and then eratinib treatment was restarted at 8 mg daily on a continuous basis, specifically once daily .

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to the use of erdatinib for the treatment of cancer in cancer patients, wherein a) erdatinib is administered in an amount of 8 mg per day on a continuous basis, specifically once a day; b) in erda Patients ’serum phosphate levels were measured during the first day of treatment with tenitin, specifically on the 14th day ± 2 days of ertinib, and more specifically on the 14th day; c-1) when serum phosphate levels At <7mg / dL or when serum phosphate levels range from 7mg / dL to At 9 mg / dL and including 7 mg / dL, erdatinib is given on a continuous basis at a certain amount of 9 mg daily, specifically once daily; and when serum phosphate levels range from 7 mg / dL to At 9 mg / dL and including 7 mg / dL, simultaneous treatment with phosphate binding agents (such as Sevelamer) can be initiated; c-2) When serum phosphate levels are> 9 mg / dL, erdatinib Treatment was temporarily discontinued until the serum phosphate level was <7 mg / dL, and then eratinib treatment was restarted with 8 mg daily on a continuous basis, specifically once daily.

In embodiments, during further administration of eratinib, serum phosphate levels may be managed according to Table 4.

The present invention relates to the use of erdatinib for the treatment of cancer in cancer patients, wherein a) erdatinib is administered in an amount of 8 mg per day on a continuous basis, specifically once a day; b) in erda Patients ’serum phosphate levels were measured during the first day of treatment with tenitin, specifically on the 14th day ± 2 days of ertinib, and more specifically on the 14th day; c-1) when serum phosphate levels When it is <5.5mg / dL and does not show early onset toxicity, erdatinib is given in a certain amount of 9mg daily on a continuous basis, specifically once daily; c-2) when the serum phosphate level ranges from 5.5 mg / dL to <7 mg / dL and including 5.5 mg / dL without showing early onset toxicity, further erdatinib is given in an amount of 8 mg per day on a continuous basis, specifically once daily; c-3) When serum phosphate levels When 7 mg / dL does not show early onset toxicity, ertintinib treatment is temporarily discontinued until the serum phosphate level is <5.5 mg / dL, and then eratinib treatment is restarted with 8 mg daily on a continuous basis , Specifically once a day.

In embodiments, during further administration of eratinib, serum phosphate levels can be managed according to Table 3.

The present invention relates to the use of erdatinib for the treatment of cancer in cancer patients, wherein a) erdatinib is administered in an amount of 8 mg per day on a continuous basis, specifically once a day; b) in erda The serum phosphate level of the patient was measured during the first day of treatment with titinib, specifically on the 14th day ± 2 days, and more specifically on the 14th day of ertinib; c-1) when the serum phosphate level Is <7mg / dL and does not show early onset toxicity, or when serum phosphate levels range from 7mg / dL to When 9 mg / dL includes 7 mg / dL and does not show early-onset toxicity, eratinib is given on a continuous basis at a daily amount of 9 mg, specifically once daily; and when serum phosphate levels range from 7 mg / dL to At 9 mg / dL and including 7 mg / dL, simultaneous treatment with phosphate binding agents (such as Sevelamer) can be initiated; c-2) When serum phosphate levels are> 9 mg / dL and no early onset toxicity is shown The ertintinib treatment was temporarily interrupted until the serum phosphate level was <7 mg / dL, and then the ertintinib treatment was restarted with 8 mg daily on a continuous basis, specifically once daily.

In embodiments, during further administration of eratinib, serum phosphate levels may be managed according to Table 4.

It should be understood that the treatment methods and uses as described herein are based on phosphate levels as a marker of pharmacodynamics, but can be modified or terminated based on toxicity. In embodiments, the treatment or use is modified or terminated as described in Table 1.

If ertintinib is discontinued, specifically due to drug-related toxicity, for a continuous period of one week or longer, it can be reintroduced at the same dose level or the first reduced dose level after recovery from toxicity. In embodiments, the eratinib dose reduction levels are as described in Table 2. The second dose reduction can be implemented after the second occurrence of drug-related toxicity, as described in Table 2.

It should be understood that if treatment or dosing with eratinib is discontinued, for example if eratinib must be discontinued for more than 28 days before a drug-related adverse event can occur, and the drug-related adverse event cannot reach an acceptable level ( Grade 1 or return to the baseline for non-hematological toxicity), the physician decides to continue treatment when the patient benefits from the treatment, and the physician can prove that it is in the patient's best interest to continue treatment with eratinib. If the dose of eratinib is reduced and the adverse events (the reason for this reduction in dose) have been completely eliminated, then if the patient benefits from treatment, the dose can be raised to a higher level and the physician can prove that It is in the patient's best interest to increase the dose of datinib.

It should be understood that patients with any degree of toxicity (Grade 1 to 4) should provide symptomatic treatment where applicable.

In embodiments, if treatment with eratinib is discontinued as described herein, and serum phosphate levels are monitored until they return to the specified level, an assessment of serum phosphate is performed at least weekly.

In an embodiment, if treatment with utatinib is discontinued as described herein for hyperphosphatemia, the discontinuation time is about 7 days, specifically 7 days.

It should be understood that when the serum phosphate level is measured as a drug marker to determine an 8 mg starting dose of up-regulated edatinib, specifically on the treatment day (specifically in Measured on day 14 ± 2, more specifically on day 14) of datinib administration, phosphate levels can be monitored during ertinib treatment. In embodiments, clinical management of serum phosphate levels is performed as described in Table 3.

In embodiments, clinical management of serum phosphate levels is performed as described in Table 4.

It should be understood that for the management of increased phosphate, it may be desirable to limit daily phosphate intake.

It should be understood that in order to manage elevated phosphate, patients may have to take it concurrently with a phosphate binding agent such as, for example, sevelamer phosphate.

The tumor response assessments reported herein were performed according to the solid tumor response assessment criteria (RECIST) version 1.1.

The invention also relates to a package containing an eratinib preparation and written information (eg, a patient brochure, a dosing regimen as described herein).

In an embodiment, the cancer referred to herein is a cancer mediated by FGFR kinase.

In an embodiment, the cancer is bladder cancer.

In an embodiment, the cancer is hepatocellular carcinoma.

In an embodiment, the cancer is squamous cell carcinoma.

In an embodiment, the cancer is squamous NSCLC (non-small cell lung cancer), specifically, squamous NSCLC (non-small cell lung cancer) with genetic alterations in selective FGFR. ), Specifically treating cancer in patients with squamous NSCLC (non-small cell lung cancer) with genetic alterations in selective FGFR (after relapse to standard of care therapy).

In an embodiment, the cancer is hepatocellular carcinoma with FGF19 amplification or overexpression.

In an embodiment, the cancer is cholangiocarcinoma, specifically advanced or metastatic cholangiocarcinoma.

In an embodiment, the cancer is urothelial cancer.

In an embodiment, the cancer is metastatic or surgically unresectable urothelial carcinoma.

In an embodiment, the cancer is advanced urothelial cancer with a selected FGFR gene change, and specifically the cancer is treated in a patient with advanced urothelial cancer with a selected FGFR gene change in a prior treatment Or make progress afterwards.

In an embodiment, the cancer is lung cancer, specifically non-small cell lung cancer.

In an embodiment, the cancer is selected from adenoid cystic carcinoma, mucoepidermoid carcinoma, follicular thyroid cancer, breast cancer, Ewing's sarcoma, small round cell bone tumor, synovial sarcoma, and pleomorphic glioblastoma Tumor, fibrous astrocytoma, lung cancer, clear cell renal cell cancer, bladder cancer, prostate cancer, ovarian cancer, colorectal cancer.

In an embodiment, the cancer is a multiple myeloma, specifically a t (4; 14) translocation-positive multiple myeloma.

In an embodiment, the cancer is a non-muscle invasive bladder cancer, specifically a non-muscle invasive bladder cancer with genetic changes (eg, translocation, fusion, and / or mutation) in FGFR.

In an embodiment, the cancer is esophageal cancer or head and neck cancer.

In an embodiment, the cancer is gastric cancer.

In an embodiment, the cancer lines referred to herein are cancers with genetic alterations (eg, translocations, fusions, and / or mutations) in FGFR, and specifically against Erda having genetic alterations (eg, translocations, fusions, and / or mutations) in FGFR. Teni-sensitive cancers, such as bladder cancer with genetic changes in FGFR (e.g., translocation, fusion, and / or mutation), or urothelial cancers with genetic changes in FGFR (e.g., translocation, fusion, and / or mutation), or having Metastatic or surgically unresectable urothelial carcinoma with genetic changes in FGFR (e.g., translocation, fusion, and / or mutation), or bile duct cancer with genetic changes in FGFR (e.g., translocation, fusion, and / or mutation), or inheritance of FGFR Altered (eg, translocation, fusion, and / or mutation) advanced or metastatic cholangiocarcinoma.

In an embodiment, the cancer line referred to herein has a cancer selected from the following: fusion FGFR3: TACC3 v1; FGFR3: TACC3 v3; FGFR3: TACC3 intron; FGFR3: BAIAP2L1; FGFR2: AFF3; FGFR2: BICC1; FGFR2: CASP7; FGFR2: CCDC6 and FGFR2: OFD1.

In embodiments, the cancers referred to herein are cancers with FGFR3-TACC3 fusion or translocation, such as bladder cancer with FGFR3-TACC3 translocation, or urothelial cancer with FGFR3-TACC3 translocation, or FGFR3- TACC3 translocation for metastatic or surgically unresectable urothelial carcinoma.

In an embodiment, the cancer line referred to herein has an altered cancer of the FGFR3 gene mutation selected from the group consisting of: FGFR3 R248C, FGFR3S249C, FGFR3 G370C, FGFR3 Y373C.

In an embodiment, the cancers referred to herein are bladder cancer or urothelial cancer or metastatic or surgically unresectable urothelial cancer with at least one of the following FGFR3 gene mutations: FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, FGFR3 Y373C.

In embodiments, a method or use for treating cancer in a subject in need thereof, particularly a cancer patient, as mentioned herein, is the treatment of a patient with metastatic or surgically unresectable urothelial cancer or Use, the patient's tumor has a selected genetic change in FGFR, the patient fails during or after at least one line of previous systemic chemotherapy, or fails within 12 months of neoadjuvant chemotherapy or adjuvant chemotherapy, or without chemotherapy but not applicable Yu cisplatin.

The use or method of treating cancer as described herein in a subject in need thereof, particularly a cancer patient, is for or treating a patient with luminal cluster I subtype urothelial cancer.

In an embodiment, eratinib is administered as a pharmaceutically acceptable salt.

In a preferred embodiment, eratinib (base) is administered.

In an embodiment, eratinib is administered as a pharmaceutically acceptable salt in an amount equivalent to 8 mg base equivalent or 9 mg base equivalent.

The salt can be prepared, for example, by reacting erdatinib with a suitable acid in a suitable solvent.

Acid addition salts can be formed with acids (both inorganic and organic acids). Examples of acid addition salts include formation with an acid selected from the group consisting of acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, Malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulphonic acid (mesylate), ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propionic acid, butyric acid, propane Diacid, glucuronic acid and lactobionic acid. Another group of acid addition salts includes salts formed from: acetic 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, methanesulfonic acid, sebacic acid, stearic acid, succinic acid, and tartaric acid.

In an embodiment, eratinib is administered as a solvate. As used herein, the term "solvate" refers to the physical association of erdatinib with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate will be able to be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The term "solvate" is intended to include both the solution phase and the separable solvate. Non-limiting examples of solvents that can form a solvate include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine, and the like.

Solvates are well known in medicinal chemistry. They are important for the process of preparing the substance, such as with regard to their purification, storage of the substance (such as its stability), and ease of handling of the substance, and often form part of the isolation or purification of the various stages of chemical synthesis. Those skilled in the art can use standard and long-term techniques to determine whether hydrates or other solvates are formed by the isolation or purification conditions used to prepare a given compound. Examples of such technologies include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (such as single crystal X-ray diffraction technology or X-ray powder diffraction), and solid state NMR (SS-NMR, (Also called Magic Angle Rotation NMR or MAS-NMR). There are as many such techniques as standard analytical kits for professional chemists such as NMR, IR, HPLC, and MS. Alternatively, the skilled person can intentionally form a solvate using crystallization conditions that include a certain amount of solvent required for a particular solvate. Thereafter, the standard methods described above can be used to determine whether a solvate is formed. Also encompassed are any complexes (eg, inclusion complexes or inclusion complexes with compounds such as cyclodextrin or complexes with metals).

In embodiments, a treatment cycle as used herein is a 28-day cycle.

In an embodiment, a patient in need of eratinib treatment, particularly a cancer patient, or a subject as described herein is a human.

The term "about" as used herein in connection with a numerical value is intended to have its ordinary meaning in the context of a numerical value. When necessary, the word "about" may be replaced by a value of ± 10%, or ± 5%, or ± 2%, or ± 1%.

All documents cited herein are incorporated by reference in their entirety.

    [Example]    

Ongoing Phase 2, Multicenter, Open Label Study (NCT02365597)

A phase 2 multicenter open-label study is underway to evaluate erdatinib in subjects with metastatic or surgically unresectable urothelial carcinoma with selective FGFR gene alterations (FGFR translocations or mutations) Efficacy and safety.

The study included a screening phase (first dose within 30 days before the first dose and molecular screening at any time before the research screening), a treatment phase, and a follow-up phase. The treatment phase includes the period from the first dose to the end of the treatment visit. The follow-up phase will be extended until subject death, withdrawal of consent, loss of follow-up, or end of study, whichever comes first.

The study treatment was performed over a 28-day cycle. Prior to Interim Analysis 1, there were 2 treatment options. Patients were randomly assigned to the following 2 protocols in a period of 1: 1 to 28 days until the protocol for further research was selected: Protocol 1 (10 mg, once daily, intermittent (7 days on / 7 days on / 7days)); Scheme 2 (6mg, once daily, continuous). After performing Interim Analysis 1 and based on results from pharmacokinetic and pharmacodynamic models linking the eratinib dose regimen to serum phosphate levels The protocol was modified to increase the starting dose to 8 mg / day for continuous administration (Scheme 3). On day 14, patients who did not reach the target serum phosphate level at this time point (patient serum phosphate level <5.5 mg / dL) and increased to 9 mg / day in patients in which no treatment-related adverse event was observed. A dose reduction based on observed toxicity (treatment-related adverse event (TRAE)) was foreseen in the protocol.

The phase 2 research plan is shown in Figure 1.

patient

Included patients were adults with measurable urothelial cancer that were measurable according to the response assessment criteria in solid tumor version 1.1.

Using custom assays, patients require at least 1 FGFR2 / FGFR3 mutation or fusion, and each central laboratory detects RNA from formalin-fixed paraffin-embedded tumor samples.

Patients have progressed before or after neoadjuvant chemotherapy or adjuvant chemotherapy for at least 1 line of systemic chemotherapy for less than 12 months.

Non-chemotherapy patients who are not eligible for cisplatin based on protocol criteria are allowed. Non-compliance with cisplatin is based on impaired renal function and is defined as: 1) glomerular filtration rate <60mL / min / 1.73m ² by 24 hour urine measurement; 2) calculated by Cockcroft-Gault; or 3) level 2 Peripheral neuropathy or higher (Common Terminology Adverse Event Standard [CTCAE] Version 4.0 (National Cancer Institute CTCAE v4.0. NCI, NIH, DHHS. May 29, 2009. NIH Public # 09-7473: 2009).

The Eastern Cooperative Oncology Group (ECOG) is required to have a behavioral status of 0-2.

There is no limit to the number of previous line treatments.

Allow previous immunotherapy (eg, treatment with PD-L1 / PD-1 inhibitors).

Patients need adequate bone marrow, liver and kidneys (creatinine clearance 40mL / min) function.

Despite medical management, uncontrolled cardiovascular disease, brain metastases, known hepatitis B or C, or known HIV, patients with persistently higher phosphate levels than the upper limit of normal are excluded.

end

The primary endpoint of this ongoing study was the objective response rate of the chosen protocol (Scheme 3).

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

Evaluation

Assessed using radiographic imaging performed within 30 days of screening, every 6 weeks in the first 3 months, every 12 weeks in the next 9 months, and then every 4 to 6 months until disease progression The efficacy of the patient.

Tumor response was evaluated by researchers according to RECIST version 1.1 (Eisenhauer EA et al., Eur J Cancer [European Journal of Cancer], 2009, 45 (2), 228-247).

Safety is continuously evaluated by the investigator and is based on the results of medical assessments and vital signs measurements, physical examinations, clinical laboratory tests, ECOG behavioral status, and other safety assessments reported by the AE.

result

For 170 patients enrolled between May 7, 2015 and June 10, 2017, baseline characteristics and efficacy data were provided, and evaluable efficacy was considered based on RECIST 1.1 (Table 5).

Provide safety data for safe populations (N = 207, May 7, 2015 to December 5, 2017), defined as patients who received at least 1 dose of study treatment. As of December 5, 2017, the median duration of treatment was 4.2 months, and patients had received a median of 5 cycles of eratinib.

During the screening phase, 21% of patients met the inclusion criteria for FGFR mutations or fusions.

Throughout the dosage regimen, 89% of patients progressed after at least 1 line of previous systemic chemotherapy.

In all dosage regimens, the determined objective response rate was 35% (95% CI, 28% -43%), with the highest rate among patients treated with 8 mg / d continuous eratinib in protocol 3 (Table 6 ). The confirmed disease control rate was 76% for all patients. Most patients treated with 8 mg / d continuous eratinib reduced tumor burden (44/59 [75%] with a reduction in the total target lesion diameter; Figure 2).

The median progression-free survival was 5.1 months, and was the longest among patients treated with 8 mg / d of continuous erdatinib in protocol 3 (Table 6).

The median response duration for the 8 mg / d continuous eratinib group (Scheme 3) was 5.4 months, and many responses continued (Table 6).

Response time

The median response time for the 59 patient subgroup in protocol 3 was 1.41 months, with a range of 1.1 to 5.5 months.

In all dosage regimens, 94% (n = 195) of patients reported TRAE; most of these were grades 1 or 2 (Table 7).

33% (n = 69) of patients reported grade 3 TRAE, 0.5% (n = 1) of patients reported grade 4 TRAE, and there were no treatment-related deaths.

AE department can manage.

Recommendations for the prevention of major AEs related to eratinib treatment:

‧ In order to reduce the risk of hyperphosphatemia, all patients are advised to use a low-phosphate diet (the daily dietary phosphate intake is 600mg-800mg).

‧ To reduce the risk of skin effects, it is recommended to use alcohol-free, moisturizing creams and avoid unnecessary sun exposure, soap, fragrance products and hot baths.

‧ To reduce the risk of nail effects, patients are advised to keep their fingers and toes clean and trim their nails.

Management

‧ Under medical guarantee, hyperphosphatemia (> 5.5mg / dL) is administered with phosphate binders.

• Use dry topical ointments (such as ammonium lactate, salicylic acid or zinc oxide cream) to manage dry skin.

‧ Nail effects are managed with a local nail enhancer; in severe cases, antibiotics or silver nitrate are used.

The TRAE associated with the FGFR inhibitor category is usually grade 1 or 2; in all dosage regimens, 2 patients reported retinopathy (grade 2 [n = 1] and grade 3 [n = 1]).

In all dosage regimens, 22 (11%) patients discontinued due to TRAE. The most common TRAEs leading to discontinuation of treatment are weakness, dry mouth, and palmar plantar red blood cell paresthesia syndrome.

Claims (15)

A method for treating cancer, the method comprising administering a certain amount of eratinib to a subject in need thereof, particularly a cancer patient, such that the level of serum phosphate ranges from 5.5 mg / dL to <7 mg / dL and include 5.5mg / dL, or range from 5.5mg / dL to 9 mg / dL and includes 5.5 mg / dL.     The method as described in item 1 of the scope of patent application, wherein the level of serum phosphate ranges from 5.5 mg / dL to <7 mg / dL and includes 5.5 mg / dL.     Erdatinib is used for the manufacture of medicine for treating cancer, and the serum phosphate level ranges from 5.5mg / dL to <7mg / dL and includes 5.5mg / dL, or ranges from 5.5mg / dL by a certain amount to 9 mg / dL and includes 5.5 mg / dL.     The use as described in claim 3 of the patent application range, wherein the level of serum phosphate ranges from 5.5 mg / dL to <7 mg / dL and includes 5.5 mg / dL.     Erdatinib, for use in the treatment of cancer, wherein the administration of Erdatinib in an amount results in a serum phosphate level ranging from 5.5 mg / dL to <7 mg / dL and including 5.5 mg / dL, or ranging from 5.5 mg / dL to 9 mg / dL and includes 5.5 mg / dL.     Erdatinib is intended for use as described in item 4 of the patent application range, where serum phosphate levels range from 5.5 mg / dL to <7 mg / dL and include 5.5 mg / dL.         A method for treating cancer, the method comprising administering to a subject in need thereof, specifically a cancer patient, 8 mg of edatinib daily, on a continuous basis, specifically once daily.         Erdatinib for use in the manufacture of a medicament for the treatment of cancer, wherein the medicament comprises erdatinib in an amount of 8 mg, and wherein the medicament is administered daily on a continuous basis, specifically once daily .         Erdatinib, for use in the treatment of cancer, where Erdatinib is administered in an amount of 8 mg per day on a continuous basis, specifically once daily.         The method or use according to any one of the foregoing patent claims, wherein the cancer is urothelial cancer, bladder cancer, hepatocellular carcinoma, squamous cell carcinoma, or lung cancer.         The method or use as described in item 10 of the scope of patent application, wherein the cancer is metastatic or surgically unresectable urothelial carcinoma.         The method or use as described in claim 10, wherein the cancer is advanced or metastatic bile duct cancer.     A method for treating cancer, which comprises a) administering 8 mg of edatinib to a subject in need thereof, specifically a cancer patient, on a continuous basis, specifically once daily; b ) The subject's serum phosphate level was measured on the treatment day during the first cycle of erdatinib treatment, specifically on day 14 ± 2 days after erdatinib administration, and more specifically on erdatinib administration 14th day of Benedict; c-1) When the serum phosphate level is <5.5mg / dL, erdatinib is given in a certain amount of 9mg daily on a continuous basis, specifically once a day; c-2 ) When serum phosphate levels range from 5.5 mg / dL to <7 mg / dL and include 5.5 mg / dL, further erdatinib is given in an amount of 8 mg daily on a continuous basis, specifically once daily; c -3) When serum phosphate levels are At 7 mg / dL, ertintinib treatment was temporarily interrupted until the serum phosphate level was <5.5 mg / dL, and then eratinib treatment was restarted at 8 mg daily on a continuous basis, specifically once daily . Erdatinib for use in the manufacture of a medicament for treating cancer in a cancer patient, wherein a) the medicament comprises eratinib in an amount of 8 mg, and wherein the medicament is administered daily on a continuous basis, specifically Is once a day; b) the patient's serum phosphate level is measured on the treatment day during the first cycle of eratinib treatment, specifically on the 14th day ± 2 days of eratinib administration, and more specifically on the 14th day Day 14; c-1) When the serum phosphate level is <5.5mg / dL, the amount of edatinib in the drug for daily, specifically once-a-day administration is increased on a continuous basis to 9mg; c-2) When the serum phosphate level ranges from 5.5mg / dL to <7mg / dL and includes 5.5mg / dL, the patient maintains continuous treatment at 8mg daily, specifically once daily; c-3) when Serum phosphate level At 7 mg / dL, ertintinib treatment was temporarily interrupted until the serum phosphate level was <5.5 mg / dL, and then eratinib treatment was restarted at 8 mg daily on a continuous basis, specifically once daily . Erdatinib, for use in the treatment of cancer in cancer patients, where a) Erdatinib is given in an amount of 8 mg per day on a continuous basis, specifically once daily; b) is treated in Erdatinib The serum phosphate level of the patient was measured on the treatment day during the first cycle, specifically on the 14th day ± 2 days of erdatinib administration, and more specifically on the 14th day; c-1) when the serum phosphate level When the dosage is <5.5mg / dL, erdatinib is given in a certain amount of 9mg daily on a continuous basis, specifically once daily; c-2) When the serum phosphate level ranges from 5.5mg / dL to <7mg / dL and including 5.5 mg / dL, further erdatinib is given in an amount of 8 mg daily on a continuous basis, specifically once daily; c-3) when the serum phosphate level is At 7 mg / dL, ertintinib treatment was temporarily interrupted until the serum phosphate level was <5.5 mg / dL, and then eratinib treatment was restarted at 8 mg daily on a continuous basis, specifically once daily .