FGFR tyrosine kinase inhibitors for the treatment of urothelial carcinoma

Abstract

This invention provides a method for treating urothelial carcinoma with an approved formulation containing a fibroblast growth factor receptor (FGFR) inhibitor. [Solution] A method for treating urothelial carcinoma, comprising administering erdafitinib to a patient having urothelial carcinoma, wherein erdafitinib is administered in combination with a P-glycoprotein (P-gp) substrate, and the administration of erdafitinib is divided to at least 6 hours before or after the administration of the P-gp substrate, wherein the P-gp substrate has a narrow therapeutic index.

Description

[Technical Field]

[0001] This specification refers to approved products containing fibroblast growth factor receptor (FGFR) inhibitors. A method for treating urothelial carcinoma with a drug will be disclosed. Also, fibroblast growth factor receptor (FGF) R) Disclosed is a method for selling or proposing an approved formulation containing an inhibitor for sale. ru. [Background technology]

[0002] Identifying genetic abnormalities can be useful in selecting appropriate treatments for cancer patients. Cancer patients who have failed the primary treatment options (state-of-the-art treatments) for their type of cancer, especially those who have tried a second or subsequent treatment. It is also useful when there is no recognized standard treatment for the condition. Fibroblast growth factor receptor (FG FR) is a receptor tyrosine kinase involved in regulating cell survival, proliferation, migration, and differentiation. It belongs to the Ze family. Changes in FGFR, including FGFR mutations and FGFR fusions or translocations. This has been observed in some cancers. To date, in patients with FGFR changes, FGFR There are no approved and effective treatments using inhibitors. [Overview of the project] [Means for solving the problem]

[0003] This specification refers to approved products containing fibroblast growth factor receptor (FGFR) inhibitors. The agent is administered to a patient with urothelial carcinoma in the amount specified on the formulation label for the said formulation. A method of treating urothelial carcinoma that includes, consists of, or is essentially derived from It is described that in certain embodiments, urothelial carcinoma is locally advanced or metastatic. In one embodiment, the administration of an FGFR inhibitor is performed on a patient who has not been treated with an FGFR inhibitor. Compared to patients with urothelial carcinoma, the response rate or duration of response is measured as follows: It provides improved antitumor activity. In some embodiments, administration of an FGFR inhibitor It causes adverse events of grade 3 or lower.

[0004] In further embodiments, urothelial carcinoma is characterized by an FGFR2 gene mutation or an FGFR3 gene mutation. It is susceptible to mutation. In certain embodiments, FGFR2 or FGFR3 gene changes are This involves FGFR3 gene mutations or FGFR2 or FGFR3 gene fusions. In this embodiment, the FGFR3 gene mutations are R248C, S249C, G370C, Y37 3C, or any combination thereof. In further embodiments, FGFR2 or FGF R3 gene fusions include FGFR3-TACC3, FGFR3-BAIAP2L1, and FGFR It is 2-BICC1, FGFR2-CASP7, or any combination thereof.

[0005] Furthermore, this specification states that before administering an FGFR inhibitor, one or more FGFR2 or FGF R3 gene alterations, particularly those affecting the FGFR2 or FGFR3 gene as described herein. This further includes, or consists of, evaluating biological samples from patients for the presence of changes. A method for treating urothelial carcinoma that is essentially derived therefrom is described. So, biological samples include blood, lymph, bone marrow, solid tumor samples, or any combination thereof. be.

[0006] In a further embodiment, the patient has received at least one prior treatment for the treatment of urothelial carcinoma. In some embodiments, at least one prior treatment for the treatment of urothelial carcinoma is , which is platinum-containing chemotherapy. In certain embodiments, the urothelial cancer has progressed during or after at least 1 line of platinum-containing chemotherapy. In further embodiments, the platinum -containing chemotherapy is neoadjuvant platinum-containing chemotherapy or adjuvant platinum -containing chemotherapy. In further embodiments, the urothelial cancer has progressed during or within 12 months after at least 1 line of neoadjuvant platinum-containing chemotherapy or adjuvant platinum-containing chemotherapy.

[0007] In some embodiments, the FGFR inhibitor is erdafitinib. In further embodiments, erdafitinib is administered daily, particularly once a day. In further embodiments , erdafitinib is administered orally. In certain embodiments, erdafitinib is administered orally on a daily dosing schedule. In some embodiments, erdafitinib is administered orally once a day at a dose of about 8 mg. In some embodiments, erdafitinib is administered orally once a day at a dose of about 8 mg on a daily dosing schedule. In further embodiments, the dose of erdafitinib is increased from once a day at 8 mg to once a day at 9 mg on days 14 - 21 after treatment is initiated if (a) the patient exhibits a serum phosphate (PO4) level of less than about 5.5 mg / dL on days 14 - 21 after treatment is initiated ; and (b) once-daily administration of erdafitinib at 8 mg does not cause ocular disorders ; or (c) once-daily administration of erdafitinib at 8 mg does not cause grade 2 or higher adverse reactions. In certain embodiments, erdafitinib is present in a solid dosage form. In further embodiments, the solid dosage form is a tablet. [[ID=3º]]

[0008] In further embodiments, erdafitinib is (a) a potent CYP2C9 inhibitor or C (b) Drug therapy with YP3A4 inhibitors; (b) potent CYP2C9 inducers or CYP3A4 inducers (c) A drug therapy that is an active agent; (c) A moderate CYP2C9 inducer or CYP3A4 inducer. Drug therapy; or (d) drug therapy that is a serum phosphate level modifier. In certain embodiments, erdafitinib is a pharmacotherapy in which (a) a CYP3A4 substrate; (b) Drug therapy that is an OCT2 substrate; or (c) P-glycoprotein (glycotpro It is not administered in combination with drug therapies that use tein (P-gp) substrates.

[0009] Furthermore, this specification provides a method for treating urothelial carcinoma in a patient, wherein (a) one or more Regarding the presence of the above fibroblast growth factor receptor (FGFR) gene mutation, a biological sample was obtained from the patient. (b) Evaluate the presence of one or more FGFR gene mutations in the sample. Approval for the aforementioned formulation to contain an FGFR inhibitor in the amount indicated on the formulation label. A method that includes, consists of, or is essentially derived from, treatment with a prepared formulation. It will be listed.

[0010] Furthermore, this specification refers to a combination of erdafitinib, consisting of, or derived from erdafitinib. A method for selling an approved formulation that is the target, wherein the method for selling such formulation It contains, consists of, or is essentially made of, and references to such preparations A method is provided for formulation labels related to stromal drugs, including instructions for treating urothelial carcinoma. In certain embodiments, the formulation is an ANDA formulation, a formulation for which a change in the drug approval application has been submitted, or It is a 505(b)(2) formulation.

[0011] Furthermore, this specification proposes for sale any approved formulations containing erdafitinib. A method which includes proposing such formulation for sale, or Consists of, or essentially consists of, such preparations, and the reference list of drugs relating to A method is provided in which the label of the formulation includes instructions for treating urothelial carcinoma. In a particular embodiment, the formulation is an ANDA formulation, a formulation for which a change in the approved drug product has been requested, or 505(b (2) It is a pharmaceutical preparation.

[0012] Furthermore, this specification includes selling approved formulations containing erdafitinib, or A method consisting of, or essentially derived from, such a preparation. The formulation labels for the listed drugs will include data on response rate or duration of response. In a particular embodiment, the response rate data for erdafitinib was approximately 40.2%. In particular, the patient has locally advanced or metastatic urothelial carcinoma. In certain embodiments, The response rate data for erdafitinib is approximately 32.2%, and in particular, patients are neoadjusted. At least one of the following, including within 12 months of a juvant or adjuvant platinum-containing chemotherapy. Progression during or after previous platinum-containing chemotherapy (chemotherapy relapse / resistance) Disease) Locally advanced or metastatic urothelial carcinoma. In further embodiments, Erdafiti The duration of response data for NIB is approximately 5.6 months, and in particular, patients with locally progressive or metastatic disease. The patient has metastatic urothelial carcinoma. In a further embodiment, the duration of response to erdafitinib is The timeframe is approximately 5.4 months, and in particular, patients receive neoadjuvant or adjuvant-platin. Previous platinum-containing chemotherapy within 12 months of at least one line of platinum-containing chemotherapy Locally advanced or metastatic epiuricular tract disease that progresses during or after therapy (chemotherapy-relapsed / resistant disease) She has skin cancer.

[0013] Furthermore, in this specification, the response rate, duration, or response in patients with urothelial carcinoma is improved. A good method, wherein the method provides the patient with an approved formulation containing erdafitinib. A method is provided that includes, consists of, or is essentially based on administering a substance. In a particular embodiment, the response rate was approximately 40.2%, and in particular, the patient had locally progressive or The patient has metastatic urothelial carcinoma. In certain embodiments, the response to erdafitinib The rate was approximately 32.2%, and in particular, patients were treated with neoadjuvant or adjuvant platinum. Previous platinum-containing chemotherapy, including at least one line within 12 months of the current platinum-containing chemotherapy. Locally advanced or metastatic urothelial disease that progressed during or after the treatment (chemotherapy-recurrent / resistant disease) The patient has cancer. In further embodiments, the response period is approximately 5.6 months, and in particular, the patient is The patient has locally advanced or metastatic urothelial carcinoma. In further embodiments, erdafitinib is used. The duration of response is approximately 5.4 months, and in particular, patients with neoadjuvant or adjuvant therapy... At least one previous line of platinum-containing chemotherapy, including within 12 months of the first platinum-containing chemotherapy. Locally progressive or metastatic disease that progressed during or after chemotherapy containing sodium (chemotherapy-relapsed / resistant disease). The patient has metastatic urothelial carcinoma. In further embodiments, the approved formulation is an ANDA formulation or This is a pharmaceutical product for which a change in the approved drug specifications has been submitted.

[0014] Furthermore, this specification describes how to improve the response rate or duration of response in patients with urothelial carcinoma. A method wherein the method provides the patient with an approved formulation containing erdafitinib. A method is provided that includes, consists of, or is essentially derived from doing. In one embodiment, the response rate was approximately 40.2%, and in particular, the patients had locally advanced or metastatic disease. The patient has urothelial carcinoma. In certain embodiments, the response rate to erdafitinib is Approximately 32.2% of patients, in particular, were using neoadjuvant or adjuvant platinum-containing During at least one line of previous platinum-containing chemotherapy, including within 12 months of the current therapy. Or, locally advanced or metastatic urothelial carcinoma that has progressed later (chemotherapy-recurrent / resistant disease) In further embodiments, the duration of response is approximately 5.6 months, and in particular, the patient experiences localized progression. The patient has urothelial or metastatic urothelial carcinoma. Further embodiments relate to erdafitinib. The duration of response is approximately 5.4 months, and in particular, patients receive neoadjuvant or adjuvant therapy. Previous platinum-containing chemotherapy, including at least one line within 12 months of a previous platinum-containing chemotherapy regimen. Locally advanced or metastatic urine that has progressed during or after chemotherapy (chemotherapy-relapsed / resistant disease) The patient has urothelial carcinoma. In certain embodiments, the approved formulation is an ANDA formulation or a pharmaceutical product. This is a formulation for which a change in product approval has been requested. Further embodiments refer to such formulations. The formulation labels for the listed drugs include instructions for treating urothelial carcinoma.

[0015] Furthermore, this specification provides for approved formulations having at least one approved efficacy. The approved formulations provided contain erdafitinib. In certain embodiments, approved Approved formulations are NDA formulations, ANDA approved formulations, formulations for which a change in drug approval has been requested, or 5 05(b)(2) Formulation. Further embodiments refer to the approved formulation. The formulation includes a formulation label. In a further embodiment, the formulation label includes response rate data. In some embodiments, the response rate data for erdafitinib is approximately 40.2%. In particular, the patient has locally advanced or metastatic urothelial carcinoma. The response rate data for erdafitinib is approximately 32.2%, and in particular, patients... At least within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Another line of treatment that progressed during or after previous platinum-containing chemotherapy (chemotherapy-induced relapse / (Resistant disease) Having locally advanced or metastatic urothelial carcinoma. In certain embodiments, formulation The label includes response duration data. In a further embodiment, the response for erdafitinib. The duration of efficacy data is approximately 5.6 months, and in particular, patients with locally advanced or metastatic urothelial carcinoma. It has. In a further embodiment, the duration of response data for erdafitinib is approximately 5. The period is 4 months, and in particular, the patient is undergoing neoadjuvant or adjuvant platinum-containing chemotherapy. During or after at least one line of previous platinum-containing chemotherapy, including within 12 months of this treatment. The patient has locally advanced or metastatic urothelial carcinoma that has progressed to a stage where chemotherapy has relapsed or become resistant.

[0016] Furthermore, in this specification, (a) susceptible to FGFR3 or FGFR2 gene alterations, and (b) within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Locally advanced disease that progressed during or after at least one line of prior platinum-containing chemotherapy. Approved formulations including erdafitinib for the treatment of adult patients with sexually transmitted or metastatic urothelial carcinoma. A prescribed medicine will be provided.

[0017] The overview and the detailed description below will be better understood when read in conjunction with the attached drawings. To illustrate the method, the drawings show exemplary embodiments of the method; however, the method is not disclosed. It is not limited to any particular embodiment. [Brief explanation of the drawing]

[0018] [Figure 1] This represents a study scheme for a phase 2, multicenter, open-label trial to evaluate the efficacy and safety of erdafitinib in patients with metastatic or surgically unresectable urothelial carcinoma who have selected FGFR (fibroblast growth factor receptor) gene alterations (FGFR translocations or mutations). [Figure 2] Patient response to treatment with 8 mg of erdafitinib per day in a continuous regimen (regmen 3): Overall response rate (ORR) is shown within the patient subgroup. [Figure 3A] Figure 3: Includes Figures 3A-C showing waterfall plots of the reduction in total target lesion diameter after treatment with erdafitinib. Reductions among all treated patients, in patients treated with (Figure 3A) continuous erdafitinib 8 mg per day (regmen 3), (Figure 3B) intermittent erdafitinib 10 mg per day (regmen 1), and (Figure 3C) continuous erdafitinib 6 mg per day (regmen 2). [Figure 3B] (As stated above.) [Figure 3C] (As stated above.) [Figure 4] This is a swimmer plot of the response to erdafitinib treatment in all patients treated with 8 mg of erdafitinib daily in a continuous course. Response is determined by the investigator. [Figure 5A]Figure 5: Includes Figures 5A-5B showing progression-free survival and overall survival in patients treated with continuous 8 mg of erdafitinib per day (regime 3). Kaplan-Meier curves for progression-free survival (Figure 5A) and overall survival (Figure 5B) after treatment with continuous 8 mg of erdafitinib. [Figure 5B] (As stated above.) [Figure 6A] Figure 6: Includes Figures 6A–6B showing overall survival among patients treated with intermittent 10 mg and continuous 6 mg per day of erdafitinib. (Figure 6A) Kaplan-Meier curves of overall survival after treatment with intermittent 10 mg of erdafitinib (regmen 1) and (Figure 6B) continuous 6 mg per day of erdafitinib (regmen 2). [Figure 6B] (As stated above.) [Modes for carrying out the invention]

[0019] For clarity, several aspects of the present invention are described herein in the context of separate embodiments. It should be understood that the features may be provided in combination in a single embodiment. Unless otherwise clearly incompatible or explicitly excluded, each individual embodiment is an optional It is considered to be combinable with other embodiments, and such combinations are in other embodiments It is considered to be so. Conversely, the present invention, described in the context of a single embodiment for the sake of brevity. The various features of can also be provided separately or in any combination of sub-features. Finally, a Embodiments may be described as part of a series of steps or as part of a more general structure. Each of the aforementioned steps is an independent embodiment in itself and can be combined with others. It could be considered as such.

[0020] Specific Terminology The transitional terms "contains," "essentially consists of," and "consist of" are used in patent applications. The word is intended to include those generally accepted meanings; that is, (i ) "including," "containing," or "characterized by" Synonymous with "comprising," meaning comprehensive or open-ended. (ii) "~consists of" means Excluding any element, process, or component not specified in the claims; and ( iii) "Essentially consisting of" refers to the specified material or process of the claimed invention. The scope of the claims is limited to those that do not substantially affect the fundamental and novel features. More specifically, the basic and novel features are compared to those described elsewhere in this specification. This includes, but is not limited to, the ability to improve the survivability of human populations compared to the survivability of human populations. No, relating to the ability of a method to provide at least one of the advantages described herein. Embodiments described in the term "including" (or its synonyms) also include embodiments and And, the terms "consisting of ~" and "essentially becoming from ~" are described independently. To provide.

[0021] When a value is represented as an approximation by the use of the descriptive word "approximately", a particular value may be represented by a different implementation. It will be understood that it is forming a form. Generally, the use of the term "about" is disclosed. It may vary depending on the desired characteristics that are required to be obtained by the subject matter. An approximation that will be interpreted based on its function in the specific context in which it is used To show. A person skilled in the art will be able to interpret this as a fixed rule. In some cases In this context, the number of significant figures used for a particular value is one that determines the range of the word "approximately". It may be a non-restrictive method. In other cases, the steps used in a series of values ​​may be used. Then, you may determine the intended range that is available for the term "approximately" for each value. If there is a limit, All scopes are comprehensive and combinable. That is, they are described within the scope. A reference to a value includes all values ​​within that range.

[0022] Unless otherwise specified, the term "approximately" indicates a variation of ±10% of the relevant value, but additional The embodiment may have a variation of ±5%, ±15%, ±20%, ±25%, or ±50%. This includes.

[0023] If a list is provided, unless otherwise stated, each individual element of that list, and It will be understood that all combinations of the list are separate embodiments. For example, the list of embodiments shown as "A, B, or C" is an example of an embodiment "A", B", C, A or B, A or C, B or C, or A, B or C It will be interpreted as including it.

[0024] As used herein, the singular forms "a," "an," and "that" are used. "(the)" can include plural forms.

[0025] The following abbreviations will be used throughout this disclosure: FGFR (Fibroblast Growth Factor Receiver). Condition); FGFR3-TACC3 V1 (the gene encoding FGFR3 and transformation acid Fusion between coiled-coil-containing protein 3 variant 1); FGFR3-TACC3_ v3 (the gene encoding FGFR3 and the transformed acid coiled coil-containing protein 3) Fusion between riant 3); FGFR3-BAIAP2L1 (the gene encoding FGFR3) Fusion between the child and brain-specific angiogenesis inhibitor 1-related protein 2-like protein 1); FGFR 2-BICC1 (between the gene encoding FGFR2 and bicaudal C homolog 1) Fusion of (FGFR2-CASP7) (between the gene encoding FGFR2 and caspase 7) (The fusion of...)

[0026] As used herein, “patient” means any animal, in particular a mammal. It is intended. Therefore, the method is applicable to humans and non-human animals, but is not to humans. This is most preferable. The terms “patient,” “subject,” and “human” can be used interchangeably. .

[0027] The terms "to treat" and "treatment" refer to the treatment of patients suffering from a disease, and cancer cells. This refers to the effect of alleviating the condition by killing off the organisms, but also to the effect of inhibiting the progression of the condition. This also refers to a decrease in the rate of progression, a cessation of the rate of progression, remission of the condition, and a cure of the condition. This also includes treatment as a preventative measure (i.e., prevention of onset).

[0028] When used herein, the term "cancer" refers to a condition that grows in an uncontrolled manner and in some cases In this context, it refers to the abnormal proliferation of cells that tend to metastasize (spread).

[0029] As used herein, terms such as "combined therapy" refer to selected therapeutic agents for a single patient. This means including the administration of, and also by the same or different routes of administration, or the same or This is intended to include treatment regimens in which medications are administered at different times.

[0030] As used herein, the term “combination drug” means a mixture of two or more active ingredients or This refers to the products resulting from a combination, including both fixed and non-fixed combinations of active ingredients. This includes both combinations. The term "fixed combination" refers to the active ingredient, e.g., erdafitinib. Both the adjunct medication and the adjunct medication are administered simultaneously to the patient in the form of a single unit or a single dosage form. This means that the term "non-fixed combination" refers to the active ingredient, for example, erdafitinib. And auxiliary drugs may be administered simultaneously, concurrently, or sequentially without specific intervention time limitations. This means that the drug is administered to the patient in units or in separate dosage forms, and such administration is human It provides safe and effective levels of two active ingredients in the body. The latter is also used in cocktail therapy. For example, this also applies to the administration of three or more active ingredients.

[0031] The term "daily administration schedule" refers to administering a specific therapeutic agent with a rest day between doses of that agent. This refers to administering without accompanying medication. In some embodiments, the daily administration schedule of a particular therapeutic agent is used. The treatment involves administering specific medications daily at approximately the same time each day.

[0032] The term "progression-free survival" refers to the period from the first dose to the documented evidence of disease progression or death. It is defined as the period until the earlier of the two days.

[0033] The term "response period" refers to the period from the documented initial response to the documented evidence of disease progression or death. It is defined as the period up to the day it was made.

[0034] The term "overall survival" is defined as the period from the first dose to the day of death. Data concerning patients who are in a state of unknown or unknown condition may be used if it is known that the patient is alive. It was cancelled on the last day.

[0035] The term "placebo," as used herein, refers to a pharmaceutical composition that does not contain an FGFR inhibitor. This means administering [the substance].

[0036] The term "randomization" means that, when referring to a clinical trial, it is not guaranteed that a patient is eligible for the clinical trial. This refers to the time when the patient is recognized and assigned to a treatment arm.

[0037] The terms "kit" and "manufactured product" are used as synonyms.

[0038] "Biological samples" can be used to obtain cancer cells and to detect changes in the FGFR gene. This refers to any sample from a particular patient. Suitable biological samples include blood, lymph, bone marrow, Examples include, but are not limited to, solid tumor specimens or any combination thereof. In one embodiment, the biological sample is formalin-fixed paraffin-embedded tissue (FFPET). could be.

[0039] FGFR gene disorder This specification refers to approved products containing fibroblast growth factor receptor (FGFR) inhibitors. The agent is administered to a patient with urothelial carcinoma in the amount specified on the formulation label for the said formulation. Methods for treating urothelial carcinoma, including the following, are disclosed.

[0040] Protein tyrosine kinase (PTK) receptor fibroblast growth factor (FGF) Lee's work encompasses a wide range of processes, including mitosis induction, wound healing, cell differentiation and angiogenesis, and development. It controls physiological functions. Both normal and malignant cell growth and proliferation are controlled by autocrine and paracrine factors. It is affected by changes in the local concentration of FGF, an extracellular signaling molecule that acts as a child. Autocrine FGF signaling is involved in the hormone-independent state of steroid hormone-dependent cancers. FGF and its receptors can be particularly important in the progression to [the disease]. It is expressed at increased levels in the strain, and overexpression is thought to be a contributing factor to malignant phenotypes. Furthermore, some oncogenes are homologs of genes encoding growth factor receptors. Furthermore, there is a possibility of abnormal activation of FGF-dependent signaling in human pancreatic cancer (Kn ights et al.,Pharmacology and Therapeuti cs 2010 125:1(105-117);Korc M.et al Curr ent Cancer Drug Targets 2009 9:5(639-651 ))

[0041] The two prototype members are acid fibroblast growth factor (aFGF or FGF1). and basic fibroblast growth factor (bFGF or FGF2), and to date at least Twenty different FGF family members have been identified. The cellular response to FGF is: Four types of high-affinity transmembrane proteins numbered 1-4 (FGFR1-FGFR4) It is transmitted by rosin kinase fibroblast growth factor receptor (FGFR).

[0042] In certain embodiments, urothelial carcinoma is caused by a change in the FGFR2 gene or the FGFR3 gene. They are sensitive to change.

[0043] As used herein, "FGFR gene alteration" refers to an FGFR fusion gene, FGFR Wild-type includes, but is not limited to, mutations, FGFR amplification, or any combination thereof. This refers to changes in the FGFR gene. The terms "variant" and "change" are used interchangeably in this specification. It is used interchangeably.

[0044] In certain embodiments, FGFR2 or FGFR3 gene changes are associated with FGFR gene fusion. It is a fusion. "FGFR fusion" or "FGFR gene fusion" is a fusion of FGFR (for example, FGR). It is caused by a gene that codes for part of F2 or FGFR3 and by a translocation between two genes. This refers to one or more of the Fusion Partners disclosed herein. The terms "Fusion" and "Translocation" is used interchangeably in this specification. The following FGFs in biological samples from patients The presence of one or more R fusion genes may be determined using the disclosed methods or uses:F GFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FG FR2-CASP7, or any combination thereof. In certain embodiments, FGFR3 -TACC3 is FGFR3-TACC3 variant 1 (FGFR3-TACC3 v1 ) or FGFR3-TACC3 variant 3 (FGFR3-TACC3 v3). Table 1 lists the FGFR fusion genes, as well as the FGFRs and fusion partner exons. The sequences of individual FGFR fusion genes are disclosed in Table 4.

[0045] [Table 1]

[0046] FGFR gene variations include FGFR single nucleotide polymorphisms (SNPs). A (SNP) refers to a single nucleotide polymorphism in the FGFR2 or FGFR3 gene that differs by one nucleotide between individuals. In certain embodiments, FGFR2 or FGFR3 gene changes are caused by FGFR3 gene mutations. Yes, in particular, "FGFR single nucleotide polymorphisms" (SNPs) are FGFR3s that differ by one nucleotide between individuals. This refers to genes. The presence of one or more of the following FGFR SNPs in a biological sample from a patient indicates that Disclosed in a manner known to the traders or in International Publication No. 2016 / 048833 This can be determined by the method (FGFR3 R248C, FGFR3 S249C, FGF R3 G370C, FGFR3 Y373C, or any combination thereof). FGFR The sequences of the SNPs are provided in Table 2.

[0047] [Table 2]

[0048] When used herein, the "FGFR gene alteration gene panel" refers to the FGFR gene alteration gene panel listed above. It includes one or more GFR gene mutations. In some embodiments, the FGFR gene mutation is inherited. The sub-panel depends on the patient's cancer type.

[0049] The FGFR gene alteration gene panel used in the evaluation step of the disclosed method is for patients Partially based on the cancer type of the individual. For patients with urothelial carcinoma, suitable FGFR gene mutations The gene panel includes FGFR3-TACC3 vl, FGFR3-TACC3 v3, F GFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, FG FR3 R248C, FGFR3 S249C, FGFR3 G370C, or FG This may include FR3 Y373C, or any combination thereof.

[0050] FGFR inhibitors for use in the disclosed method or use Suitable FGFR inhibitors for use in the disclosed method are provided herein.

[0051] In some embodiments, if one or more FGFR gene mutations are present in the sample, urine Patients with urothelial carcinoma, U.S. Patent Application Publication No. 2013 / 0072457A1 (see reference) FGFR inhibitors (any of which are tautomutated) disclosed in this specification (and incorporated herein) Sexual or stereochemical isomers, their N-oxides, and their pharmaceutically acceptable salts. (including, or solvates thereof) (Preferred R groups are also included in U.S. Patent Application Publication No. 2013 / 0072) It can be treated with (disclosed in Specification No. 457A1).

[0052] In some embodiments, for example, the patient is N-(3,5-dimethoxyphenyl)-N'- (1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoyl [Sarin-6-yl]ethane-1,2-diamine (referred to as "JNJ-4275649" in this specification) (Also known as "3" or "JNJ493" or erdafitinib) (Either of the following alternatives) (Including variant forms, their N-oxides, their pharmaceutically acceptable salts, or their solvates) It can be treated with: In some embodiments, the FGFR inhibitor is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutically acceptable salt The salt is an HCl salt. In a preferred embodiment, erdafitinib base is used.

[0053] In some embodiments, urothelial carcinoma patients may be treated with FGFR inhibitors, F GFR inhibitors are Gavine, PR, et al., AZD4547: An Or ally Bioavailable, Potent, and Selective I inhibitor of the Fibroblast Growth Factor Receptor Tyrosine Kinase Family, Cancer As described in Res.April 15,2012 72;2045, N-[5- [2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazole-3-yl]-4- (3,5-dimethylpiperazin-1-yl) Nzuamide (AZD4547): [ka] (If chemically possible, any of the tautomers or stereochemical isomers thereof, (and its N-oxide, its pharmaceutically acceptable salt, or its solvate).

[0054] In some embodiments, urothelial carcinoma patients may be treated with FGFR inhibitors, F GFR inhibitors are as described in International Publication No. 2006 / 000420. 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[4-(4- Ethyl-piperazine-1-yl)-phenylamino]-pyrimido-4-yl}-methyl- Urea (NVP-BGJ398): [ka] (If chemically possible, any of the tautomers or stereochemical isomers thereof, (and its N-oxide, its pharmaceutically acceptable salt, or its solvate).

[0055] In some embodiments, urothelial carcinoma patients may be treated with FGFR inhibitors, F GFR inhibitors are as described in International Publication No. 2006 / 127926. 4-amino-5-fluoro-3-[6-(4-methylpiperazine-1-yl)-1H- [Benzimidazole-2-yl]-1H-quinoline-2-one (dovitinib): [ka] (If chemically possible, any of the tautomers or stereochemical isomers thereof, (and its N-oxide, its pharmaceutically acceptable salt, or its solvate).

[0056] In some embodiments, urothelial carcinoma patients may be treated with FGFR inhibitors, F GFR inhibitors are described in Bello, E. et al., E-3810. t Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Pr eclinical models,Cancer Res February 15, 2011 71(A)1396-1405 and International Publication No. 2008 / 112408 Pan 6-(7-((1-aminocyclopropyl)-methoxy) as indicated on the fretboard -6-Methoxyquinoline-4-yloxy)-N-methyl-1-naphthamide(AL38 10) (Lusitanib; E-3810): [ka] (If chemically possible, any of the tautomers or stereochemical isomers thereof, (and its N-oxide, its pharmaceutically acceptable salt, or its solvate).

[0057] Further suitable FGFR inhibitors include BAY1163877 (Bayer), BA Y1179470 (Bayer), TAS-120 (Taiho), ARQ087 (Ar Qule), ASP5878 (Astellas), FF284 (Chugai), FP -1039(GSK / FivePrime), Blueprint, LY-287445 Examples include 5 (Lilly), RG-7444 (Roche), or any combination thereof. And, if chemically possible, any of its tautomers or stereochemical isomers Examples include the substance, its N-oxide, its pharmaceutically acceptable salt, or its solvate.

[0058] In one embodiment, FGFR inhibitors in general, and more specifically erdafitinib, It is administered as a pharmaceutically acceptable salt. In preferred embodiments, it is generally an FGFR inhibitor. , and more specifically erdafitinib is administered in base form. In one embodiment, Generally, FGFR inhibitors, and more specifically erdafitinib, are used in a 8 mg base equivalent dose. It is administered as a pharmaceutically acceptable salt in an amount equivalent to 9 mg of base equivalent. In one embodiment, FGFR inhibitors in general, and more specifically erdafitinib, are 8 It is administered in the form of the base in amounts of mg or 9 mg.

[0059] Salts are generally used as FGFR inhibitors, and more specifically as eldaf, in a suitable solvent. It can be prepared by reacting itinib with a suitable acid.

[0060] Acid addition salts can be formed by both inorganic and organic acids. Examples of acid addition salts include: Acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, ma Leic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfone Acids, methanesulfonic acid (mesylates), ethanesulfonic acid, naphthalenesulfonic acid, valerian Acids, acetic acid, propionic acid, butanoic acid, malonic acid, glucuronic acid, and lactobionic acid Examples of salts formed by acids selected from the group include vinegar. Another group of acid addition salts includes vinegar. Acids, adipic acid, ascorbic acid, aspartic acid, citric acid, DL-lactic acid, fumaric acid, Gluconic acid, glucuronic acid, hippuric acid, hydrochloric acid, glutamic acid, DL-malic acid, meta Examples include salts formed from sulfonic acid, sebacic acid, stearic acid, succinic acid, and tartaric acid. It is possible.

[0061] In one embodiment, FGFR inhibitors in general, and more specifically erdafitinib, It is administered in the form of a solvate. As used herein, the term “solvate” means Eldaf This refers to the physical association of itinib with one or more solvent molecules. This physical association is a hydrogen bond. It includes various degrees of ionic and covalent bonding, including those found in certain cases. If one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, isolation is possible. It is likely that the term "solvate" encompasses both the solution phase and the isolateable solvate. Intended. Non-limiting examples of solvents that can form solvates include water and isopropanol. Examples include ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine. It can be done.

[0062] Solvates are well known in pharmaceutical chemistry. They are used in the preparation of substances. Seth (for example, in relation to their purification), preservation of substances (for example, their stability), and matter Ease of handling the substance is important, and often in the isolation or saturation stage of chemical synthesis. It is formed as part of the manufacturing process. Those skilled in the art will know that by standard and long-used methods, the hydrate is formed Or other solvates may be affected by the isolation or purification conditions used to prepare the given compound. It is possible to determine whether or not it was formed. An example of such a method is thermogravimetric analysis. X-ray crystallography (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g., single-crystal X-ray crystallography or (X-ray powder diffraction) and solid-state NMR (SS-NMR, magic angle spinning NMR) Examples include NMR, IR, Like HPLC and MS, it is part of the standard toolkit for those skilled in the art. If you are an expert, you can use crystallization conditions that include the amount of solvent required for a particular solvate, The solvate can be formed intentionally. Subsequently, the solvate is formed using the standard method described above. It is possible to check if it has been done. Any complex (for example, a compound such as cyclodextrin) This also includes inclusion complexes or clathrates with other substances, or complexes with metals.

[0063] Furthermore, the compound may have one or more polymorphs (crystalline) or amorphous forms.

[0064] The compound includes compounds having one or more isotopic substitutions, and references to specific elements are of that It includes all isotopes of an element. For example, a reference to hydrogen is within that range. 1 H, 2 H(D), and 3Includes H(T). Similarly, references to carbon and oxygen are within their respective ranges. Each 12 C, 13 C, and 14 C, and 16 O and 18 Contains O. It may be radioactive or non-radioactive. In one embodiment, the compound is radioactive. It does not contain isotopes. Such compounds are preferable for therapeutic use. However, another practical application In the application form, the compound may contain one or more radioactive isotopes. Compounds containing these nucleotides may be useful from a diagnostic standpoint.

[0065] Methods of treatment / Compounds for use This specification refers to approved products containing fibroblast growth factor receptor (FGFR) inhibitors. The agent is administered to a patient with urothelial carcinoma in the amount specified on the formulation label for the said formulation. This document describes methods for treating urothelial carcinoma, including the following.

[0066] Furthermore, this specification provides for the use of fibroblast growth factors in the treatment of urothelial carcinoma in patients. Approved formulations containing sub-receptor (FGFR) inhibitors are listed, and the approved formulations are: The preparation is administered in the amount indicated on the preparation label.

[0067] Furthermore, this specification also describes the manufacture of a pharmaceutical product for the treatment of urothelial carcinoma in patients. The use of approved formulations containing blast growth factor receptor (FGFR) inhibitors is described. The pharmaceutical product is administered in the amount indicated on the product label for the aforementioned preparation.

[0068] In certain embodiments, urothelial carcinoma is locally advanced or metastatic. In terms of treatment methods, patients are high-risk patients, particularly those with metastatic or surgically unresectable urothelial carcinoma. In particular, metastatic or surgically altered FGFR gene changes (FGFR translocations or mutations) Unresectable urothelial carcinoma, particularly one having FGFR gene alterations as defined above. This patient is at high risk. High-risk patients are defined by the following criteria: age 75 years or older; ECOG 2 PS; hemoglobin <10 g / dL; visceral metastases, particularly those of the liver, lungs and / or bones. ; and patients who meet one or more of two or three Bellmunt risk factors. Morphologically, hemoglobin concentration is measured in whole blood.

[0069] In a particular embodiment, administration of an FGFR inhibitor is performed in accordance with the treatment by the FGFR inhibitor. Compared to patients with urothelial carcinoma who have not had a urothelial carcinoma, the response rate, progression-free survival, duration of response, or It provides improved antitumor activity as measured by overall survival. In terms of administration methods, FGFR inhibitors are administered to urinary tract patients who have not received FGFR inhibitor treatment. Compared to patients with skin cancer, improvement was observed as measured by response rate or duration of response. It provides antitumor activity. In certain embodiments, administration of an FGFR inhibitor provides FGFR Compared to patients with urothelial carcinoma who have not received inhibitor treatment, the response rate was measured. It provides improved antitumor activity as defined. In certain embodiments, FGFR Inhibitor administration is compared to patients with urothelial carcinoma who have not received treatment with FGFR inhibitors. In comparison, it provides improved antitumor activity as measured by the complete response rate. In certain embodiments, administration of an FGFR inhibitor is performed on a patient who has not been treated with an FGFR inhibitor. Compared to patients with urothelial carcinoma, the improvement was as measured by the partial response rate. It provides antitumor activity. In certain embodiments, administration of an FGFR inhibitor provides FGFR Compared to patients with urothelial carcinoma who have not received treatment with inhibitors, the partial response rate or complete response rate It provides improved antitumor activity as measured by the overall response rate. Morphologically, administration of FGFR inhibitors is used in urothelium that has not been treated with FGFR inhibitors. Compared to patients with cancer, improved anti-tumor as measured by progression-free survival. It provides ulcer activity. In certain embodiments, administration of an FGFR inhibitor provides an FGFR inhibitor Compared to patients with urothelial carcinoma who have not received treatment with [the drug], the duration of response was measured. It provides improved antitumor activity as described. In certain embodiments, FGFR inhibition The administration of the drug was compared to patients with urothelial carcinoma who were not receiving treatment with FGFR inhibitors. It provides improved antitumor activity, as measured by overall survival.

[0070] In certain embodiments, the improvement in antitumor activity is compared to treatment with placebo. They are opposites. In certain embodiments, improvement in antitumor activity is observed in the absence of treatment. It is relative to the combination. In certain embodiments, the improvement in antitumor activity is It is relative to standard treatment.

[0071] To assess the response rate or future progression, the overall tumor volume at baseline is estimated, and It is necessary to use this as a comparison for subsequent measurements. Measurable diseases are This is defined by the presence of at least one measurable lesion.

[0072] In some embodiments, a safe and effective dose of an FGFR inhibitor is administered in grade 2 or lower. The following adverse events occur. In other embodiments, administration of a safe and effective amount of FGFR inhibitor is performed. This results in adverse events of grade 3 or lower. In some embodiments, FGFR inhibitors Safe and effective doses result in adverse events of grade 4 or lower.

[0073] Furthermore, in this specification, a biological sample from the patient is collected using one or more F2F inhibitors before administration. A method further comprising assessing the presence of GFR2 or FGFR3 gene alterations, approval The formulation and its use are described. In certain embodiments, the method disclosed herein The law, approved formulations, and use further require that biological samples from patients be used to identify FGFR3 gene mutations or This includes evaluating the presence of FGFR2 or FGFR3 gene fusions. In certain embodiments, the methods, approved formulations, and uses disclosed herein may further affect patients. This includes evaluating biological samples from individuals for the presence of FGFR3 gene mutations. In the embodiments disclosed herein, the methods, approved formulations, and uses are further used by patients. Biological samples from FGFR3 R248C, FGFR3 S249C, FGFR3 G3 Evaluate the presence of 70C, FGFR3 Y373C, or any combination thereof. This includes the methods disclosed herein, approved formulations, and Further use involves evaluating the presence of FGFR3 R248C in biological samples from patients. This includes the methods disclosed herein, approved formulations, and Further use involves evaluating the presence of FGFR3 S249C in biological samples from patients. This includes the methods disclosed herein, approved formulations, and Further use involves evaluating the presence of FGFR3 G370C in biological samples from patients. This includes the methods disclosed herein, approved formulations, and Further use involves evaluating the presence of FGFR3 Y373C in biological samples from patients. This includes.

[0074] In certain embodiments, the methods, approved formulations, and uses disclosed herein are... Furthermore, biological samples from patients are examined for the presence of FGFR3 gene fusions or FGFR2 gene fusions. This includes evaluating the method disclosed herein. The formulation and its use further involve taking a biological sample from the patient and using FGFR3-TACC3, FGFR 3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or as such This includes evaluating the existence of combinations of meanings. In some embodiments, this specification The methods and uses disclosed herein further involve the preparation of a biological sample from a patient for FGFR3-TACC3. This includes evaluating the current state. In some embodiments, the method disclosed herein Approved formulations and their use further involve the use of biological samples from patients with FGFR3-BAIAP2L This includes evaluating the presence of 1. In some embodiments, as disclosed herein The method, approved formulation, and use further involve taking a biological sample from a patient into FGFR2-BICC This includes evaluating the presence of 1. In some embodiments, as disclosed herein The method, approved formulation, and use further involve taking a biological sample from a patient using FGFR2-CASP. This includes evaluating the existence of 7.

[0075] Furthermore, in this specification, (a) susceptible to FGFR3 or FGFR2 gene alterations, and (b) within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Locally advanced disease that progressed during or after at least one line of prior platinum-containing chemotherapy. Approved formulations including erdafitinib for the treatment of adult patients with sexually transmitted or metastatic urothelial carcinoma. A prescribed medicine will be provided.

[0076] Evaluation of the sample for the presence of one or more FGFR gene alterations Furthermore, this specification provides a method for treating urothelial carcinoma in a patient, wherein (a) one or more Regarding the presence of the above fibroblast growth factor receptor (FGFR) gene mutation, a biological sample was obtained from the patient. (b) Evaluate the presence of one or more FGFR gene mutations in the sample. Approval for the aforementioned formulation to contain an FGFR inhibitor in the amount indicated on the formulation label. A method is provided which includes treating with the formulation.

[0077] Furthermore, this specification provides for the use of fibroblast growth factors in the treatment of urothelial carcinoma in patients. Approved formulations containing sub-receptor (FGFR) inhibitors are listed, and the approved formulations are: The preparation is administered in the amount indicated on the preparation label, and the biopsy of the patient is performed. The test assesses the presence of one or more FGFR gene mutations.

[0078] Furthermore, this specification also describes the manufacture of a pharmaceutical product for the treatment of urothelial carcinoma in patients. The use of approved formulations containing blast growth factor receptor (FGFR) inhibitors is described. The medicine is administered in the amount indicated on the formulation label for the said formulation, and the patient The biological sample is evaluated for the presence of one or more FGFR gene alterations.

[0079] The following methods for evaluating the presence of one or more FGFR gene alterations in biological samples or equivalently applicable to any of the methods disclosed for treatment and use.

[0080] The disclosed method involves the presence of one or more FGFR gene alterations in a patient's biological sample. In such cases, it is suitable for treating cancer in patients. In some embodiments, FGF The R gene alteration may be one or more FGFR fusion genes. In some embodiments, An FGFR gene alteration can be one or more FGFR mutations. In some embodiments, FGFR gene alterations can be one or more FGFR amplifications. In some embodiments, One or more combinations of FGFR gene alterations can be present in biological samples from patients. For example, in some embodiments, an FGFR gene mutation is one or more FGFR fusion genes. This can be a gene and one or more FGFR mutations. In some embodiments, the FGFR gene The changes may include one or more FGFR fusion genes and one or more FGFR amplifications. In that embodiment, the FGFR gene change is one or more FGFR mutations and one or more FG FR amplification is possible. In yet another embodiment, the FGFR gene change is one or more FG This can be an FR fusion gene, mutation, or amplification. Exemplary FGFR fusion genes are listed in Table 1. Provided, FGFR2-BICC1;FGFR2-CASP7;FGFR3-BAIAP2 L1; FGFR3-TACC3 V1; FGFR3-TACC3 V3; or a combination thereof Examples include, but are not limited to, those listed above.

[0081] A preferred method for evaluating the presence of one or more FGFR gene alterations in a biological sample is The Methods section of this specification and the entirety of International Publication No. 2016 / 04 are incorporated herein. This is described in pamphlet No. 8833. For example, although there is no intention to limit it, biological samples Evaluating the presence of one or more FGFR gene alterations can be done using any combination of the following steps. This may include: the isolation of RNA from a biological sample; the synthesis of cDNA from RNA. to amplify cDNA (pre-amplified or not pre-amplified). In this embodiment, a biological sample is evaluated for the presence of one or more FGFR gene alterations. This involves a pair of plastics that bind cDNA from the patient to one or more FGFR gene mutations and amplify them. Amplify with an imer; and determine whether one or more FGFR changes are present in the sample. This may include the following. In some embodiments, cDNA may be pre-amplified. In this case, the evaluation process involves isolating RNA from the sample and extracting cDNA from the isolated RNA. This may include synthesis and pre-amplification of cDNA.

[0082] Suitable primer pairs for carrying out the amplification process are internationally published, as exemplified below. This includes information disclosed in pamphlet No. 2016 / 048833, but is not limited to these. It is not determined.

[0083] [Table 3]

[0084] The presence of one or more FGFR gene mutations is indicated at the time of diagnosis, after tumor resection, and after first-line therapy. It can be evaluated at any suitable point in time, including during clinical treatment or any combination thereof.

[0085] For example, a biological sample taken from a patient may indicate whether the patient has or is susceptible to cancer. Which pathological conditions or diseases cause upregulation of FGFR levels or activity, or normalization of FGFR activity? Sensitization of the sexual pathway, or growth factor ligand levels or growth factor ligand activity, etc. Upregulation of growth factor signaling pathways, or downstream biochemical pathways of FGFR activation Does it feature a genetic abnormality or abnormal protein expression that leads to upregulation? It can be analyzed to determine whether or not.

[0086] Examples of such abnormalities that lead to activation or sensitization of FGFR signaling include apothesis Loss or inhibition of the cis pathway, upregulation of the receptor or ligand, or the receptor or Genetic changes in ligands, such as the presence of PTK variants, can be cited. FGFR1, F Genetic changes in GFR2, FGFR3, or FGFR4, or upregulation of FGFR1. In particular, tumors with overexpression or gain-of-function gene changes in FGFR2 or FGFR3 The ulcer may be particularly sensitive to FGFR inhibitors.

[0087] The method, approved formulation, and use further involve one or more F in the biological sample prior to the administration step. This may include evaluating the presence of GFR gene alterations.

[0088] Diagnostic tests and examinations typically involve tumor biopsy samples and blood samples (for the isolation and concentration of shed tumor cells). (Shrinkage), stool biopsy, sputum, chromosome analysis, pleural fluid, ascites, oral paracentesis, biopsy, circulating DNA, or urine The procedure is performed on a biological sample selected from the following. In a particular embodiment, the biological sample is blood A fluid, lymph fluid, bone marrow, solid tumor sample, or any combination thereof. A specific implementation Morphologically, the biological sample is a solid tumor sample.

[0089] Methods for identifying and analyzing genetic alterations and upregulations of proteins are known to those skilled in the art. Screening methods include reverse transcription polymerase chain reaction (RT-PCR) or fluorescence In situ hybridization (FISH) and other in situ hybridizers Standard methods such as [mention specific methods] are examples, but are not limited to these.

[0090] Preserving genetic alterations in FGFR, particularly FGFR gene alterations as described herein. Identifying individuals who are particularly suitable for treatment with erdafitinib means that the patient would be especially well-suited for this treatment. It is possible. Tumors should be screened preferentially for the presence of FGFR variants before treatment. It is possible. The screening process usually involves direct sequencing, nucleotide my This would involve cross-array analysis or the use of mutant-specific antibodies. In addition, such genetic mutations The diagnosis of tumors with morphology is known to those skilled in the art, including RT-PCR and FISH. It can be carried out using the methods described in the details.

[0091] In addition, for example, FGFR gene changes are, for example, PCR and as previously described herein. Direct sequencing of tumor biopsies using a method that directly sequences the PCR product described. It can be identified by testing. Those skilled in the art can test for overexpression, activation, or mutation of the aforementioned protein. We recognize that all such well-known methods for obtaining the necessary information are applicable to this case. It is likely.

[0092] In RT-PCR screening, the level of mRNA in tumors is After creating a cDNA copy, it is evaluated by amplification of the cDNA by PCR. The method of R amplification, primer selection, and amplification conditions are known to those skilled in the art. Nucleic acid manipulation PCR is, for example, Ausubel, FM et al., eds. (2004) Current Protocols in Molecular Biology,J ohn Wiley & Sons Inc. or Innis, MAet al., eds.(1990) PCR Protocols: a guide to meth ods and applications,Academic Press,San The reaction and operation will be carried out according to the standard methods described in Diego, including nucleic acid techniques. Also, Sambrook et al., (2001), 3rd Ed, Molecul lar Cloning:A Laboratory Manual,Cold Spr. It will be published in the Harbor Laboratory Press. Or, RT - Commercially available kits for PCR (e.g., Roche Molecular Bioch) (Emicals), or U.S. Patent No. 4,666,828; also No. 4,683,20 Specification No. 2; Specification No. 4,801,531; Specification No. 5,192,659; Specification No. 5,192,659; Specification No. 5,272,057, Specification No. 5,882,864, and Specification No. 6,218, The methodology described in Specification No. 529 (incorporated herein by reference) It can be used. In situ hybridization techniques for evaluating mRNA expression. An example of this would be fluorescence in situ hybridization (FISH) (Anger See r(1987) Meth. Enzymol., 152:649).

[0093] Generally, in situ hybridization involves the following main steps: (1) fixation of the tissue to be analyzed; (2) pretreatment of the sample to increase the accessibility of the target nucleic acid and reduce non-specific binding; (3) hybridization of the nucleic acid mixture to the biological structure or nucleic acids in the tissue; (4) post-hybridization washing to remove nucleic acid fragments that did not bind during hybridization, and (5) detection of the hybridized nucleic acid fragments. Probes used for such applications are usually labeled with, for example, radioisotopes or fluorescent reporters. Preferred probes are long enough to allow specific hybridization to the target nucleic acid under stringent conditions, for example, about 50, 100, or 200 nucleotides to about 1000 nucleotides or more. Standard methods for performing FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M.S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pp.077-088; Series: Methods in Molecular Medicine. fixation of the tissue to be analyzed; (2) pretreatment of the sample to increase the accessibility of the target nucleic acid and reduce non-specific binding; (3) hybridization of the nucleic acid mixture to the biological structure or nucleic acids in the tissue; (4) post-hybridization washing to remove nucleic acid fragments that did not bind during hybridization, and (5) detection of the hybridized nucleic acid fragments. Probes used for such applications are usually labeled with, for example, radioisotopes or fluorescent reporters. Preferred probes are long enough to allow specific hybridization to the target nucleic acid under stringent conditions, for example, about 50, 100, or 200 nucleotides to about 1000 nucleotides or more. (4) post-hybridization washing to remove nucleic acid fragments that did not bind during hybridization, and (5) detection of the hybridized nucleic acid fragments. Probes used for such applications are usually labeled with, for example, radioisotopes or fluorescent reporters. Preferred probes are long enough to allow specific hybridization to the target nucleic acid under stringent conditions, for example, about 50, 100, or 200 nucleotides to about 1000 nucleotides or more. (5) detection of the hybridized nucleic acid fragments. Probes used for such applications are usually labeled with, for example, radioisotopes or fluorescent reporters. Preferred probes are long enough to allow specific hybridization to the target nucleic acid under stringent conditions, for example, about 50, 100, or 200 nucleotides to about 1000 nucleotides or more. Preferred probes are long enough to allow specific hybridization to the target nucleic acid under stringent conditions, for example, about 50, 100, or 200 nucleotides to about 1000 nucleotides or more. Preferred probes are long enough to allow specific hybridization to the target nucleic acid under stringent conditions, for example, about 50, 100, or 200 nucleotides to about 1000 nucleotides or more. Standard methods for performing FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M.S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pp.077-088; Series: Methods in Molecular Medicine. Standard methods for performing FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M.S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pp.077-088; Series: Methods in Molecular Medicine. Standard methods for performing FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M.S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pp.077-088; Series: Methods in Molecular Medicine. Standard methods for performing FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M.S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pp.077-088; Series: Methods in Molecular Medicine. Standard methods for performing FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M.S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pp.077-088; Series: Methods in Molecular Medicine. Standard methods for performing FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M.S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pp.077-088; Series: Methods in Molecular Medicine. Standard methods for performing FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M.S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pp.077-088; Series: Methods in Molecular Medicine. Standard methods for performing FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M.S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pp.077-088; Series: Methods in Molecular Medicine. are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M.S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pp.077-088; Series: Methods in Molecular Medicine.

[0094] Methods for gene expression profiling are described in (DePrimo et al. (20 03), described by BMC Cancer, 3:3). In short, this The protocol is as follows: Double-stranded cDNA is used to prime the synthesis of the first strand of cDNA. (dT)24 oligomer (SEQ ID NO: 38: tttttttttt ttt After being synthesized from total RNA using tttttttt tttt), a random hexamer is produced. This is done by the synthesis of the second strand of cDNA using primers. Double-stranded cDNA is produced by biotin Used as a template for in vitro transcription of cRNA using ribonucleotides. cRNA was developed by Affymetrix (Santa Clara, CA, USA). Chemically fragmented according to the protocol described, followed by human genome It is hybridized overnight on the array.

[0095] Alternatively, protein products expressed from mRNA can be used in immunohistochemistry of tumor samples, and by microscopy. Solid-phase immunoassay using Rotiter plates, Western blotting, 2D SDS - Polyacrylamide gel electrophoresis, ELISA, flow cytometry and the art. The assay may be performed by other methods to detect specific proteins known as [protein name]. The method of output would involve the use of site-specific antibodies. Those skilled in the art will know FGFR, and / or Detection of upward control of VEGFR, or FGFR and / or VEGFR variants All such well-known methods for detecting mutants are applicable to this case. They will realize this.

[0096] Abnormal levels of proteins such as FGFR can be detected by standard enzyme assays, e.g., this specification. It can be measured using the assay described in the book. Activation or overexpression can also be measured using tissue samples, e.g. For example, it can be detected in tumor tissue. (From Chemicon International) The tyrosine kinase activity is measured by assays of the obtained substances, etc. Tyrosine kinase will be immunoprecipitated from the sample lysate, and its activity will be measured.

[0097] Alternative methods for measuring FGFR overexpression or activation, including isoforms, are microvascular dense This includes the measurement of degrees. This is, for example, Orre and Rogers (Int J Ca It can be measured using the method described in ncer (1999), 84(2)101-8). The assay method also includes the use of markers.

[0098] Therefore, all of these methods are particularly suitable for treating tumors with the compounds of the present invention. It can be used to determine.

[0099] Erdafitinib is used in patients with genetically altered FGFR, particularly those with mutated FGFR. It is particularly useful in the treatment of urothelial carcinoma with FGFR2 It is sensitive to genetic mutations or FGFR3 gene mutations. In certain embodiments, FGFR 2. FGFR3 gene changes are FGFR3 gene mutations or FGFR2 or FGFR It is a 3-gene fusion. In some embodiments, the FGFR3 gene mutation is R248C, S249C, G370C, Y373C, or any combination thereof. Further implementation Morphologically, FGFR2 or FGFR3 gene fusions are FGFR3-TACC3, FGFR 3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or as such It is a combination of meanings.

[0100] Pharmaceutical Composition and Administration Route In view of the useful pharmacological properties, generally FGFR inhibitors, and more specifically erdafitinib can be formulated into various pharmaceutical forms for the purpose of administration.

[0101] In one embodiment, the pharmaceutical composition (e.g., formulation) comprises at least one active compound of the present invention in combination with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants, or other substances well-known to those skilled in the art and optionally in combination with other therapeutic or prophylactic agents.

[0102] To prepare the pharmaceutical composition, an effective amount of a generally FGFR inhibitor, and more specifically erdafitinib as an active ingredient, is combined in a homogeneous mixture with a pharmaceutically acceptable carrier which can take a wide variety of forms depending on the desired preparation for administration. The pharmaceutical composition can be in any form suitable for oral, parenteral, topical, intranasal, ocular, aural, rectal, intravaginal, or transdermal administration and is preferably in a unit dosage form suitable for oral administration, rectal administration, transdermal administration, or parenteral injection. For example, when preparing this composition in an oral dosage form, for oral liquid preparations such as suspensions, syrups, elixirs, and solutions, for example, water, glycols, oils, alcohols, etc.; or for powders powders, pills, capsules, and tablets, any of the usual pharmaceutical media such as solid carriers, for example, starch, sugars, kaolin , lubricants, binders, disintegrants, etc. can be used. , lubricants, binders, disintegrants, etc. can be used. can be used.

[0103] The pharmaceutical compositions of the present invention, particularly capsules and tablets, comprise one or more pharmaceutically acceptable excipients Forming agents (pharmaceutically acceptable carriers), for example, disintegrants, diluents, fillers, binders, buffers, It may contain lubricants, viscous agents, thickeners, sweeteners, flavorings, colorings, preservatives, etc. Formulating agents can serve multiple purposes.

[0104] Suitable disintegrants are those with a high expansion rate. Examples include hydrophilic, insoluble, or water-soluble disintegrants. Poorly soluble crosslinked polymers, such as crospovidone (crosslinked polyvinylpyrrolidone) and This is roscarmellose sodium (cross-linked carboxymethylcellulose sodium). For convenience, the amount of disintegrant in the tablet according to the invention is preferably in the range of approximately 2.5 to approximately 15% w / w. The range is approximately 2.5-7% w / w, and in particular, it can be in the range of approximately 2.5-5% w / w. Disintegrants, when used in large quantities, naturally result in sustained-release formulations; therefore, disintegrants are used as diluents or fillers. It is advantageous to dilute it with an inert substance called a dilution agent.

[0105] Various materials may be used as diluents or fillers. For example, lactose monohydrate, Anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch , cellulose (for example, microcrystalline cellulose (Avicel®), silicified microcrystalline cellulose) (Low), dihydrated or anhydrous calcium hydrogen phosphate, and other known in the art The substance, and mixtures thereof (for example, those marketed as Microcelac®) It is a spray-dried mixture of lactose monohydrate (75%) and microcrystalline cellulose (25%). Microcrystalline cellulose and mannitol are preferred. Diluents in the pharmaceutical composition of the present invention or For convenience, the total amount of filler should be in the range of approximately 20% to approximately 95% w / w, preferably approximately 55% to approximately 95% w / w, or in the range of approximately 70% to approximately 95%, or in the range of approximately 80% to approximately 95% w / w It could be within the range of approximately 85% to 95% w / w.

[0106] Lubricants and slicksers may be used in the manufacture of specific dosage forms, typically in the manufacture of tablets. It will be used in such cases. Examples of lubricants and abrasives include hydrogenated vegetable oil, for example, water. Cottonseed oil, magnesium stearate, stearic acid, sodium lauryl sulfate, lauryl Magnesium lyl sulfate, colloidal silica, colloidal anhydrous silica, talc, and mixtures thereof. , and others known in the art. An interesting lubricant is stearate. It is a mixture of magnesium and magnesium stearate and colloidal silica, Magnesium allate is preferred. A preferred lubricant is colloidal anhydrous silica.

[0107] If present, lubricants are generally present in an amount of 0.2-7.0% w / w of the total composition weight, especially It contains 0.5-1.5% w / w, or more specifically, 1-1.5% w / w.

[0108] If present, the lubricant is generally 0.2-7.0% w / w of the total composition weight, especially 0.2-2% w / w, or 0.5-2% w / w, or 0.5-1.75% w / w, Or it contains 0.5-1.5% w / w.

[0109] A binder may be optionally used in the pharmaceutical composition of the present invention. A suitable binder is: Water-soluble polymers, such as alkylcelluloses like methylcellulose; hydroxymethylcellulose Cellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxycellulose Hydroxyalkylcellulose such as xybutylcellulose: hydroxyethylmethylcellulose Lurose and hydroxypropylmethylcellulose, etc. Lurose; Carboxymethylcellulose and other carboxyalkylcelluloses; Sodium Alkali metal salts of carboxyalkyl cellulose, such as mucarboxymethylcellulose; Carboxymethylethylcellulose and other carboxyalkylalkylcelluloses; Boxyalkylcellulose ester; starch; sodium carboxymethyl amylopectin Pectin such as tin; chitin derivatives such as chitosan; trehalose, cyclodextrin and disaccharides, oligosaccharides and polysaccharides such as their derivatives, alginic acid, and its alkali metals and compounds Monium salt, carrageenan, galactomannan, tragacanth, agar, gum arabic, guar Rubber and xanthan rubber; polyacrylic acid and its salts; polymethacrylic acid, its salts and Sterl, methacrylate copolymer; polyvinylpyrrolidone (PVP), polyvinyl alcohol The material is PVA (PVA) and its copolymers, for example, PVP-VA. Preferably, it is water-soluble. The polymer is, for example, hydroxypropyl methylcellulose, for example, hydroxypropyl This is a hydroxyalkylalkylcellulose such as methylcellulose 15cps.

[0110] Other excipients, such as colorants and pigments, may also be added to the composition of the present invention. It contains titanium dioxide and food-grade dyes. The coloring agent or pigment in the formulation of the present invention Although optional, when used, the colorant shall be used in the maximum amount based on the total composition weight. It can exist in an amount of 3.5% w / w.

[0111] The fragrance is optional in the composition and may be synthetic flavoring oils and aromatic compounds for flavoring or natural It can be selected from oils, extracts from plant leaves, flowers, fruits, etc., and combinations thereof. These contain cinnamon oil, wintergreen oil, peppermint oil, bay oil, anise oil, eucalyptus oil, and thyme oil. Obtain vanilla, citrus oils, such as lemon, orange, grape, lime, and grapefruit. Fruit essences such as apple, banana, pear, peach, strawberry, Raspberries, cherries, plums, pineapples, and apricots are also useful as flavorings. The amount of fragrance can depend on several factors, including the desired sensory receptor effect. Generally, fragrance It will be present in an amount of approximately 0% to approximately 3% (w / w).

[0112] Formaldehyde scavengers are compounds that can absorb formaldehyde. One or more reversible or irreversible bonds are formed between the formaldehyde scavenger and formaldehyde. It contains compounds that have a nitrogen center that is reactive with formaldehyde, such as by forming a compound. For example, Formaldehyde scavengers are reactive with formaldehyde and form Schiff base imines. It then contains one or more nitrogen atoms / centers that can subsequently bond with formaldehyde. For example, a formaldehyde scavenger is reactive with formaldehyde and contains one or more 5- It contains one or more nitrogen centers that form an 8-membered ring. The formaldehyde scavenger is preferably, It contains one or more amine or amide groups. For example, formaldehyde scavengers contain amino acids, Amino sugars, alpha-amine compounds, or their conjugates or derivatives, or mixtures thereof. It is possible. The formaldehyde scavenger may contain two or more amines and / or amides.

[0113] Formaldehyde scavengers include, for example, glycine, alanine, serine, threonine, and cis. Theine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, Aspartic acid, glutamic acid, arginine, lysine, ornithine, citrulline, tauri Pyrrolidine, meglumine, histidine, aspartame, proline, tryptophan , citrulline, pyrrolidine, asparagine, glutamine, or their conjugates or mixtures ; or contain, as far as possible, a pharmaceutically acceptable salt thereof.

[0114] In an embodiment of the present invention, the formaldehyde scavenger is meglumine or a pharmaceutically acceptable agent thereof. The salts that are produced are, in particular, meglumine bases.

[0115] Another object of the present invention is to provide pharmaceutical compositions as described herein, particularly in the form of tablets or capsules. A process for preparing a formaldehyde scavenger in capsule form, particularly a formaldehyde scavenger. n, and erdafitinib, its pharmaceutically acceptable salts or solvates, in particular, erda The phytinib base is mixed with a pharmaceutically acceptable carrier, and the mixture is compressed into a tablet. To provide a process characterized by either doing so or filling the aforementioned mixture into capsules. That is the case.

[0116] Tablets and capsules are the most advantageous oral dosage forms because they are easy to administer. In that case, a solid drug carrier is naturally used. In the case of parenteral compositions, the carrier is usually sterile water. It contains at least a large portion of it, but may also contain other components that aid solubility, for example, An injection containing a carrier that is physiological saline, glucose solution, or a mixture of physiological saline and glucose solution. A solution preparation may be prepared. A suspension for injection may also be prepared, in which case a suitable liquid carrier may be prepared. Suspensions and the like can be used. In a composition suitable for transdermal administration, the carrier has any properties. A combination of suitable additives in low proportions as desired, comprising a penetration enhancer and / or suitable It may optionally contain humectants, but these additives may cause serious adverse effects on the skin. No. The additive may facilitate administration to the skin and / or the desired composition These compositions may be useful in preparation. These compositions can be used in various ways, for example, as transdermal patches. It can be administered as a spot-on formulation or as an ointment. To ensure uniformity, it is particularly advantageous to formulate the aforementioned pharmaceutical composition into unit dosage forms. The unit dosage form, as used herein and in the claims, is suitable as a unit dose. This refers to physically separate units, each unit, along with the necessary drug carrier, producing the desired therapeutic effect. It contains a predetermined amount of the active ingredient calculated to achieve this. An example of such a unit dosage form is a tablet. Tablets (including scored tablets or coated tablets), capsules, pills, powdered preparations, and cachet preparations. , injectable solutions or suspensions, teaspoon and tablespoon amounts, and divided and compounded thereof There is something.

[0117] To facilitate administration and ensure uniformity of the dosage, the aforementioned pharmaceutical composition is formulated into a single dosage form. This is particularly advantageous. The unit dosage forms used herein are suitable as unit doses. This refers to a physically individual unit, and each unit, along with the necessary drug carrier, produces the desired therapeutic effect. It contains a predetermined amount of the active ingredient calculated to achieve the desired result. An example of such a unit dosage form is: Tablets (including scored tablets or coated tablets), capsules, pills, powdered preparations, cachets Preparations, injectable solutions or suspensions, teaspoon and tablespoon amounts, and combinations thereof. There are such products. The preferred forms are tablets and capsules.

[0118] In certain embodiments, the FGFR inhibitor is available in solid unit dosage form and suitable for oral administration. It is present in the unit dosage form. The unit dosage form contains approximately 1, 2, 3, 4, 5, 6, 7 units per unit dosage form. 8, 9, or 10 mg of an FGFR inhibitor or values ​​thereof, in particular 3, 4 or It may contain an amount limited by two of the 5 mg values.

[0119] Depending on the mode of administration, the pharmaceutical composition is preferably 0.05 to 99% by weight, more preferably The compound of the present invention is present in an amount of 0.1 to 70% by weight, more preferably 0.1 to 50% by weight, and 1 to 99.95% by weight, more preferably 30 to 99.9% by weight, even more preferably This will result in the inclusion of 50-99.9% by weight of pharmaceutically acceptable carriers, and the percentage is total The total weight of the composition is used as the basis.

[0120] The tablets or capsules of the present invention may be further film-coated to improve, for example, the taste. This can provide ease of swallowing and a superior appearance. Polymer film coating material This is known in the art. Preferred film coatings are aqueous films. It is a coating, and in contrast to solvent-based film coatings, but the latter This is because it may contain a smaller amount of aldehyde. Preferred film coating The material is Opadry® II aqueous film coating system, for example, Opad Opadory(registered trademark)II 85F92209 and others A more preferred film coating is a water-based moisture barrier film coating. Readilycoat (registered trademark) (for example, Readilycoat (registered trademark) Trademark) D), AquaPolish (registered trademark) MS, Opadry (registered trademark) amb Water-based films that protect against environmental moisture, such as Opadry® amb II. It is a coating. A preferred film coating is one which involves polyethylene glycol. Opadori is a high-performance moisture barrier film coating that is a PVA-based rapid release system. (Registered trademark) amb II.

[0121] In the tablets according to the present invention, the film coating is approximately 4% (w / w) of the total tablet weight. It is preferable that the total area is less than or equal to the following:

[0122] Regarding the capsule preparation according to the present invention, the hypromellose (HPMC) capsule preparation is gelatin It is preferable to capsules.

[0123] In one aspect of the present invention, the medical preparation described herein, in particular in the form of a capsule or tablet, The drug composition contains 0.5 mg to 20 mg base equivalents, or 2 mg to 20 mg base equivalents, or 0. 5 mg to 12 mg base equivalent, or 2 mg to 12 mg base equivalent, or 2 mg to 10 mg base Equivalents, or 2mg to 6mg base equivalents, or 2mg base equivalents, 3mg base equivalents, 4mg base equivalents Equivalent, 5 mg base equivalent, 6 mg base equivalent, 7 mg base equivalent, 8 mg base equivalent, 9 mg base Equivalent, 10 mg base equivalent, 11 mg base equivalent, or 12 mg base equivalent of erdafitini This includes , a pharmaceutically acceptable salt thereof or a solvate thereof. In particular, the medical The drug composition contains erdafitinib in amounts of 3 mg base equivalent, 4 mg base equivalent, or 5 mg base equivalent. It contains a pharmaceutically acceptable salt or solvate thereof.

[0124] In one aspect of the present invention, a pharmaceutical product described herein, in particular in the form of a capsule or tablet. The composition is 0.5 mg to 20 mg, or 2 mg to 20 mg, or 0.5 mg to 12 mg. Or 2mg to 12mg, or 2mg to 10mg, or 2mg to 6mg, or 2mg, 3mg g, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, or 1 Contains 2 mg of erdafitinib base. In particular, the pharmaceutical compositions described herein contain 3 mg Contains g, 4 mg, or 5 mg of erdafitinib base. In particular, the pharmaceuticals described herein The composition contains 3 mg, 4 mg, or 5 mg of erdafitinib base and approximately 0.5 to approximately 5% w / w, about 0.5 to about 3% w / w, about 0.5 to about 2% w / w, about 0.5 to about 1.5% Formaldehyde scavengers in w / w, or approximately 0.5 to 1% w / w, especially meglumine Includes. In particular, the pharmaceutical compositions described herein contain 3 mg, 4 mg, or 5 mg of eldaf. itinib base and approximately 0.5 to 1.5% w / w, or approximately 0.5 to 1% w / w of holopropyl alcohol. Maldehyde scavengers, particularly those containing meglumine.

[0125] In one aspect of the present invention, two or more, for example, two pharmaceutical compositions described herein are It may be administered to obtain a desired dose, for example, a daily dose.

[0126] The amount of formaldehyde scavenger, particularly meglumine, in the pharmaceutical composition according to the present invention is about 0 0.1 to approximately 10% w / w, approximately 0.1 to approximately 5% w / w, approximately 0.1 to approximately 3% w / w, approximately 0 0.1 to approximately 2% w / w, approximately 0.1 to approximately 1.5% w / w, approximately 0.1 to approximately 1% w / w, approximately 0.5 to approximately 5% w / w, approximately 0.5 to approximately 3% w / w, approximately 0.5 to approximately 2% w / w, approximately 0 It can range from 0.5% to approximately 1.5% w / w, and from approximately 0.5% to approximately 1% w / w.

[0127] The term "safe and effective amount" is defined in accordance with the amended Federal Food, Drug, and Cosmetic Act, and is used to describe the life of the subject. In a system, the desired biological or medical response is not outweighed by the benefits of such a response. This refers to the amount of active ingredient that is induced without the presence of squirting (secs.201-902,52 Sta t.1040 et seq., amended; 21 USC §§ 321-392). Totality is the most acceptable dose or optimal amount of the active ingredient necessary to achieve the desired benefit. It is often measured by toxicity tests that determine the dosage.

[0128] Furthermore, safety-focused testing can detect potential adverse effects that may arise from exposure to the drug. It is necessary to specify the application. Efficacy is determined by the active ingredient in strictly controlled clinical trials. When tested in appropriate circumstances such as those mentioned above, it provides health benefits that outweigh placebo or other interventions. It is often measured by determining whether or not it exhibits a certain characteristic.

[0129] The term “acceptable” in relation to a formulation, composition, or component means “treatment” as used herein. The beneficial effects of the preparation, composition, or component on the overall health of the person being treated are present. It means that, to a certain extent, it substantially outweighs the harmful effects.

[0130] All formulations for oral administration are available in dosage forms suitable for such administration.

[0131] Method of administration and treatment regimen Generally, FGFR inhibitors, and specifically erdafitinib, exert their antitumor activity. It is administered in an amount sufficient to achieve the desired result. Those skilled in the art will understand from the test results presented below in this specification. The effective dose can be easily determined. Generally, the therapeutically effective dose is 0.005 mg / kg to 1 It is thought that the dosage is 00 mg / kg body weight, especially between 0.005 mg / kg and 10 mg / kg body weight. The required dose is administered in 1, 2, 3, or 4 or more divided doses at appropriate intervals throughout the day. It may be appropriate to administer the divided dose, for example, 0.5 to 500 per unit dosage form. Contains mg, specifically 1 mg to 500 mg, and more specifically, 10 mg to 500 mg of the active ingredient. It can be formulated as a single dosage form.

[0132] In one embodiment, this specification describes using a safe and effective amount of FGFR inhibitor to treat urothelial carcinoma. This includes, consists of, or is essentially derived from administering to patients having a urinary tract This document describes a method for treating skin cancer in which an FGFR inhibitor is administered orally. In some embodiments, FGFR inhibitors in general, and specifically erdafitinib, are used every It is administered daily, especially once a day. In some embodiments, it is generally an FGFR inhibitor, and In some embodiments, erdafitinib is administered twice daily. GFR inhibitors, and specifically erdafitinib, are administered three times a day. In terms of administration, FGFR inhibitors, and specifically erdafitinib, are generally administered four times a day. In some embodiments, FGFR inhibitors are used in general, and specifically, erdafiti The nib is administered every other day. In some embodiments, generally an FGFR inhibitor, and Specifically, erdafitinib is administered once a week. In some embodiments, generally FGFR inhibitors, and specifically erdafitinib, are administered twice a week. In this embodiment, FGFR inhibitors in general, and specifically erdafitinib, are administered every other week. In some embodiments, FGFR inhibitors are used in general, and specifically, erdafiti Nib is administered orally on a daily schedule.

[0133] Generally, F is used in humans for the treatment of diseases or conditions described herein. The typical dosage of GFR inhibitors, and specifically erdafitinib, is approximately 1 to 20 mg per day. It is in the range of g. In some embodiments, FGFR inhibitors, and specifically Eldafi Tinib is administered at approximately 1 mg per day, approximately 2 mg per day, approximately 3 mg per day, and per day Approximately 4 mg, approximately 5 mg per day, approximately 6 mg per day, approximately 7 mg per day, per day Approximately 8 mg, approximately 9 mg per day, approximately 10 mg per day, approximately 11 mg per day, per day Approximately 12 mg per day, approximately 13 mg per day, approximately 14 mg per day, approximately 15 mg per day Approximately 16 mg per day, approximately 17 mg per day, approximately 18 mg per day, approximately It is administered orally to humans at a dose of 19 mg or approximately 20 mg per day.

[0134] In a particular embodiment, erdafitinib is administered orally once daily at a dose of approximately 8 mg. In further embodiments, the dose of erdafitinib is such that (a) the patient starts treatment. On the 14th to 21st day afterward, serum phosphate (PO4) levels should be less than approximately 5.5 mg / dL. (b) In cases where administration of erdafitinib at 8 mg once daily causes ocular disorders (c) administration of erdafitinib at 8 mg once daily was grade 2 If none of the above adverse reactions occur, take 1 dose per day from day 14 to day 21 after starting treatment. The dosage is increased from 8 mg once daily to 9 mg once daily.

[0135] In a particular embodiment, the dose of erdafitinib is given on the 14th day after the start of treatment. The dose is increased from 8 mg once daily to 9 mg once daily. In certain embodiments, The dose of dafitinib starts at 8 mg once daily on day 15 after the start of treatment, and then increases to once daily. The dose is increased up to 9 mg. In certain embodiments, the dose of erdafitinib is used to open up the treatment On the 16th day after initiation, the dosage is increased from 8 mg once daily to 9 mg once daily. In this embodiment, the dose of erdafitinib is once daily on the 17th day after the start of treatment. The dose is increased from 8 mg to 9 mg once daily. In certain embodiments, erdafitini The dosage of the drug is 8 mg once daily to 9 mg once daily starting on the 18th day after the start of treatment. The dose of erdafitinib is increased. In certain embodiments, the dose of erdafitinib is increased after the start of treatment. On day 19, the dose is increased from 8 mg once daily to 9 mg once daily. (In a specific embodiment) So, the dosage of erdafitinib starts at 8 mg once daily on day 20 after starting treatment. The dosage may be increased to 9 mg once a day.

[0136] In one embodiment, erdafitinib is administered in a dose of 10 mg. In this case, erdafitinib is administered intermittently in doses of 10 mg. In one embodiment, Erdafitinib is administered intermittently at a dose of 10 mg, with a 7-day onset / 7-day rest period. It can be done.

[0137] In one embodiment, erdafitinib is administered at a dose of 8 mg, particularly 8 mg once daily. In one embodiment, erdafitinib is administered in doses of 8 mg, particularly 8 mg once daily. Given, serum phosphate levels (for example, serum phosphate levels are <5.5 mg / dL) It is either <7 mg / dL, or in the range of 7 mg / dL to ≤9 mg / dL. Depending on the observed treatment-related (and including that range or ≤9 mg / dL), and the observed treatment-related Depending on the adverse events, there is an option to increase the dose to 9 mg. In one embodiment, the dose is increased. Serum phosphate levels are used to determine whether or not erdafitinib treatment is the first phase. During the course of treatment, specifically on day 14±2 of erdafitinib administration, more specifically on day 14. It is measured at [location].

[0138] In one embodiment, the treatment cycle used herein is a 28-day cycle.

[0139] In one embodiment, the desired dose is administered as a single dose or simultaneously (or over a short period of time). In divided doses, or at appropriate intervals, for example, 2, 3, 4 or more times per day. It is convenient to provide it in a quantity. In some embodiments, the FGFR inhibitor is administered once a day. It is convenient to provide divided doses that are administered simultaneously (or over a short period of time). In this embodiment, the FGFR inhibitor is administered in divided doses, with equal allocations given twice daily. It is convenient that it be provided in this form. In some embodiments, the FGFR inhibitor is administered three times a day. It is preferable to be provided in divided doses administered in equal allocations. In terms of administration, FGFR inhibitors are administered in divided doses, with each dose being given four times a day in equal portions. It would be convenient if it were provided.

[0140] In a particular embodiment, the desired dose is obtained by administering partial units over the course of a day. The total amount of FGFR inhibitor delivered throughout the day provides the total daily dose. It can be delivered in units of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 parts.

[0141] In some embodiments, the amount of FGFR inhibitor administered to a human is determined by the state of the disease or condition. The circumstances and severity, the identity of the person (e.g., weight), and any specific additional treatments to be administered. This includes, but is not limited to, other factors that can cause fluctuations.

[0142] In a further embodiment, the patient has received at least one prior treatment for the treatment of urothelial carcinoma. In some embodiments, at least one prior treatment for the treatment of urothelial carcinoma is , a platinum-containing chemotherapy. In certain embodiments, urothelial carcinoma is treated with at least 1 The treatment progressed during or after one line of platinum-containing chemotherapy. In further embodiments, Tina-containing chemotherapy is either neoadjuvant platinum-containing chemotherapy or adjuvant platinum It is a chemotherapy regimen containing. In a further embodiment, urothelial carcinoma is treated with at least one line of During neoadjuvant platinum-containing chemotherapy or adjuvant platinum-containing chemotherapy or It progressed within the following 12 months.

[0143] In further embodiments, erdafitinib is (a) a potent CYP2C9 inhibitor or C (b) Drug therapy with YP3A4 inhibitors; (b) potent CYP2C9 inducers or CYP3A4 inducers (c) A drug therapy that is an active agent; (c) A moderate CYP2C9 inducer or CYP3A4 inducer. Drug therapy; or (d) drug therapy that is a serum phosphate level modifier. In certain embodiments, erdafitinib is a potent CYP2C9 inhibitor or CYP3A inhibitor. 4. Not administered in combination with drug therapy that is an inhibitor. In certain embodiments, erdafitini B is not administered in combination with drug therapy that involves potent CYP2C9 inhibitors. In this context, erdafitinib is administered in combination with drug therapy, which is a potent CYP3A4 inhibitor. No. In certain embodiments, erdafitinib is a potent CYP2C9 inducer or C It is not administered in combination with drug therapy that is a YP3A4 inducer. Fitinib is not administered in combination with drug therapies that are potent CYP2C9 inducers. In this embodiment, erdafitinib is used in combination with drug therapy, which is a potent CYP3A4 inducer. Not administered. In certain embodiments, erdafitinib induces moderate CYP2C9 induction. It is not administered in combination with drug therapies that are pharmacokinetics or CYP3A4 inducers. In certain embodiments Erdafitinib is a moderate CYP2C9 inducer and is administered in combination with other drug therapies. In certain embodiments, erdafitinib is a moderate CYP3A4 inducer. It is not administered in combination with drug therapy. In certain embodiments, erdafitinib is used with serum phosphorus It is not administered in combination with drug therapies that modify the salt level.

[0144] In certain embodiments, erdafitinib is a drug therapy that (a) is a CYP3A4 substrate. (b) Drug therapy that is an OCT2 substrate; or (c) P-glycoprotein (glycotp It is not administered in combination with drug therapies that use rotein (P-gp) substrates. In this context, erdafitinib is not administered in combination with CYP3A4 substrate-based drug therapies. In certain embodiments, erdafitinib is administered in combination with a drug therapy that is an OCT2 substrate. It is not possible. In certain embodiments, erdafitinib is a P-glycoprotein (glyco It is not administered in combination with drug therapies that use tprotein (P-gp) substrates.

[0145] Non-exclusive examples of potent CYP3A4 inhibitors include boceprevir and aprepitant. Clarithromycin, conivaptan, grapefruit juice, indinavir, lopina Viru, itraconazole, mibefurazil, ketoconazole, nefazodone, ritonavir, Posaconazole, nelfinavir, saquinavir, conivaptan, telaprevir, bocepre Viru, telithromycin, clarithromycin, voriconazole, clotrimazole, di Lutiazem, erythromycin, fluconazole, verapamil, and troleandmycin One example is n.

[0146] Non-exclusive examples of moderate to potent CYP3A4 inducers include abasimib, and Western cyptocyan. St. John's wort, carbamazepine, efavirenz, f Enytoin, etravirine, bosentan, nafcillin, rifampin, modafinil, ri Examples include fabutin and barbiturates.

[0147] A non-limiting example of a potent CYP2C9 inhibitor is fluconazole.

[0148] A non-exclusive example of a CYP2C9 inducer is carbamazepine. pine), rifampin, enzalutamide, secobarbital, nevirapine, Western Examples include St. John's wort and phenobarbital. .

[0149] Kit / Manufactured product For use in the methods of use described herein, the kit and manufactured products are also as described herein. Such kits are described in detail. Includes packaging or containers that are compartmentalized to accept dosages. Suitable containers include Examples include bottles. In one embodiment, the container is made of glass or plastic. It is formed from a variety of materials.

[0150] The products provided herein contain packaging materials. Packaging materials used for packaging pharmaceuticals. For example, see U.S. Patent No. 5,323,907 and No. 5,052,558. Examples include those specified in Specification No. 5,033,252. Examples of pharmaceutical packaging materials and This includes, but is not limited to, blister packs, bottles, tubes, bags, containers. Vessels, bottles, and selected formulations, as well as any packaging materials suitable for the intended mode of administration and treatment. These are some examples.

[0151] The kit typically includes a label listing the contents and / or instructions for use, as well as instructions for use. This includes accompanying documentation with instructions for use. A set of instructions would also typically be included.

[0152] In one embodiment, the label is present on or attached to the container. The letters, numbers, or other symbols forming the label are affixed, molded, or etched onto the container itself. In that case, the label is present on the container and also within the receptacle or carrier that holds the container. If so, the label will be attached to the container (for example, as part of the accompanying leaflet).

[0153] In one embodiment, the label is used to indicate that the contents are intended for a specific therapeutic use. The label also indicates how to use the contents, for example, how to use the method described herein.

[0154] In a particular embodiment, the pharmaceutical composition contains one of the compounds provided herein. The above unit dosage forms are provided in a pack or dispenser device. The container may contain, for example, metal foil or plastic foil, or, for example, a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. It is attached. In one embodiment, the pack or dispenser also has the markings for the manufacture, use, or sale of the pharmaceutical. A notice attached to the container is in a format specified by the government agency regulating sales, and this notice This does not mean that the drug form for human or veterinary administration has been approved by the institution. This is a projection. Such notifications are issued, for example, by the U.S. Food and Drug Administration regarding prescription drugs. Approved labeling information or approved product documentation. In one embodiment, conformity Compositions containing the compounds provided herein, formulated in a pharmaceutical carrier, are also prepared. They are then placed in appropriate containers and labeled for the treatment of the specified condition.

[0155] Sales methods This specification describes a method for selling an approved formulation containing erdafitinib, the method However, this includes selling such formulations and the reference list of drugs for such formulations. A method is provided in which the formulation label includes instructions for treating urothelial carcinoma. In the embodiment, the formulation is an ANDA formulation, a formulation for which a change in the approved drug product has been requested, or 505(b)( 2) It is a pharmaceutical product.

[0156] The terms “product” or “approved product” refer to government agencies, such as the Food and Drug Administration or other national government agencies. Approved by a similar institution in [location] to be marketed for at least one efficacy This product contains sexually transmitted medicinal ingredients.

[0157] The term "Reference List Drug (RLD)" refers to a new generic version of a drug that is biologically unsafe. These are formulations used for comparison to demonstrate scientific equivalence. 21 CFR 314.3( b)) It also includes the completed investigation documents, namely Article 8 of Directive 2001 / 83 / EC. (3) Submission of quality, preclinical and clinical data in accordance with Article 10a, Article 10b or Article 10c The submission of appropriate bioavailability tests is usually used to demonstrate bioequivalence. Research documents referenced in applications for marketing authorization of generic / hybrid drugs A drug that has received marketing authorization from a member state of the European Union or the European Commission based on its classification. .

[0158] In the United States, a company seeking approval to market a generic equivalent is required to use its abbreviated new The RLD must be referenced in the ANDA application. For example, in the ANDA application... The applicant has already approved the formulation, namely RLD, which the FDA has confirmed to be safe and effective. This view is based on the fact that the proposed generic drug is RLD and in certain respects. They must be proven to be identical. Specifically, with limited exceptions, AN The formulations submitted for DA will, in particular, have the same active ingredient, usage conditions, route of administration, and dosage form as RLD. It must have a potency and labeling information (with a permissible difference). RLD The ANDA applicant stated that the proposed ANDA formulation has, among other features, an active ingredient and dosage form. It must be shown that the administration route, potency, labeling information, and conditions of use are identical. It is a drug that is not listed in the table. In the electronic version of the Orange Book, there is a column and label for RLD. There is a column for standard products. In the printed version of the Orange Book, RLDs and standard products are specific Identified by a symbol. ANDA based on an approved conformity petition (petitioned AND Regarding A), the reference list drugs are generally listed in the table referenced in the approved conformity petition. It is a drug that was listed.

[0159] The standard product is required by applicants seeking ANDA approval to perform in vivo biological tests necessary for approval. This is an FDA-selected formulation that must be used when conducting equivalence testing. The FDA generally states that ANDA applicants should not use in in vivo bioequivalence studies. A single standard must be selected. Typically, the FDA designates a reference list drug as the standard. You will have to make a choice. However, in some cases (for example, if a reference list drug is discontinued) The FDA has determined that the product was not withdrawn from the market for safety or efficacy reasons, and If DA selects ANDA as the standard, the reference list drugs and standard may differ. be.

[0160] The FDA has identified reference list drugs in its list of prescription drugs, over-the-counter drugs, and discontinued drugs. Identify. Drugs listed in the table identified as reference list drugs are those for which the applicant has obtained ANDA approval. This refers to formulations that can be relied upon when seeking a drug. The FDA defines these as prescription formulations, over-the-counter (OTC) formulations, and We plan to regularly update the reference list of drugs identified in the list of discontinued formulations. .

[0161] The FDA also identifies reference standards in its lists of prescription and over-the-counter (OTC) formulations. The drugs listed in the identified table have undergone in vivo bioequivalence testing required for approval. This represents the FDA's best judgment at this time regarding the appropriate comparator drug to administer.

[0162] In some cases where the FDA does not designate a drug as a reference list drug, Drugs listed in tables like the one shown may be protected from competition with generic drugs. If the FDA has not designated a reference list drug for the formulation that the applicant intends to manufacture, the applicant candidate must You may ask the FDA to designate a reference list drug for that formulation.

[0163] The FDA ensures that generic drug applications can be submitted and evaluated. If it helps to prove, for example, if it is listed in the table of currently selected standard products If a drug is discontinued for reasons other than safety and efficacy, we will proactively select a new standard. There may be cases where you need to choose.

[0164] The different simplified approval routes for formulations under the FD&C Act are defined in Section 505 (j) of the FD&C Act. ) and including the simplified approval routes described in Section 505(b)(2) (21 each) USC355(j) and USC23 355(b)(2).

[0165] According to the FDA (https: / / www.fda.gov / downloads / D rugs / GuidanceComplianceRegulatoryInforma (tion / Guidances / UCM579751.pdf), NDA and ANDA are They can be classified into the following four categories: (1) A “standalone NDA” is filed under Section 505(b)(1) of the FD&C Act, An application approved under Section 505(c) of the Act, which is put into practice by or on behalf of the applicant. Full report of safety and effectiveness studies conducted or that the applicant has the right to refer to or use. It contains writing. (2) A 505(b)(2) application is filed under Section 505(b)(1) of the FD&C Act. This is an NDA approved under Section 505(c) of the Act, and covers the entire safety and efficacy investigation. The report contains at least some of the information necessary for approval provided by or to the applicant. It is not based on a test conducted for that purpose, and the applicant does not have the right to refer to or use it. It is what it is. (3) ANDA has been submitted and approved under Section 505(j) of the FD&C Act, This is an application for a duplicate of an approved formulation. ANDA is an application for a duplicate of an already approved formulation, that is, This relies on the FDA's determination that the Reference List Drugs (RLDs) are safe and effective. DA generally refers to the proposed generic product as (a) the active ingredient, conditions of use, route of administration, and agent. It is identical to RLD in terms of shape, potency, and labeling (with some permissible differences), (b) It must contain information demonstrating that it is biologically equivalent to RLD. If testing is required to establish the safety and effectiveness of the product, ANDA will not be submitted. There are cases where this is the case. (4) The petitioned ANDA shall specify its dosage form, route of administration, potency, or active ingredients (two or more) In products containing active ingredients, unlike RLD, Section 505(j)(2) of the FD&C Act In response to a petition (suitability petition) submitted under (C), the FDA has decided that the proposed formulation ANDA's determination that no further testing is required to establish the safety and efficacy of a formulation. It is one type.

[0166] The scientific premise underlying the Hatch-Waxman amendment is Section 505 of the FD&C Act (j The formulations approved under ANDA (under which the RLD is estimated to have equivalent therapeutic effect) are presumed to have the same therapeutic effect. This is what is meant to be done. Products classified as having equivalent therapeutic effects are subject to the requirements specified in the labeling. When administered to patients under these circumstances, the alternative product exhibits the same clinical efficacy and safety profile as the prescribed product. It can be replaced with the expectation that it will bring the file. In effect, the 505(b)(2) application offers greater flexibility regarding the characteristics of the proposed product. Approved. A 505(b)(2) application is permitted if the drug and therapeutic effect are the same as those listed in the table referenced at the time of approval. It is not necessarily the case that it will be evaluated as such.

[0167] In Europe, applicants can obtain generic / high-performance products that are the same as ANDA or sNDA formulations. In the application for a hybrid drug, the reference drug (product name, potency, dosage form) is synonymous with RLD. Identify the MAH, initial approval, member states / communities as follows: 1. A drug that is or was approved in the EEA and is defined in the European Pharmaceutical Affairs Law. This is used as evidence to indicate that the data protection period has expired. The reference drug identified for calculating the end of the period is a generic / hybrid drug. It may have a different potency, dosage form, route of administration, or be intended for presentation purposes than a pharmaceutical product. 2. Investigation documents for drugs cross-referenced in generic / hybrid drug applications (product name, generic / hybrid drug application) (Price, dosage form, MAH, marketing authorization number). This reference drug will be used to calculate the end of its data protection period. It was approved under a different name through a separate procedure from the reference drug identified for that purpose. Obtain. This reference drug product information is, in principle, for generic / hybrid drugs. This will serve as the basis for the product information requested. 3. The medicinal products used for bioequivalence testing (if applicable) (product name, potency, Dosage form, MAH, supplier's country of origin).

[0168] The term "equivalent therapeutic effect to the reference list drug" means that the formulation is a generic version of the reference list drug. The equivalent of a drug, i.e., a pharmaceutical equivalent, and as such, actual or potential The issue of bioequivalence is that sufficient in vivo and / or in vivo evidence supporting bioequivalence is required. The evidence in the FDA has resolved the issue, and the drug is now on the Reference List and A This means that the treatments are considered equivalent.

[0169] A "pharmaceutical equivalent" is a drug with the same dosage form and route of administration, and contains the same active drug component as the reference list drug. This refers to a preparation containing the same amount of [ingredient].

[0170] The FDA considers products that meet the following general criteria to have equivalent therapeutic effects. Classify them as follows: (1) They are approved as safe and effective; (2) They are (a) contains the same active drug component in the same dosage form and route of administration, and (b ) In terms of meeting official or other applicable standards of potency, quality, purity, and identity, medical (3) They are drug equivalents; (a) They are known or potential bioequivalents (b) The test does not involve sexual issues and meets the in vitro standards in which they are permissible, or If they exhibit such known or potential problems, they should be treated with appropriate biological care. They are biologically equivalent in that they are shown to meet the criteria of equality; (4) They are ten (5) They shall be marked with a minute; and they shall be manufactured in accordance with the regulations of the current Good Manufacturing Practices.

[0171] The term "biologically equivalent" or "bioequivalence" refers to drug equivalents or drug replacements. The active ingredient or active portion of the substitute under similar conditions in a properly designed test. In terms of the rate and extent to which a drug becomes available at the site of action when administered at the same molar dose. There is no statistically significant difference. Section 505(j)(8)(B) of the FD&C Act applies to the study and reference List one set of conditions for a drug to be considered bioequivalent. : [Test] The rate and extent of drug absorption were compared using the same molar dose of the therapeutic component under similar experimental conditions. [Reference] Rate and degree of drug absorption when administered in single or multiple doses. Not showing a significant difference from; or [Test] The degree of drug absorption is compared when the same molar dose of the therapeutic component is used under similar experimental conditions for a single dose. [Reference] When administered in either a single dose or multiple doses, a significant difference in the degree of drug absorption was observed. The absence of, and the difference in the rate of drug absorption from [reference] drugs, is intentional, and This will be reflected in the proposed labeling requirements and is essential for achieving effective drug concentrations for long-term use. It is not present, and the drug is considered medically insignificant.

[0172] If the above methods are not applicable (for example, if the substance is intended to be absorbed into the bloodstream) (In the case of a formulation that does not have bioequivalence) Other scientifically valid in vivo or in vitro studies to demonstrate bioequivalence In vitro testing methods may be appropriate in some cases.

[0173] For example, bioequivalence is determined using in vitro bioequivalence criteria, in particular, In vitro trials like these correlated with in vivo bioavailability data in humans. This can sometimes be demonstrated. In other circumstances, bioequivalence can be demonstrated in comparative clinical trials or This can sometimes be demonstrated through pharmacodynamic testing.

[0174] The term "sale" or "selling" refers to the transfer of a pharmaceutical product, such as a medical composition, from a seller to a buyer. This means transferring the oral dosage form.

[0175] The term "to propose for sale" refers to pharmaceutical preparations, such as pharmaceutical compositions and oral dosage forms. This refers to a sales proposal from a seller to a buyer.

[0176] Furthermore, this specification proposes for sale any approved formulations containing erdafitinib. A method, wherein the method includes proposing such formulation for sale, Reference list for such formulations, drug label for drug, for treating urothelial carcinoma A method including instructions is provided. In a particular embodiment, the formulation is an ANDA formulation, a pharmaceutical It is a product for which a change in product approval has been requested or a 505(b)(2) product.

[0177] Furthermore, this specification includes methods that involve selling approved formulations containing erdafitinib. If such a formulation exists, the formulation label for the reference list drug for that formulation may indicate the response rate or efficacy. A method including period data is described. In a particular embodiment, for such a formulation The formulation label for the reference list drug includes response rate data. In a particular embodiment, The response rate data is complete response rate data. In a particular embodiment, the response rate data is This is partial response rate data. In a particular embodiment, the response rate data is complete response rate data. and partial response rate data. In a particular embodiment, response rate for erdafitinib The prevalence rate was approximately 40.2%, and in particular, patients had locally advanced or metastatic urothelial carcinoma. In a particular embodiment, the response rate data for erdafitinib is approximately 32.2 In particular, patients undergoing neoadjuvant or adjuvant platinum-containing chemotherapy... During or after at least one line of previous platinum-containing chemotherapy, including within two months prior. The patient has locally advanced or metastatic urothelial carcinoma that has undergone chemotherapy (recurrent / resistant disease). In certain embodiments, the complete response rate data for erdafitinib is approximately 2.3%. In particular, patients undergoing neoadjuvant or adjuvant platinum-containing chemotherapy for 12 months or longer Progression during or after at least one line of prior platinum-containing chemotherapy, including within ( (Recurrent / resistant to chemotherapy) locally advanced or metastatic urothelial carcinoma. In terms of administration methods, the partial response rate data for erdafitinib was approximately 29.9%, particularly The patient must have received neoadjuvant or adjuvant platinum-containing chemotherapy within the past 12 months. The disease progressed during or after at least one line of previous platinum-containing chemotherapy (chemotherapy (Recurrent / resistant disease) locally advanced or metastatic urothelial carcinoma. In certain embodiments The complete response rate and partial response rate data for erdafitinib are approximately 32.2%. In particular, patients undergoing neoadjuvant or adjuvant platinum-containing chemotherapy... During or after at least one line of previous platinum-containing chemotherapy, including within two months prior. The patient has locally advanced or metastatic urothelial carcinoma (chemotherapy-induced recurrent / resistant disease). In one embodiment, the response duration data for erdafitinib was approximately 5.6 months. In particular, the patient has locally advanced or metastatic urothelial carcinoma. In further embodiments, The response duration data for dafitinib is approximately 5.4 months, and in particular, patients are neoadjuvant. At least one, including within 12 months of adjuvant or platinum-containing chemotherapy The disease progressed during or after the previous platinum-containing chemotherapy regimen (chemotherapy-relapsed / resistant disease). Patients have locally advanced or metastatic urothelial carcinoma.

[0178] Furthermore, this specification aims to improve the response rate or duration of response in patients with urothelial carcinoma. A method comprising administering an approved formulation containing erdafitinib to the patient. A method is provided which includes doing so in patients with urothelial carcinoma. A method for improving response rates, wherein the method comprises an approved formulation containing erdafitinib. A method is provided which includes administering to the patient. Furthermore, in this specification, urothelial carcinoma A method for improving the complete response rate in patients having erdafitinib A method is provided which includes administering an approved formulation containing to the patient. The book describes a method for improving the partial response rate in patients with urothelial carcinoma, and the method However, a method is provided which includes administering an approved formulation containing erdafitinib to the patient. In a particular embodiment, the response rate for erdafitinib is approximately 40.2%. In particular, the patient has locally advanced or metastatic urothelial carcinoma. In certain embodiments The response rate for erdafitinib is approximately 32.2%, and in particular, patients are neoadjuvant. At least one, including within 12 months of adjuvant or platinum-containing chemotherapy The disease progressed during or after the previous platinum-containing chemotherapy regimen (chemotherapy-relapsed / resistant disease). Patients have locally advanced or metastatic urothelial carcinoma. In certain embodiments, Eldafiti The complete response rate data for nib is approximately 2.3%, and in particular, patients with neoadjuvants... or at least one line of adjuvant platinum-containing chemotherapy within 12 months Local disease that has progressed during or after previous platinum-containing chemotherapy (chemotherapy-relapsed / resistant disease) The patient has advanced or metastatic urothelial carcinoma. In certain embodiments, the patient is related to erdafitinib. The partial response rate data is approximately 29.9%, and in particular, patients respond well to neoadjuvant or a Prior to at least one line of juvant platinum-containing chemotherapy, including within 12 months. Locally progressive disease that has progressed during or after platinum-containing chemotherapy (chemotherapy-relapsed / resistant disease) or has metastatic urothelial carcinoma. In certain embodiments, complete The overall response rate and partial response rate data were approximately 32.2%, and in particular, patients were neoadjusted. At least one, including within 12 months of adjuvant or platinum-containing chemotherapy The disease progressed during or after the previous platinum-containing chemotherapy regimen (chemotherapy-relapsed / resistant disease). Patients) have locally advanced or metastatic urothelial carcinoma. In further embodiments, Erdafitini The duration of response for b was approximately 5.6 months, and in particular, patients with locally progressive or metastatic urinary tract disease The patient has epithelial carcinoma. In a further embodiment, the duration of response to erdafitinib is approximately 5. The period is 4 months, and in particular, the patient is undergoing neoadjuvant or adjuvant platinum-containing chemotherapy. During or after at least one line of previous platinum-containing chemotherapy, including within 12 months of this treatment. The patient has locally advanced or metastatic urothelial carcinoma that has progressed to a stage where chemotherapy has relapsed or become resistant. In further embodiments, the approved formulation is an ANDA formulation or a formulation for which a change in drug approval has been requested. It is a drug.

[0179] Furthermore, this specification describes how to improve the response rate or duration of response in patients with urothelial carcinoma. A method wherein the method provides the patient with an approved formulation containing erdafitinib. A method is provided which includes doing so in patients with urothelial carcinoma. A method for improving response rates, wherein the method comprises an approved formulation containing erdafitinib. A method is provided which includes providing to the aforementioned patient. Furthermore, this specification also includes providing to urothelial carcinoma A method for improving the complete response rate in patients, wherein the method involves erdafitinib A method is provided which includes providing the patient with an approved formulation containing the specified. Therefore, a method for improving the partial response rate in patients with urothelial carcinoma, wherein the method A method is provided which includes providing the patient with an approved formulation containing erdafitinib. In a particular embodiment, the response rate for erdafitinib is approximately 40.2%. In particular, the patient has locally advanced or metastatic urothelial carcinoma. In certain embodiments, The response rate data for erdafitinib is approximately 32.2%, and in particular, patients are Neo At least 12 months including adjuvant or adjuvant platinum-containing chemotherapy Progression (chemotherapy relapse / resistance) during or after a previous line of platinum-containing chemotherapy. (Sexual disease) Having locally advanced or metastatic urothelial carcinoma. In certain embodiments, Eldaf The complete response rate data for itinib is approximately 2.3%, and in particular, patients with neoadjuvant At least one regimen including 12 months of ant or adjuvant platinum-containing chemotherapy (chemotherapy-related relapsed / resistant disease) that progressed during or after previous platinum-containing chemotherapy. The patient has locally advanced or metastatic urothelial carcinoma. In certain embodiments, erdafitinib The partial response rate data for this is approximately 29.9%, and in particular, patients are receiving neoadjuvant or This includes at least one line of adjuvant platinum-containing chemotherapy within 12 months. Locally progressive disease (chemotherapy-relapsed / resistant disease) that has progressed during or after previous platinum-containing chemotherapy. The patient has urothelial or metastatic urothelial carcinoma. In certain embodiments, the patient is related to erdafitinib. The complete response rate and partial response rate data were approximately 32.2%, and in particular, patients were Neo At least 12 months including adjuvant or adjuvant platinum-containing chemotherapy Progression (chemotherapy relapse / resistance) during or after a previous line of platinum-containing chemotherapy. (Sexual disease) Having locally advanced or metastatic urothelial carcinoma. In further embodiments, Eldafi The duration of response for tinib is approximately 5.6 months, and in particular, patients with locally advanced or metastatic disease The patient has urothelial carcinoma. In a further embodiment, the duration of response to erdafitinib is approximately 5.4 months, and in particular, patients receive neoadjuvant or adjuvant platinum-containing chemicals. During at least one line of previous platinum-containing chemotherapy, including within 12 months of the therapy. The patient subsequently developed locally advanced or metastatic urothelial carcinoma (chemotherapy-resistant / recurrent disease). In certain embodiments, the approved formulation is an ANDA formulation or a change in the drug approval. This is the application formulation. In further embodiments, the reference list of drugs relating to such formulations is as follows. The product label includes instructions for treating urothelial carcinoma.

[0180] Furthermore, this specification provides for approved formulations having at least one approved efficacy. The approved formulations provided contain erdafitinib. In certain embodiments, approved Approved formulations are NDA formulations, ANDA approved formulations, formulations for which a change in drug approval has been requested, or 5 05(b)(2) Formulation. Further embodiments refer to the approved formulation. The formulation includes a formulation label. In a further embodiment, the formulation label includes response rate data. In further embodiments, the formulation label includes partial response rate data. Further embodiments In a further embodiment, the formulation label includes complete response rate data. Includes partial and complete response rate data. In some embodiments, relating to erdafitinib. The response rate data was approximately 40.2%, and in particular, the patients had locally advanced or metastatic urothelial carcinoma. It has. In a particular embodiment, the response rate data for erdafitinib is approximately 32 The rate was 0.2%, and in particular, patients were receiving neoadjuvant or adjuvant platinum-containing chemotherapy. During or after at least one line of previous platinum-containing chemotherapy, including within 12 months of this treatment. The patient has locally advanced or metastatic urothelial carcinoma that has progressed to a stage where chemotherapy has relapsed or become resistant. In a particular embodiment, the complete response rate data for erdafitinib was approximately 2.3%. Yes, in particular, patients undergoing neoadjuvant or adjuvant platinum-containing chemotherapy for 12 months Progression during or after at least one line of previous platinum-containing chemotherapy, including within the last month (Chemotherapy-recurrent / resistant disease) locally advanced or metastatic urothelial carcinoma. In this embodiment, the partial response rate data for erdafitinib is approximately 29.9%. In particular, patients within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. The disease progressed during or after at least one line of prior platinum-containing chemotherapy, including ( (Therapeutic recurrent / resistant disease) locally advanced or metastatic urothelial carcinoma. Certain implementation In terms of morphology, complete response rate data and partial response rate data for erdafitinib are approximately 32 The rate was 0.2%, and in particular, patients were receiving neoadjuvant or adjuvant platinum-containing chemotherapy. During or after at least one line of previous platinum-containing chemotherapy, including within 12 months of this treatment. The patient has locally advanced or metastatic urothelial carcinoma that has progressed to a stage where chemotherapy has relapsed or become resistant. In certain embodiments, the formulation label includes duration of response data. In further embodiments, The response duration data for erdafitinib is approximately 5.6 months. Further embodiments The response duration data for erdafitinib is approximately 5.4 months, and in particular, patients less than 12 months prior to neoadjuvant or adjuvant platinum-containing chemotherapy. Both conditions progressed during or after a previous line of platinum-containing chemotherapy (chemotherapy-induced relapse). (Resistant disease) Has locally advanced or metastatic urothelial carcinoma.

[0181] Nucleotide sequence of FGFR fusion gene Nucleotide sequences for FGFR fusion cDNAs are provided in Table 4. The sequence corresponds to either FGFR3 or FGFR2, and the sequence shown in black is the fusion partner. The italicized sequence represents the intron sequence of the FGFR3 gene.

[0182] [Table 4]

[0183] [Table 5]

[0184] [Table 6]

[0185] [Table 7]

[0186] [Table 8]

[0187] [Table 9]

[0188] [Table 10]

[0189] [Table 11]

[0190] [Table 12] [Examples]

[0191] These examples are provided for illustrative purposes only and are not part of the claims provided herein. It is not limited to.

[0192] Example 1: Phase 2 multicenter open-label trial (NCT02365597) Phase 2 multicenter open-label trials are conducted on selected FGFR gene mutations (FGFR translocations or mutations). In patients with metastatic or surgically unresectable urothelial carcinoma (with different characteristics), Eldafi This study was conducted to evaluate the efficacy and safety of tinib.

[0193] This study includes a screening phase (molecular screening at any point before the first dose and This includes the clinical screening within 30 days of the first dose, the treatment period, and the post-treatment follow-up period. The treatment period includes the time from the first dose to the follow-up visit after treatment is completed. The observation period is until the patient dies. Until death, withdrawal of consent, loss of traceability, or completion of the trial, whichever comes first. It will be extended.

[0194] The experimental treatment was administered in 28-day cycles. Prior to interim analysis 1, there were two treatment regimens. The patient underwent the following two regimens until a regimen was selected for further testing: Regimen 1 (10 mg once daily intermittently (7 days / 7 days)); Regimen 2 (6 mg once daily) Participants were randomized in a 1:1 ratio to follow a 28-day cycle (one consecutive cycle). Randomization was performed based on performance. Performance status (0-1 vs. 2), hemoglobin level (<10 vs. ≥10g per dl), FG The type of FR mutation (mutation vs. fusion), prior treatment status (chemotherapy resistance vs. no chemotherapy), and The patients were stratified by disease distribution (presence or absence of visceral metastases [liver, lung, bone]). Selection of starting dose. This was based on the efficacy and tolerability of Phase 1 trials.

[0195] Based on interim analysis and pharmacokinetic-pharmacodynamic modeling of serum phosphate levels, the starting dose is The dosage was continuously increased to 8 mg per day (regime 3). Therefore, after the interim analysis... This became a single-arm trial. The administration further aimed to raise serum phosphate levels by the target day 14. (In Phase 1, doses of ≥5.5 mg per dl were accompanied by an improvement in response rate) In patients where no treatment-related adverse events were observed, pharmacodynamically guided The dosage was individualized by increasing it up to 9 mg per day. Treatment was administered according to the principal investigator's instructions for each disease. The condition continued until it progressed or an unacceptable adverse event occurred. Patients who experienced disease progression as assessed by the principal investigator. The patient was able to continue taking erdafitinib at the discretion of the principal investigator and the sponsor. Phase 2 Please refer to Figure 1 for the test scheme.

[0196] the purpose Main purpose: • Having metastatic or surgically unresectable urothelial carcinoma with specific FGFR genomic alterations. The response rate (complete response [CR] + partial response [PR]) of the selected dose regimen in the target population. To evaluate ). Secondary purpose • Evaluate the response rate of selected dose regimens in patients resistant to chemotherapy. • Progression-free survival for selected dose regimens in all and chemotherapy-resistant patients ( Evaluate PFS, duration of response, and overall survival. • In biomarker-specific subgroups (translocation pair mutations) with selected dose regimens Evaluating performance efficiency • Evaluate the response rate, PFS, duration of response, and overall survival of other dose regimens being tested. to • Evaluate the safety and pharmacokinetics of erdafitinib in all dose regimens.

[0197] patient The patients included were subject to Response Evaluation Criteria. In Solid Tumors version 1.1, patients with measurable urothelial carcinoma have been diagnosed. He was an adult.

[0198] The patient uses a custom reverse transcriptase polymerase chain reaction assay, formalin-contained. According to concentrated RNA analysis from paraffin-embedded tumor samples, at least one FGF The presence of an R2 / FGFR3 mutation or fusion was required.

[0199] Patients had progressive disease within 12 months after or during at least 1 line of prior systemic chemotherapy or neoadjuvant or adjuvant chemotherapy.

[0200] Treatment-naive patients who were ineligible for cisplatin according to protocol criteria were enrolled. Ineligibility for cisplatin was based on renal dysfunction defined as 1) a glomerular filtration rate of less than 60 mL / min / 1.73 m 2 by 24-hour urine measurement; 2) calculated values by the Cockcroft-Gault formula; or 3) grade 2 or greater peripheral neuropathy (Common Terminology Criteria for Adverse Events [CTCAE] version 4.0 (National Cancer Institute. CTCAE v4. 0. NCI, NIH, DHHS. May 29, 2009. NIH publication #09-7473:2009.)).

[0201] An Eastern Cooperative Oncology Group (ECOG) performance status (a 5-point scale where higher numbers reflect greater disability) of 0 to 2 was required. There was no limit on the number of prior treatment lines.

[0202] Prior immunotherapy (e.g., treatment with immune checkpoint inhibitors) was permitted.

[0203] Patients were required to have adequate bone marrow, liver, and renal (creatinine clearance ≥ 40 mL / min) function.

[0204] Patients with phosphate levels persistently above the upper limit of normal despite medical treatment, uncontrolled cardiovascular disease, brain metastases, known hepatitis B or C, or known HIV infection were

[0205] excluded. ​It was excluded.

[0206] judgement During screening, patients will be screened once every 6 weeks for the first 3 months, and then 12 times for the following 9 months. Once a week, followed by once every 4-6 months until the disease progresses, the chest, abdomen, and pelvis are computerized. Using CT or magnetic resonance imaging scans, RECIST is used to assess effectiveness. Evaluated according to v1.1. All objective responses were assessed within 4-6 weeks of the initial assessment. Confirmation by the principal investigator was required. Disease evaluation for regimen 3 was also independent. The X-ray examination was conducted by the X-ray examination review committee. Patients were contacted every 12 weeks for survival assessment. Safety was assessed based on clinical tests, physical examinations, electrocardiograms, and ophthalmological examinations. Adverse events and abnormalities are evaluated by the principal investigator and reported to NCI CTCAE v.4.0. Therefore, they were classified accordingly.

[0207] Evaluation items The primary endpoint of this trial is the response rate to the selected regimen (regmen 3). .

[0208] Secondary endpoints include progression-free survival (PFS), duration of response, overall survival, safety, and biopharmaceuticals. This includes the response rate and pharmacokinetics in marker-specific subgroups.

[0209] statistical analysis The trial was designed and 180 patients with specified FGFR changes were enrolled. Of these, more than 88 were required in the selected regimen. The main hypothesis is that the regimen The objective response rate (ORR) in step 3 was over 25%. The test showed that the true response rate was 42 Since it is a percentage, the power to reject the null hypothesis that the ORR is 25% or less is 85%, The alpha value on the side was 0.025. The response was judged by the principal investigator and an independent ER board. Therefore, it was evaluated. Progression-free survival and overall survival were evaluated using the Kaplan-Meier positive limit protocol. This was estimated using data from patients who were not aggravated and were alive or whose condition was unknown. Data was censored at the final tumor diagnosis. The primary efficacy endpoint was cut off in the primary analysis. It was analyzed at the time.

[0210] result patient 2214 patients were evaluated for eligibility. 210 patients were eligible / treated. Of these, 33 were enrolled in Regimen 1, 78 in Regimen 2, and 99 were selected. It was registered as regimen 3, a Phase 2 dose regimen.

[0211] Among patients treated with regimen 3, 40 deaths occurred at the cutoff date for the primary analysis. After death, the median follow-up period for survival was 11.0 months (interquartile range, 0.7+). 17.4 [95% confidence interval (CI), 9.1~12.2]). Within the monthly cycle received. The median value was 5.0 (range, 1-18); the median treatment duration was 5.3 months. In regimen 3, 41 out of 99 patients received 9 mg of Eldafi per day. The dosage was increased to tinib; 13 patients progressed at least as permissible by protocol. The treatment continued for four weeks.

[0212] Among patients treated with regimen 1 or 2, survival time was measured at the cutoff date for the primary analysis. The median follow-up period was 22.9 months in the group receiving regimen 1 (four Quantile range, 1.7+~25.3+[95% CI, 20.5~24.5]), Regimen 2 In the group receiving the treatment, the average time was 18.5 months (interquartile range, 0.4+~21.6 [95% CI]). The median number of cycles in regimens 1 and 2 was 15.0-19.4. The values ​​were 5.0 (range, 1-25) and 4.5 (range, 1-22), respectively. The values ​​were 4.4 months and 3.9 months for regimen 1 and 2, respectively.

[0213] The demographics and baseline disease characteristics of patients in regimens 1-3 are shown in Table 5. It will be shown.

[0214] [Table 13]

[0215] [Table 14]

[0216] [Table 15]

[0217] Across all regimens, prior to trial enrollment, 184 patients were first-line platinum-based. Of those who underwent chemotherapy, 83 received second-line chemotherapy and 24 received third-line chemotherapy. Throughout all regimens, the best ORR based on the investigator's judgment is the first-choice gemstone. Regarding Tabine + Cisplatin, 35% (33 out of 94 patients) were first-line: gemcitabine + calorie-containing syrup. Regarding voplatin, 25% (15 out of 59 patients); first-line treatments: methotrexate, vin bladder 23% (5 out of 22 people) reported adverse reactions to tin, doxorubicin, and cisplatin (MVAC). ; 17% (8 / 46) of the second-line treatments docetaxel, vinflunin, or paclitaxel ); and 15% (3) for third-line docetaxel, vinflunin, or paclitaxel. It was / 20).

[0218] Key evaluation criteria ORR confirmed based on the judgment of the principal investigator (40.4%, 30.7% to 50.1%) Table 6 shows the time to response among patients treated with bilateral 95% CI and regimen 3. This is shown. Since the lower boundary of the confidence interval was >25%, the primary endpoint was achieved. The additional 39 patients (39%) had stable disease with a disease assessment rating of ≥1. (>36 days). Two patients did not have disease assessment after baseline. OOR was, Previous chemotherapy, number of previous treatment lines, presence of visceral metastases, or age, sex, hemoglobin level. The results were similar regardless of baseline characteristics such as Bell's test or renal function (Table 6, Figure 2). Of the 97 patients with a post-baseline disease assessment of ≥1, 75 (77%) had a symptom. There was a decrease in the total diameter of the lesions, and 48 patients (49%) had the largest tumor between 30% and 100%. It showed reduction (Figure 3A). The ORR in regimen 3 based on independent X-ray examination was: The figure was 34.3% (95% CI, 25%~43.7%).

[0219] [Table 16]

[0220] [Table 17]

[0221] Among patients with FGFR mutations treated with regimen 3 (n=74), the ORR was 48. The rate was 0.6% (Table 6). The additional 26 patients had a median of 3.7 months (range, 0+~). (13.6 months) The patient had a stable disease. The response was not affected by specific mutations. F Among 25 patients with GFR fusion in regimen 3, the ORR was 16.0%. (Table 6). FGFR3-TACC3 V1 is the most common fusion (n=11; Table 5); Four of these patients (36.4%) responded.

[0222] In regimen 3, 22 patients received immunotherapy before trial enrollment (Table 5); The confirmed objective response rate (ORR) to rudafitinib was 59% among these patients. The analysis revealed that only one of these 22 patients (5%) was affected based on the investigator's judgment. It was determined that the patient had responded to previous immunotherapy.

[0223] The ORRs for regimens 1 and 2 are also shown in Table 6.

[0224] Of the 99 patients treated with regimen 3, 87 had at least one previous The disease progresses during or after chemotherapy (chemotherapy-induced recurrent / resistant disease), and is diagnosed by a central laboratory. The following genetic changes were determined by the clinical trial assays performed: FGFR3 gene Sub-mutations (R248C, S249C, G370C, Y373C) or FGFR gene fusion ( FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, F The patient had a disease in which at least one of the following was present (GFR2-CASP7) (Table 5). Within the group, the median age was 67 years (range: 36-87 years), and 79% were male. 74% were of Caucasian descent. The majority of patients (92%) had a baseline of 0 or 1. Three individuals achieved performance status with the East Coast Cancer Clinical Group (ECOG). 3% of patients had previously received only platinum-containing neoadjuvant or adjuvant therapy. The disease progressed afterward. 84 patients (97%) had previously received cisplatin or carbop They received at least one of the latin compounds. 56% of the patients had previously received cisplatin-based resistance therapy. Of those who received only the treatment, 29% had previously received only carboplatin-based regimens, and 10% had received the treatment. They received both suplatin and carboplatin regimens. 24% of the patients had a prior anti-P regimen. They were treated with D-L1 / PD-1 therapy. 79% of patients had visceral metastases (bone, liver, or lungs). I had it.

[0225] Among 87 chemotherapy-resistant patients in regimen 3, evaluated by the principal investigator The overall response rate was 40.2%; the results for this patient population are shown in Table 7A. This is shown in [the relevant section]. Responders have not previously responded to anti-PD-L1 / PD-1 therapy. This included patients with FGFR changes. ORRs based on FGFR changes are shown in Table 8A.

[0226] [Table 18]

[0227] [Table 19]

[0228] Among 87 chemotherapy-relapsed / resistant patients in regimen 3, a blinded independent review committee... The overall response rate, as assessed by the association, was 32.2%; for this group of patients... The results are shown in Table 7B. Responders had previously received anti-PD-L1 / PD-1 therapy. This included patients who did not respond to the law. ORRs based on FGFR changes are shown in Table 8B. ru.

[0229] [Table 20]

[0230] [Table 21]

[0231] Secondary evaluation items The duration of response among patients receiving regimen 3 is shown in Table 6; of the responses Approximately 30% were maintained for >12 months. Among 39 patients with stable disease, Thirteen patients (33%) experienced disease stabilization lasting >6 months (Figure 4). 21% of patients were deaf. The treatment was still ongoing at the time of the cutoff.

[0232] In patients receiving regimen 3, the median follow-up period was 11.2 months, and the clinical trial responsibility was determined. The median progression-free survival based on physician assessment is shown in Figure 5A. The progression survival rate (95% CI) was 19% (11%–29%). The median overall survival at the median follow-up period of 11.0 months is shown in Figure 5B. The survival rate at 2 months was 55% (43%–66%).

[0233] Of the 99 patients receiving regimen 3, 34 (34%) continued with subsequent therapy. Of those, 25 (25%) received one follow-up call, and 9 (9%) received two follow-up calls. They received the initial treatment. As the first subsequent therapy, 19 (19%) received chemotherapy, and 15 (15%) received immunotherapy. Patients who showed an objective response to the initial subsequent chemotherapy. No patients achieved a complete response; one patient showed a partial response to the initial subsequent immunotherapy.

[0234] The duration of response for patients treated with regimens 1 and 2 is also shown in Table 6. The progression-free survival and overall survival among patients receiving Dimen 1 and 2 are shown in Figures 6A-6B. This is shown in [the document].

[0235] The median progression-free survival (95% CI) based on the investigator's assessment was for regimen 1 and Among patients receiving treatment 2, the average duration was 4.8 (2.7-5.5) months and 5.3 (4.1) months, respectively. The progression-free survival rate at 12 months was ~5.5 months. The 95% CI values ​​were 18% (7%-33%) and 11% (5%-19%), respectively. The median overall survival (95% CI) for patients receiving regimens 1 and 2 was... Follow-up observations regarding survival at 22.9 months in regimen 1 and 18.5 months in regimen 2. The median periods were 7.5 months (6.0-10.7 months) and 8.6 months (6.5-9.7 months), respectively. The survival rate was ) months (Figures 6A-6B). The overall survival rate at 12 months (95% CI) was: Among patients in Men 1 and 2, 31% (16%-48%) and 33% (22%) respectively It was ~44%).

[0236] Preventive measures Preventive measures are in place to minimize the risk of common adverse events associated with FGFR inhibition. To reduce the risk of hyperphosphatemia, a low-phosphate diet is recommended for all patients. (Daily intake of 600-800 mg of phosphates from diet). Skin effects To reduce the stinging, apply an alcohol-free skin-softening and moisturizing cream, and also use a sunscreen. It is recommended to avoid unnecessary exposure to light, soap, scented products, and hot baths. The patient was instructed to keep their fingers and toes clean and trim their nails to reduce the risk of nail-related complications. I was asked to do so.

[0237] Central serous retinopathy (central serous retinopathy) is a reversible retinal disorder that occurs when medication is temporarily discontinued. Severe retinopathy is treated with kinase inhibitors and FGFR inhibitors. As has also been reported, patients were tested at baseline and in Amslaghri Eye examinations including eye examinations, fundus examinations, and, where available, optical coherence tomography (OCT) imaging. This ocular adverse event was monitored regularly. Additional monitoring was performed when clinically necessary. An ophthalmological examination was performed.

[0238] safety All patients in regimen 3 reported adverse events that occurred as a result of treatment (Table 14). 67% were grade 3 or 4. Serious treatment-induced adverse events occurred in 39 patients. It was reported in 39% of patients (Table 10). Disease progression occurred in 62 patients (63%). This was the most common reason for discontinuing treatment. Thirteen patients (13%) had retinal color Includes scabbing, hand-foot syndrome, and dry mouth and skin / nail events (n=2 each). Treatment was discontinued due to adverse events. 55 patients (56%) experienced dose reduction. The most common adverse events resulting from the treatment that led to dose reduction were observed in 16 patients. Stomatitis was present in 16% of patients, and hyperphosphatemia in 9 patients. The overall profile showed that with the 8 mg regimen, 5.5 mg of the target per dl by day 14 was In 41 patients whose serum phosphate levels did not reach the target, continuous administration of 9 mg of erda per day was used. They allowed an increase in the dosage of fitinib. Of these 41 patients, 24 (59%) were ≥ A dose reduction of 1 was required. The dose was increased to 9 mg per day, followed by a continuous dose of 8 mg per day. In this group, a similar percentage of patients had a curative treatment of grade ≥3 compared to the overall study population. Adverse events resulting from treatment were reported (68% and 66%, respectively). The adverse events and treatment-related adverse events that occurred were similar across all regimens (Table 11 and Table 11). Table 12). One patient experienced adverse events (myocardial infarction considered unrelated to treatment). The patient died as a result. Treatment-related adverse events of interest or clinical importance and their management. The reason is shown in Table 13. 76% of cases are central serous retinopathy. (Urgent retinopathy) The event has recovered; all unrecovered events are, It was grade 1 or 2.

[0239] [Table 22]

[0240] [Table 23]

[0241] [Table 24]

[0242] [Table 25]

[0243] [Table 26]

[0244] [Table 27]

[0245] [Table 28]

[0246] [Table 29]

[0247] Treatment-related adverse events of interest or considered clinically significant include central serous reticulum. Hyperphosphatemia, skin effects, and nail effects, including ocular membranous ocular events (CSR) and other non-CSR ocular events. , and eye disorders (Table 13). Treatment-related hyperphosphatemia and effects on the skin and nails were 73 patients treated with 8 mg of erdafitinib daily in each case. It was reported in %, 49%, and 52% of cases. Most events were mild to moderate. In this group, the most common treatment-related effects on the skin were dry skin (32%) and Hand-foot syndrome (22%) is the most common treatment, and nail effects are associated with 16% of each patient. In % of cases, onycholysis and onychomadesis were observed. Overall, the daily dose was 8 mg. 63% of patients treated with secondary erdafitinib and 54% of patients overall experienced treatment I have experienced several types of eye disorders, whether they were considered related or not. Among patients with harm (n=62), the majority (n=52, 84%) had Grade 1 or 2 The following event was experienced: 21 patients who received continuous erdafitinib at a dose of 8 mg per day. In these patients (21%), treatment-related CSRs (choroidal retinoretinopathy, retinal detachment, and retinal pigment epithelial detachment) occurred. (including preferred terminology); only 3 of these patients (3%) had a grade ≥ Three events occurred. The majority of patients with CSR events experienced discontinuation or dose reduction of the medication. Treatment could be continued after management by [method]. CSR resulted in discontinuation in 3 patients. There were no patients with occlusion of retinal veins or arteries.

[0248] Management of adverse events Hyperphosphatemia (Tables 11, 12, and 14), the most common treatment-related adverse event, is medically... When justified, treatment is discontinued (23%), dose reduced (9%), and phosphate binders are used. It was managed with treatment. Elevated phosphate levels usually peak 6 weeks after starting erdafitinib. The condition improved and normalized by cycle 5. One patient had grade 1 hyperphosphatemia. Treatment was discontinued. Skin dryness can be treated with ammonium lactate, salicylic acid, or zinc oxide cream. It was managed with additional topical ointments such as Mu. The effects on the nails were managed with topical nail strengtheners. In severe cases, antibiotics or silver nitrate were administered.

[0249] Consideration This trial met its primary objective, with 40% receiving continuous 8 mg of Eldafi per day. Locally advanced disease with specific FGFR gene mutations, in which ORR is confirmed after tinib treatment. In patients with sexually transmitted and unresectable / metastatic urothelial carcinoma, currently available treatment options and It showed comparative antitumor activity. The response to erdafitinib was rapid and pre-treatment. It was not dependent on the number of lines and types of tumors, the presence of visceral metastases, or the location of the tumor.

[0250] Importantly, the median progression-free survival and overall survival were 5.5 months, respectively (Figure 5A). And 13.8 months (Figure 5B), with visceral metastasis progressing during or after multiple lines of therapy. This included patients with translocation and insufficient renal function. As permitted by the protocol, 1 Three patients experienced either limited progression of the target lesion or the appearance of small, new lesions. Treatment continued after progression, and the patient was evaluated as having continued clinical benefit. Safety The profile is guided by serum phosphate levels, with doses increasing up to 9 mg per day. Along with the dosage, continuous administration of 8 mg per day was permitted. Grade ≥ 3 events - Since the incidence was similar across both groups, increasing the dose increased the severity of adverse events. It was not allowed. Hyperphosphatemia, a known effect of FGFR inhibitors, occurred in 77% (resistance) Reported in Men3), it was typically manageable and reversible. Central serous fluid Ocular events such as uterine retinopathy are caused by inhibitors of the mitogen-activated protein kinase pathway. This is a known class of adverse event. Ocular adverse events were common with erdafitinib treatment. However, most of these cases were mild to moderate and resolved with discontinuation or dose reduction.

[0251] Patients with FGFR mutations or fusions may be less responsive to immunotherapy. (This invention) In their study, only one out of 22 patients (5%) responded to previous immunotherapy. Of those patients, 59% responded to erdafitinib after immunotherapy failure. This observation was also seen in the logalatinib study, with 9 out of 10 patients (9 0% had disease progression with previous immunotherapy, and 30% responded to rogalatinib.

[0252] These results indicate that the pan-FGFR inhibitor erdafitinib is effective in treating progressive urine with altered FGFR levels. This demonstrates a measurable benefit in patients with urothelial carcinoma.

[0253] Example 2: Pharmacodynamics and Pharmacokinetics Pharmacodynamics Cardiac electrophysiology Evaluation of QTc interval in open-label dose escalation and dose expansion studies in 187 patients with cancer. Based on the values, erdafitinib did not have a significant effect on the QTc interval. Wow, >20ms).

[0254] Serum phosphate Erdafitinib increased serum phosphate levels as a result of FGFR inhibition. Rudafitinib targets 5.5–7.0 mg / dL in early cycles with daily administration. The dosage should be increased to the highest recommended dose to achieve the desired serum phosphate levels.

[0255] In clinical trials of erdafitinib, potassium phosphate and vitamin D supplements were used. It is known that the drug contains an excipient, antacid, phosphate-containing enema or laxative, and phosphate as an excipient. The use of drugs that can raise serum phosphate levels, such as those mentioned above, is not recommended if alternatives are available. It was prohibited unless it did not exist. Phosphate binders were permitted to manage elevated phosphate levels. Before the first dose-increase period based on serum phosphate levels, serum phosphate levels were changed. Avoid using this product simultaneously with drugs that may cause adverse reactions.

[0256] Pharmacokinetics After administering 8 mg once daily, the steady-state peak plasma concentration (Cma) of erdafitinib was measured. x), area under the curve (AUCtau), and mean value of minimum plasma concentration (Cmin) (variability factor) The percentages [CV%] are 1399 ng / mL (51%) and 29268 ng·h / mL, respectively. The results were (60%) and 936 ng / mL (65%).

[0257] After a single and repeated dose per day, the exposure level of erdafitinib (maximum plasma concentration) was measured. [Cmax] and area under the plasma concentration-time curve [AUC] are 0.5-12 mg (approved) The dose increased proportionally over a dose range of 0.06 to 1.3 times the highest recommended dose. The condition was achieved after two weeks with one dose per day, and the average accumulation rate was four-fold.

[0258] absorption The median time to reach peak plasma concentration (tmax) is 2.5 hours (range: 2-6 hours). (It was between.)

[0259] The effects of diet High-fat and high-calorie diets in healthy subjects (800-1,000 calories) - After administration of a diet in which approximately 50% of the total calorie content of the meal comes from fat, erdafitinib No clinically significant differences were observed in the pharmacokinetics of the drug.

[0260] distribution The mean apparent volume of distribution of erdafitinib in patients was 29 L. The protein binding rate of erdafitinib is 99.8% in patients, mainly alpha- It was a 1-acid glycoprotein.

[0261] Disappearance The mean total apparent clearance (CL / F) of erdafitinib is measured in patients. The rate was 0.362 L / h. The mean effective half-life of erdafitinib in patients was 59 hours.

[0262] metabolism Erdafitinib is primarily metabolized by CYP2C9 and CYP3A4. The contributions of CYP2C9 and CYP3A4 to the total clearance of fitinib are, respectively It is estimated to be 39% and 20%. Unchanged erdafitinib is the major agent in plasma. It was a drug-related portion, and no metabolites were found in the circulating blood.

[0263] discharge After a single oral administration of radiolabeled erdafitinib, approximately 69% of the dose was found in the feces (unknown). 19% were recovered as changed, and 19% (13% as unchanged) were recovered in the urine. It was collected.

[0264] A specific group A clinically significant trend in the pharmacokinetics of erdafitinib is age (21-88 years). ), sex, race, weight (36-132 kg), mild (eGFR [estimated glomerular filtration rate, renal disease) [Use the formula for dietary modification in patients] 60-89 mL / min / 1.73 m 2 ) or in Moderate (eGRR 30~59mL / min / 1.73m 2 ) Renal impairment or mild hepatic impairment (total biliary) Bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1.0~1.5 × ULN and any other Not observed based on AST.

[0265] In patients with severe renal impairment, renal impairment requiring dialysis, or moderate or severe hepatic impairment The pharmacokinetics of erdafitinib are unknown.

[0266] Example 3: Drug Interactions Effects of other drugs on erdafitinib 1. Potent CYP2C9 or CYP3A4 inhibitors Clinical impact • Concomitant administration of a potent CYP2C9 or CYP3A4 inhibitor with erdafitinib is effective. It increased the plasma concentration of rudafitinib; • Increased plasma concentrations of erdafitinib may lead to increased drug-related toxicity. be. Clinical response • In patients receiving treatment with erdafitinib, potent inhibitors of CYP2C9 or CYP3A4 are used. Consider alternative therapies that are not available. • If concomitant administration of potent CYP29 or CYP3A4 inhibitors is unavoidable, adverse reactions may occur. Closely monitor the response and consider adjusting the dosage accordingly. If discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. .

[0267] 2. Potent CYP2C9 or CYP3A4 inducers Clinical impact • Concomitant administration of a potent inducer of CYP2C9 or CYP3A4 with erdafitinib is effective. This may significantly reduce the plasma concentration of rudafitinib. A decrease in plasma concentration of erdafitinib may lead to a decrease in its activity. Clinical response Avoid concomitant administration of erdafitinib with potent inducers of CYP2C9 or CYP3A4. To do.

[0268] 3. Moderate CYP2C9 or CYP3A4 inducers Clinical impact • Concomitant administration of erdafitinib with a moderate inducer of CYP2C9 or CYP3A4 is appropriate. This may reduce the plasma concentration of erdafitinib. A decrease in plasma concentration of erdafitinib may lead to a decrease in its activity. Clinical response • Moderate doses of CYP2C9 or CYP3A4 inducers are used at the start of erdafitinib treatment. If concomitant administration is necessary, use the recommended dose of erdafitinib (14 days) The dosage is increased to 9 mg once daily based on serum phosphate levels and tolerability from day 1 to day 21. Administer 8 mg once daily (if possible). • Moderate doses of CYP2C9 or CYP3A4 inducers are suitable for serum phosphate levels and tolerability. When it must be administered concomitantly after the initial dose escalation period, erdafitinib Increase the dose to 9 mg. • If a moderate inducer of CYP2C9 or CYP3A4 is discontinued, drug-related toxicity may occur. Continue erdafitinib at the same dose in the absence of erdafitinib.

[0269] 4. Serum phosphate level modifier Clinical impact • Concomitant administration of erdafitinib with other serum phosphate level modifiers may affect serum phosphate levels. It can increase or decrease the value. • Changes in serum phosphate levels caused by serum phosphate level modifiers (other than erdafitinib) The serum phosphate is necessary for determining the starting dose, which is increased based on serum phosphate levels. This could affect salt levels. Clinical response • Eldaf before the period of increasing the starting dose based on serum phosphate levels (days 14-21) Avoid concomitant administration of itinib and serum phosphate level modifiers.

[0270] Effects of erdafitinib on other drugs 1.CYP3A4 substrate Clinical impact • Concomitant administration of CYP3A4 substrate and erdafitinib is effective in increasing the plasma concentration of the CYP3A4 substrate. It can be changed. Changes in plasma concentrations of CYP3A4 substrates indicate loss of activity or toxicity of the CYP3A4 substrate. It could lead to an increase. Clinical response • Avoid concomitant administration of erdafitinib with CYP3A4-sensitive substrates that have a narrow therapeutic index. and.

[0271] 2.OCT2 substrate Clinical impact • Concomitant administration of OCT2 substrate and erdafitinib increases the plasma concentration of OCT2 substrate. Can; Increased plasma concentrations of the OCT2 substrate may lead to increased toxicity of the OCT2 substrate. Clinical response • Consider alternative therapies that do not use OCT2 substrates, or consider OCT2 substrates (e.g.) based on tolerability. For example, consider reducing the dose of metformin.

[0272] 3. P-glycoprotein (P-gp) substrates Clinical impact • Concomitant administration of P-gp substrate and erdafitinib increases the plasma concentration of P-gp substrate. Can; Increased plasma concentrations of P-gp substrates may lead to increased P-gp toxicity. Clinical response • If concomitant administration of P-gp substrate and erdafitinib is unavoidable, the P-gp substrate with a narrow therapeutic index is used. - Divide erdafitinib administration at least 6 hours before or 6 hours after administration of the gp substrate. and.

[0273] Example 4: Final FDA-approved formulation label Erdafitinib for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma. A pharmaceutical product containing urothelial carcinoma, • Having a susceptible FGFR3 or FGFR2 gene alteration, • Fewer than 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy at least one line of medication that progressed during or after a previous platinum-containing chemotherapy regimen. , This follows the labels below: Highlights of the attached document These highlights are necessary for the safe and effective use of BALVERSA®. This does not include all information. Please refer to the full package insert for BALVERSA. stomach. BALVERSA (erdafitinib) tablets for oral use Date of initial approval in the United States: 2019 Efficacy and Effects BALVERSA is for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma. A kinase inhibitor for which there is an indication, urothelial carcinoma, • Having a susceptible FGFR3 or FGFR2 gene alteration, • Less than 12 months including neoadjuvant or adjuvant platinum-containing chemotherapy Both cases progressed during or after a previous line of platinum-containing chemotherapy. Patients are treated with BALVERSA based on FDA-approved companion diagnostics. To make a choice regarding this. (1,2.1) This indication will be approved under accelerated approval based on tumor response rate. Continuation of approval for this indication This may involve verification and description of clinical utility in confirmatory trials. (1,14) Usage / Dosage • The presence of FGFR gene alterations in tumor specimens before initiating treatment with BALVERSA. Confirm. (2.1) • Recommended initial dose: 8 mg orally once daily, provided the criteria are met. The dose may be increased up to 9 mg per day. (2.2) Take the entire dose regardless of whether you have eaten or not. (2.2) Dosage form / content Tablets: 3 mg, 4 mg, and 5 mg. (3) contraindications None. (4) Warnings and Precautions for Use • Ocular disorders: BALVERSA is associated with central serous retinopathy / retinal pigment epithelial detachment (CSR / It can cause RPED. Treatment involves once a month for the first four months, and then every three months thereafter. Ophthalmological examinations should be performed regularly, and whenever visual symptoms occur. CSR / RPED If symptoms persist, discontinue BALVERSA and continue taking it if recovery does not occur within 4 weeks or if the severity of the condition does not improve. If the result is 4, completely discontinue the process. (2.3, 5.1) • Hyperphosphatemia: Increased phosphate levels are a pharmacodynamic effect of BALVERSA. Monitor for phosphate levels and manage them by changing the dosage if necessary. (2.3, 5.2) • Embryo-fetal toxicity: May cause harmful effects on the fetus. Inform patients about the risks and advise them to use effective contraception (5.3, 8.1 ,8.3). Adverse reactions The most common adverse reactions (≥20%), including abnormal clinical laboratory values, are elevated phosphate levels, stomatitis, Fatigue, elevated creatinine, diarrhea, dry mouth, onychomadesis, elevated alanine aminotransferase, Elevated alkaline phosphatase, decreased sodium, loss of appetite, decreased albumin, taste disturbances. Decreased hemoglobin, dry skin, elevated aspartate aminotransferase, decreased magnesium levels. Dry eyes, alopecia, palmar-plantar erythrodysesthesia syndrome, constipation, phosphate deficiency, abdominal pain, The symptoms included elevated calcium levels, nausea, and musculoskeletal pain. (6.1) To report a suspected adverse reaction, please contact Janssen Products, LP.1- 800-526-7736 (1-800-JANSSEN and www.BALVERSA) .com) or FDA 1-800-FDA-1088 or www.fda.gov / m Contact edwatch. Drug interactions • Potent CYP2C9 or CYP3A4 inhibitors: Consider alternative drugs or if adverse reactions occur. Monitor closely. (7.1) • Avoid simultaneous use with strong CYP2C9 or CYP3A4 inducers such as BALVERSA. (7.1) • Moderate CYP2C9 or CYP3A4 inducers: BALVERSA dose up to 9 mg To increase. (7.1) • Serum phosphate level modifiers: May modify serum phosphate levels before the initial dose change period. Avoid simultaneous use with other medications. (2.3, 7.1) • CYP3A4 substrates: Avoid co-use with sensitive CYP3A4 substrates that have a narrow therapeutic index. (7.2) • OCT2 substrate: Consider alternative medications or reduce the dose of the OCT2 substrate based on tolerability. Consider reducing it. (7.2) • P-gp substrate: B at least 6 hours before or after administration of a P-gp substrate with a narrow therapeutic index. Divide ALVERSA administration. (7.2) Use in a specific group • Breastfeeding: Advise against breastfeeding. (8.2) For information to be provided to patients and for FDA-approved patient labeling requirements, see 17. stomach. Full text of the attached document: Table of Contents* 1. Efficacy and Effects 2 Dosage / Dosage 2.1 Patient Selection 2.2 Recommended Dosage and Schedule 2.3 Dose changes due to adverse reactions 3 Dosage form / content 4 Contraindications 5. Warnings and Precautions for Use 5.1 Ocular disorders 5.2 Hyperphosphatemia 5.3 Embryo-fetal toxicity 6. Adverse reactions 6.1 Results of clinical trials 7. Drug Interactions 7.1 Effects of other drugs on BALVERSA 7.2 Effects of BALVERSA on other drugs 8. Use in specific populations 8.1 Pregnancy 8.2 Breastfeeding 8.3 Females and men of reproductive capacity 8.4 Administration to children 8.5 Administration to the elderly 8.6 Poor CYP2C9 metabolizer 11 Properties 12 Clinical Pharmacology 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacological Genomics 13 Non-clinical toxicity 13.1 Oncogenicity, mutagenicity, and impaired fertility 14 Clinical Trials 14.1 Urothelial carcinoma with susceptibility FGFR gene alteration 16. Supply / Storage and Handling Methods 17. Providing information to patients *Items or sub-items omitted in the full text of the attached document will not be included.

[0274] Full text of the attached document 1. Efficacy and Effects BALVERSA (trademark) is a treatment for adult patients with locally advanced or metastatic urothelial carcinoma. There are indications for treatment, and this urothelial carcinoma (mUC) is: • Having a susceptible FGFR3 or FGFR2 gene alteration, • Less than 12 months including neoadjuvant or adjuvant platinum-containing chemotherapy Both cases progressed during or after a previous line of platinum-containing chemotherapy.

[0275] The patient is treated based on a companion diagnostic approved by the FDA for BALVERSA. Regarding selection, see Dosage and Administration (2.1) and Clinical Trials (14).

[0276] This indication will be approved under accelerated approval based on tumor response rate. Continued approval of this indication. The conditions may include verification and description of clinical utility in confirmatory trials [see Clinical Trials (14)]. [Regarding Teru].

[0277] 2. Usage and dosage 2.1 Patient Selection Sensitivity in tumor specimens as detected by FDA-approved companion diagnostics Local progression or metastasis due to BALVERSA based on the presence of receptive FGFR gene alterations Selecting patients for the treatment of urothelial carcinoma [See Clinical Trials (14.1)] .

[0278] Regarding the FDA-approved trial for detecting FGFR gene changes in urothelial carcinoma The information is,

[0279] 2.2 Recommended Dosage and Schedule The recommended initial dose of BALVERSA is 8 mg orally once daily (two 4 mg tablets). The drug is administered daily based on serum phosphate (PO4) levels and tolerability on days 14-21. This involves increasing the dose to 9 mg (three 3 mg tablets) in a single dose.

[0280] Take all tablets regardless of whether you have eaten or not. If vomiting occurs at any point, the next dose should be taken the following day. Treatment is Treatment should be continued until disease progression or unacceptable toxicity occurs.

[0281] If you miss a dose of BALVERSA, take it as soon as possible on the same day. You may do so. The next day, resume the usual daily dose schedule for BALVERSA. Open the box. Extra tablets should not be taken to make up for a missed dose.

[0282] Dose increase based on serum phosphate levels Serum phosphate levels should be assessed 14 to 21 days after the start of treatment. If the salt level is <5.5 mg / dL and there are no ocular disorders or adverse reactions of grade 2 or higher In addition, increase the dose of BALVERSA to 9 mg once daily. Hyperphosphatemia Monitor phosphate levels monthly [see pharmacodynamics (12.2)].

[0283] 2.3 Dose changes due to adverse reactions Detailed recommended modifications for adverse reactions are listed in Table 1.

[0284] [Table 30]

[0285] Table 2 shows the discontinuation, dose reduction, or management of BALVERSA in specific adverse reactions. Summarize the recommendations regarding cancellation.

[0286] [Table 31]

[0287] 3 Dosage form / content tablet: • 3mg: Yellow, round, biconvex, film coated, one side engraved with "3"; the other side engraved with It is engraved with "EF". • 4mg: Orange, round, biconvex, film coated, one side engraved with "4"; the other side engraved with It is engraved with "EF". • 5mg: Brown, round, biconvex, film-coated, one side engraved with "5"; the other side engraved with It is engraved with "EF".

[0288] 4 Contraindications none.

[0289] 5. Warnings and Precautions for Use 5.1 Ocular disorders BALVERSA is used for central serous retinopathy / retinal pigment epithelial detachment, which causes visual field defects. It may cause ocular disorders, including CSR / RPED.

[0290] CSR / RPED was reported in 25% of patients treated with BALVERSA. The median time to initial onset was 50 days. Grade 3 C with central visual field involvement. SR / RPED was reported in 3% of patients. CSR / RPED was reported in 13% of patients. Recovery occurred and persisted in 13% of patients at the trial cutoff. CSR / RPED This resulted in discontinuation of the drug and a decrease in 9% and 14% of patients, respectively, and 3% of patients BALVERSA has been cancelled.

[0291] Dry eye symptoms occurred in 28% of patients during treatment with BALVERSA. Grade 3 was observed in 6% of patients. All patients received eye protective medication as needed. You should get treatment to prevent dry eyes.

[0292] Treatment involves monthly visits for the first four months, followed by visits every three months, and as needed if visual symptoms persist. An emergency ophthalmological examination should be conducted. The ophthalmological examination should include visual acuity, slit-lamp examination, fundus examination, and photoresistance. This should include the evaluation of cross-sectional tomography.

[0293] If CSR occurs, refrain from taking BALVERSA and check if recovery is not achieved within 4 weeks or if the condition worsens. If the severity is Grade 4, discontinue completely. For ocular adverse reactions, consider changing the dosage. Follow the instructions on the prescription line [see Dosage and Administration (2.3)].

[0294] 5.2 Hyperphosphatemia The increase in phosphate levels is a pharmacodynamic effect of BALVERSA [Pharmacodynamics (12.2 (See reference) Hyperphosphatemia occurred in 76% of patients treated with BALVERSA. It was reported as an adverse reaction. During the time of onset of an event of any grade of hyperphosphatemia. The median value was 20 days after starting BALVERSA (range: 8-116). 32% received phosphate binders during treatment with BALVERSA.

[0295] Monitor hyperphosphatemia and follow the dosage adjustment guidelines if necessary. [Dosage] • See sections 2.2 and 2.3 for dosage information.

[0296] 5.3 Embryo-fetal toxicity Based on the mechanism of action and findings in animal reproductive studies, BALVERSA is administered to pregnant women. When administered, it may cause health problems in the fetus. In embryo-fetal toxicity tests, the embryo Oral administration of erdafitinib to pregnant rats during endothelial development increased the area under the curve (AUC). Maternal exposure levels that were below the human exposure level at the highest clinically recommended dose in humans based on the above-mentioned malformations. It also caused embryo-fetal death. Pregnant women should be advised of the potential risks to the fetus. Reproductive In female patients with the ability to respond to BALVERSA, the effect was observed during treatment with BALVERSA and for one month after the last dose. Advise men with fertile female partners to use effective contraception. Patients should use effective contraception during treatment with BALVERSA and for one month after the last dose. To advise the use of [use in specific populations (8.1, 8.3) and clinical pharmacology ( See 12.1).

[0297] 6. Adverse reactions The following serious adverse reactions are also listed elsewhere in the labeling information. • Ocular disorders [See Warnings and Precautions for Use (5.1)]. • Hyperphosphatemia [See Warnings and Precautions for Use (5.2)].

[0298] 6.1 Results of clinical trials Clinical trials are conducted under a wide variety of conditions, and therefore, in clinical trials of a particular drug, The incidence rate of adverse reactions cannot be directly compared to the incidence rate in clinical trials of other drugs. This may not accurately reflect the incidence rates observed in clinical settings.

[0299] The safety of BALVERSA is for those with susceptible FGFR3 or FGFR2 gene mutations. And at least prior to 12 months of neoadjuvant or adjuvant chemotherapy. Locally advanced or metastatic urothelial carcinoma that has progressed during or after one line of chemotherapy Evaluated in the BLC2001 trial, which included 87 patients [Clinical trial (14.1 (See reference). Patients are treated with BALVERSA orally at a dose of 8 mg once daily. In patients with phosphate levels <5.5 mg / dL on day 14 of cycle 1, 9 The dose was increased to mg. The median treatment duration was 5.3 months (range: 0-17 months). .

[0300] The most common adverse reactions (≥20%), including abnormal clinical laboratory values ​​(AR), are elevated phosphate levels. Mouth ulcers, fatigue, elevated creatinine, diarrhea, dry mouth, onychomadesis, alanine aminotransferase Increased sodium levels, elevated alkaline phosphatase, decreased sodium levels, loss of appetite, decreased albumin levels, taste Memory disturbance, decreased hemoglobin, dry skin, elevated aspartate aminotransferase, magnesium Decreased phosphate levels, dry eyes, alopecia, palmar-plantar erythrodysesthesia syndrome, constipation, decreased phosphate levels. The symptoms included abdominal pain, elevated calcium levels, nausea, and musculoskeletal pain. The most common was Grade 3 or higher (A). R (>1%) is associated with stomatitis, onychomycosis, palmar-plantar erythrodyssesmus, paronychia, The symptoms included nail disorders, keratitis, onychomadesis (dislodgement of the nail), and hyperphosphatemia.

[0301] The most fatal adverse reaction in 1% of patients was acute myocardial infarction.

[0302] Serious adverse reactions, including eye disorders (10%), occurred in 41% of patients.

[0303] Complete discontinuation due to adverse reactions occurred in 13% of patients. The high frequency of these issues included eye disorders (6%).

[0304] Medication discontinuation occurred in 68% of patients. The most frequent reason for medication discontinuation was Adverse reactions include hyperphosphatemia (24%), stomatitis (17%), eye disorders (17%), and palmar and foot problems. This included basal redness dysphoria syndrome (8%).

[0305] Dose reduction occurred in 53% of patients. The most frequent adverse reaction related to dose reduction was... The symptoms include eye disorders (23%), stomatitis (15%), hyperphosphatemia (7%), and redness and sensation in the palms and soles of the hands and feet. This included insufficiency syndrome (7%), paronychia (7%), and onychomycosis (6%).

[0306] Table 3 shows the odor percentage of patients ≥10% treated with BALVERSA at 8 mg once daily. This shows the AR that was reported.

[0307] [Table 32]

[0308] [Table 33]

[0309] 7. Drug Interactions 7.1 Effects of other drugs on BALVERSA Table 5 shows the BALVERSA exposure levels or serum phosphate levels and their clinical responses. Summarize the drug interactions that affect this.

[0310] [Table 34]

[0311] 7.2 Effects of BALVERSA on other drugs Table 6 summarizes the effects of BALVERSA on other drugs and their clinical responses. .

[0312] [Table 35]

[0313] 8. Use in specific populations 8.1 Pregnancy Risk Overview Based on the mechanism of action and findings in animal reproductive studies, BALVERSA is administered to pregnant women. When administered, it may cause health problems in the fetus [see Clinical Pharmacology (12.1)]. [Regarding the use of BALVERSA in pregnant women to inform them of drug-related risks] No data is available. Oral administration of erdafitinib to pregnant rats undergoing organogenesis is... Maternal exposure levels that were below the human exposure level at the highest clinically recommended dose based on AUC. It caused malformations and embryo-fetal death [see data]. Potential risks to the fetus. Advise pregnant women and women of reproductive capacity to use the suku.

[0314] The estimated background risks of major congenital anomalies and miscarriages in the indication population are unknown. All pregnancies carry a background risk of birth defects, miscarriage, or other adverse outcomes. In the U.S. population, clinically recognized major birth defects and miscarriages The estimated background risks are 2-4% and 15-20%, respectively.

[0315] data Animal data In embryo-fetal toxicity studies, erdafitinib was administered to pregnant rats during the organogenesis period. Administered orally. Dosage ≥ 4 mg / kg / day (highest clinical recommended dose in humans based on AUC) Total maternal exposure (<0.1% of total human exposure) is associated with embryo-fetal death and major vascular malformations. Common and other vascular abnormalities, limb deformities (missing fingers, missing or deformed long bones), multiple bones (vertebrae, sternum) This resulted in an increased incidence of skeletal abnormalities (in the ribs and ribs) and a decrease in fetal weight.

[0316] 8.2 Breastfeeding Risk Overview The presence of erdafitinib in human breast milk, or in breastfed children or in relation to milk production. There is no data on the effects of erdafitinib in breastfed children. Due to the possibility of serious adverse reactions originating from BALVERSA, during and after treatment with BALVERSA Advise breastfeeding mothers not to breastfeed for one month after administration.

[0317] 8.3 Females and men of reproductive capacity Pregnancy test Pregnancy tests are for women of reproductive fertility before starting treatment with BALVERSA. Recommended.

[0318] contraception woman BALVERSA may cause health problems to the fetus when administered to pregnant women. In women of reproductive capacity, the effect of BALVERSA is maintained during treatment and for one month after the last dose. Advising the use of effective contraception [see Use in specific populations (8.1)] [Regarding].

[0319] male Male patients with a female partner of reproductive capacity during treatment with BALVERSA And advise using an effective method of contraception for one month after the last dose [for a specific population] See Usage (8.1).

[0320] infertility woman Based on findings from animal studies, BALVERSA is effective in fertile women. It may reduce fetal development [see nonclinical toxicity (13.1)].

[0321] 8.4 Administration to children The safety and efficacy of BALVERSA in pediatric patients have not been established.

[0322] In repeated-dose toxicity studies at 4 and 13 weeks in rats and dogs, the effects on bone and teeth were observed. The toxicity was observed at exposure levels (AUC) below the human exposure level at the highest clinically recommended dose in humans. Chondrodysplasia / dysplasia was reported in multiple bones in both specimens, and tooth abnormalities were observed. This involves abnormal / irregular indentations in rats and dogs, and odontoblasts in rats. Includes discoloration and deterioration.

[0323] 8.5 Administration to the elderly In clinical trials, among 416 patients treated with BALVERSA, 45% had 65 They were over 75 years old, with 12% being 75 years or older. There was a difference in safety between these patients and younger patients. No overall difference in efficacy was observed [see clinical trial (14)].

[0324] 8.6 Poor CYP2C9 metabolizer CYP2C9*3 / *3 genotype: Plasma concentration of erdafitinib is related to CYP2C9* A higher incidence was predicted in patients with the 3 / *3 genotype. CYP2C9*3 / *3 Increased adverse reactions in patients known or suspected to have the genotype Monitor the patient's condition [see Pharmacological Genomics (12.5)].

[0325] 11 Properties The active ingredient in BALVERSA, erdafitinib, is a kinase inhibitor. The chemical name is N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N- [3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1 It is a 2-diamine. Erdafitinib is a yellow powder. It is soluble in organic solvents. Almost insoluble or insoluble to readily soluble in aqueous media across a wide pH range. It is poorly soluble in the body, or hardly soluble at all, or not soluble at all. The molecular formula is C 25 H 30 N6O2 Its molecular weight is 446.56.

[0326] The chemical structure of erdafitinib is as follows: [ka]

[0327] BALVERSA (erdafitinib) is available for oral administration in doses of 3 mg, 4 mg, or 5 mg. Supplied as g film-coated tablets, they contain the following active ingredients: Tablet core: Croscarmellose sodium, magnesium stearate (from vegetable sources) (In the future), mannitol, meglumine, and microcrystalline cellulose. Film coating: (Opadry amb II): Monocaprylocaprine Ricerol type I, polyvinyl alcohol - partially saponified, sodium lauryl sulfate, tar Titanium dioxide, yellow iron oxide, red iron oxide (for orange and brown tablets only), tetroxide San-iron / black iron oxide (for brown tablets only).

[0328] 12 Clinical Pharmacology 12.1 Mechanism of Action Based on in vitro data, erdafitinib is effective in reducing FGFR1, FGFR2, and F It is a kinase inhibitor that binds to GFR3 and FGFR4 and inhibits their enzymatic activity. Dafitinib is also known as RET, CSF1R, PDGFRA, PDGFRB, FLT4, K It binds to IT and VEGFR2. Erdafitinib is a signaling agent for FGFR phosphorylation and signaling. In cell lines that inhibit FGFR transmission and express FGFR gene alterations including point mutations, amplification, and fusion, It reduced cell viability in FGFR-expressing cell lines and bladder cancer. Erdafitinib reduced cell viability in FGFR-expressing cell lines and bladder cancer. It showed antitumor activity in xenograft models derived from various tumor types.

[0329] 12.2 Pharmacodynamics Cardiac electrophysiology Evaluation of QTc interval in open-label dose escalation and dose expansion studies in 187 patients with cancer. Based on the values, erdafitinib did not have a significant effect on the QTc interval. Wow, >20ms).

[0330] Serum phosphate Erdafitinib increased serum phosphate levels as a result of FGFR inhibition. ALVERSA targets 5.5-7.0 mg / dL in early cycles with daily administration. The dosage should be increased to the highest recommended dose to achieve serum phosphate levels. [Dosage and Administration] See (2.3) for quantity.

[0331] In clinical trials of erdafitinib, potassium phosphate and vitamin D supplements were used. It is known that the drug contains an excipient, antacid, phosphate-containing enema or laxative, and phosphate as an excipient. The use of drugs that can raise serum phosphate levels, such as those mentioned above, is not recommended if alternatives are available. It was prohibited unless it did not exist. Phosphate binders were permitted to manage elevated phosphate levels. Before the first dose-increase period based on serum phosphate levels, serum phosphate levels were changed. Avoid simultaneous use with drugs that may cause adverse reactions [see Drug Interactions (7.1)]. [Regarding].

[0332] 12.3 Pharmacokinetics After administering 8 mg once daily, the steady-state peak plasma concentration (C) of erdafitinib was determined. ma x ), area under the curve (AUCtau), and minimum plasma concentration (C) min ) average value (variability coefficient The values ​​[CV%] are 1,399 ng / mL (51%) and 29,268 ng·h / The results were mL (60%) and 936 ng / mL (65%).

[0333] After a single and repeated dose per day, the exposure level of erdafitinib (maximum plasma concentration) was measured. [Cmax] and area under the plasma concentration-time curve [AUC] are 0.5-12 mg (approved) The dose increased proportionally over a dose range of 0.06 to 1.3 times the highest recommended dose. The condition was achieved after two weeks with one dose per day, and the average accumulation rate was four-fold.

[0334] absorption Time to reach peak plasma concentration (t max The median is 2.5 hours (range: 2-6 hours). (It was between.)

[0335] The effects of food High-fat and high-calorie diets in healthy subjects (800-1,000 calories) - After administration of a diet in which approximately 50% of the total calorie content of the meal comes from fat, erdafitinib No clinically significant differences were observed in the pharmacokinetics of the drug.

[0336] distribution The mean apparent volume of distribution of erdafitinib in patients was 29 L.

[0337] The protein binding rate of erdafitinib is 99.8% in patients, primarily alpha- It was a -1-acid glycoprotein.

[0338] Disappearance The mean total apparent clearance (CL / F) of erdafitinib is measured in patients. The rate was 0.362 L / h.

[0339] The mean effective half-life of erdafitinib in patients was 59 hours.

[0340] metabolism Erdafitinib is primarily metabolized by CYP2C9 and CYP3A4. The contributions of CYP2C9 and CYP3A4 to the total clearance of fitinib are, respectively It is estimated to be 39% and 20%. Unchanged erdafitinib is the major agent in plasma. It was a drug-related portion, and no metabolites were found in the circulating blood.

[0341] discharge After a single oral administration of radiolabeled erdafitinib, approximately 69% of the dose was found in the feces (unknown). 19% were recovered as changed, and 19% (13% as unchanged) were recovered in the urine. It was collected.

[0342] A specific group A clinically significant trend in the pharmacokinetics of erdafitinib is age (21-88 years). ), sex, race, weight (36-132 kg), mild (eGFR [estimated glomerular filtration rate, renal disease) [Use the formula for dietary modification in patients] 60-89 mL / min / 1.73 m 2 ) or in Moderate (eGRR 30~59mL / min / 1.73m 2 ) Renal impairment or mild hepatic impairment (total biliary) Bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1.0~1.5 × ULN and any other Not observed based on AST.

[0343] In patients with severe renal impairment, renal impairment requiring dialysis, or moderate or severe hepatic impairment The pharmacokinetics of erdafitinib are unknown.

[0344] Drug interaction testing Clinical trial and model-based methods A potent CYP2C9 inhibitor: Fluconazole, potent CYP2C9 inhibitors, and moderate CYP3A4 inhibitors are used in combination. When administered, compared to erdafitinib alone, erdafitinib's C max and AU C inf The average percentages (90% CI) for each are 121% (99.9, 147), respectively. The percentages were 148% (120, 182).

[0345] Powerful CYP3A4 inhibitors: It is administered in combination with itraconazole (a potent CYP3A4 inhibitor and a medium P-gp inhibitor). When compared to erdafitinib alone, erdafitinib's C max and AUC in f The average percentages (90% CI) for each are 105% (86.7, 127) and 1, respectively. The percentage was 34% (109, 164).

[0346] Powerful CYP3A4 / 2C9 inducers: The simulation showed that rifampicin (a potent CYP3A4 / 2C9 inducer) is effective against El. Dafitinib C max This suggests that it could significantly reduce AUC.

[0347] In vitro testing CYP substrates: Erdafitinib is a time-dependent CYP3A4 inhibitor and inducer. (Sensitivity C) The effect of erdafitinib on the YP3A4 substrate is unknown. Erdafitinib is It is not an inhibitor of other major CYP isoenzymes at clinically meaningful concentrations.

[0348] Transport Erdafitinib is a substrate and inhibitor of P-gp. P-gp inhibitors are clinically used. It is not expected to have any meaningful impact on erdafitinib exposure levels. Tinib is an inhibitor of OCT2.

[0349] Erdafitinib is effective at clinically meaningful concentrations against BCRP, OATP1B, and OATP1 Does not inhibit B3, OAT1, OAT3, OCT1, MATE-1, or MATE-2K. .

[0350] Acid-reducing agents: Erdafitinib has good solubility over a pH range of 1 to 7.4. Acid reduction Agents (e.g., antacids, H2 antagonists, proton pump inhibitors) are used by erdafiti. It is not expected to affect the bioavailability of the nib.

[0351] 12.5 Pharmacological Genomics CYP2C9 activity is related to gene barriers such as CYP2C9*2 and CYP2C9*3 polymorphisms. It is reduced in individuals with the cyptophenoid gene. Erdafitinib exposure is reduced by CYP2C9*1 / *1 Compared to subjects with genotype (wild type), CYP2C9*1 / *2 and *1 / * The same was true for subjects with three genotypes. Other genotypes (e.g., *2 / *2, * Data is not available for subjects characterized by 2 / *3, *3 / *3). The simulation was performed on subjects with CYP2C9*2 / *2 and *2 / *3 genotypes. This suggests that there is no clinically significant difference in erdafitinib exposure levels. The estimated exposure levels to rudafitinib are found in 0.4% to 3% of populations across various racial groups. It is predicted that the risk will be 50% higher in subjects with the specified CYP2C9*3 / *3 genotype. It can be done.

[0352] 13 Non-clinical toxicity 13.1 Oncogenicity, mutagenicity, and impaired fertility Carcinogenicity trials were not conducted for erdafitinib.

[0353] Erdafitinib is mutagenic in bacterial reverse mutation (Ames) assays. There is no evidence of chromosomal abnormalities being induced in in vitro micronucleus or in vivo rat bone marrow micronucleus assays. It wasn't a first-acting disease.

[0354] Fertility studies in animals were not performed with erdafitinib. (3-month repeated administration) In toxicity studies, erdafitinib showed a human exposure level at the highest clinically recommended dose in humans. At exposure levels (AUC) below a certain level, the effects on female reproductive organs (necrosis of the ovarian corpus luteum) were observed in rats. I showed it.

[0355] 14 Clinical Trials 14.1 Urothelial carcinoma with susceptibility FGFR gene alteration The BLC2001 trial (NCT02365597) is for locally advanced or metastatic urothelial carcinoma. A multicenter evaluation of the efficacy and safety of BALVERSA in patients with mUC (muscular ulcerative colitis). This was a collaborative, open-label, single-arm trial. Fibroblast growth was performed for patient screening and registration. The growth factor receptor (FGFR) mutation status was determined by clinical trial assays (CTAs). The efficacy population is defined as patients who have progressed at least once during or after a previous chemotherapy regimen, and who have undergone central examination. The following gene changes, as determined by the CTA performed at the institution: FGFR3 gene Mutations (R248C, S249C, G370C, Y373C) or FGFR gene fusion (F GFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FG In this study, patients with a disease having at least one of the following conditions (FR2-CASP7) The study consisted of a cohort of 87 registered patients. Tumor samples from 69 patients were collected using BALV. QI is an FDA-approved trial for the selection of patients with mucus related to ERSA. AGEN therascreen (registered trademark) FGFR RGQ RT-PCR Kit It was retrospectively tested by [the relevant authority].

[0356] The patient accepts an initial dose of BALVERSA at 8 mg once daily, and serum phosphate levels... In patients whose blood sugar level was below the target value of 5.5 mg / dL between day 14 and day 17, The dose was increased to 9 mg once daily; this dose increase occurred in 41% of patients. BALVERSA was administered until disease progression or unacceptable toxicity occurred. Primary efficacy outcome The scale was determined by a blinded independent evaluation committee (BIRC) in accordance with RECIST v1.1. As determined, the objective response rate (ORR) and duration of response (DR) were the key metrics.

[0357] The median age was 67 years (range: 36-87 years), 79% were male, and 74% were They were of Caucasian descent. The majority of patients (92%) had a baseline of 0 or 1 in the East China Sea. The Kishi Cancer Clinical Trials Group (ECOG) had a performance status. 66% of the patients , visceral metastases. 84 patients (97%) had previously received cisplatin or carboplatin. They received at least one of the following. 56% of the patients had previously received a cisplatin-based regimen. Of those who received only this treatment, 29% had previously received a carboplatin regimen, and 10% had received cisplatin. They received both steroids and carboplatin regimens. Three patients (3%) had previously received platinum Patients who experienced disease progression after receiving neoadjuvant therapy containing na or adjuvant therapy alone. 24% of these patients had been treated with previous anti-PD-L1 / PD-1 therapy.

[0358] The efficacy results are summarized in Tables 7 and 8. The overall response rate was 32.2%. Responders included patients who had previously not responded to anti-PD-L1 / PD-1 therapy.

[0359] [Table 36]

[0360] [Table 37]

[0361] 16. Supply / Storage and Handling Methods BALVERSA (trademark) (erdafitinib) tablets have the following potency and packaging. It is available at: • 3mg tablets: yellow, round, double-convex, film-coated, with "3" engraved on one side and on the other side It is engraved with "EF". - A bottle containing 56 tablets with a child-resistant stopper (NDC 596 76-030-56). - A bottle containing 84 tablets with a child-resistant stopper (NDC 596 76-030-84). - It is contained in one box (NDC 59676-030-55) with 56 tablets. Two unit packaging wallets, each containing 28 tablets (NDC 59676-030-2 2). - It is contained in one box (NDC 59676-030-88) with 84 tablets. Two unit packaging wallets, each containing 42 tablets (NDC 59676-030-4 4). • 4mg tablets: Orange, round, double-convex, film-coated, with "4" imprinted on one side and on the other side It is engraved with "EF". - A bottle containing 28 tablets with a child-resistant stopper (NDC 596 76-040-28). - A bottle containing 56 tablets with a child-resistant stopper (NDC 596 76-040-56). - One starter pack wallet containing 14 tablets in one box (NDC 59676-040-14) - One starter pack wallet containing 28 tablets in one box (NDC (59676-040-22) - It is contained in one box (NDC 59676-040-55) with 56 tablets. Two unit packaging wallets, each containing 28 tablets (NDC 59676-040-2 2). • 5mg tablets: brown, round, biconvex, film-coated, one side engraved with "5", the other side It is engraved with "EF". - A bottle containing 28 tablets with a child-resistant stopper (NDC 596 76-050-28). - One unit packaging wallet containing 28 tablets in one box (NDC 596 76-050-22)

[0362] Store at 20°C to 25°C (68°F to 77°F); 15°C to 30°C (59°F to 77°F) A variation of 86°F is acceptable [USP Controlled Room Temperature]. See the rature.

[0363] 17. Providing information to patients Advise patients to read the FDA-approved patient information labeling.

[0364] FGFR gene changes: Sensitivity FGFR3 or FGFR2 mutations or genetic mutations in tumor specimens. Evidence of chromosome fusion is necessary to identify patients who require treatment, and this should be advised to the patient. [See Dosage and Administration (2.1)].

[0365] Eye disorders: If a patient experiences any of the following visual changes, contact their healthcare provider. Advise them to do so [see Warnings and Precautions for Use (5.1)]. Dry eyes To prevent or treat this condition, artificial tears and fluids should be administered at least every two hours while the child is awake. Advise the patient to frequently use a ophthalmic gel or ointment that lubricates or soothes the eyes. [See Dosage and Administration (2.3)].

[0366] Skin, mucous membrane, or nail disorders: For patients, progressive or unbearable skin, mucous membrane disorders. Or, advise people to contact their healthcare provider if they experience any nail problems [Adverse reactions (6 See .1).

[0367] Hyperphosphatemia: Between 14 and 21 days after the start of treatment, the healthcare provider monitors serum phosphate levels. Advise patients that they will be evaluated and the dosage adjusted as needed [Warning and Use] Precautions for use (5.2)]. During the initial phosphate assessment period, do not alter serum phosphate levels. Advise patients to avoid concurrent use with medications that may cause adverse reactions. After a set period, monthly monitoring of phosphate levels for hyperphosphatemia is performed at BALVER. Advising patients that this should be done during treatment with SA [drug interaction( See 7.1).

[0368] Drug interactions: All concomitant medications, including prescription drugs, over-the-counter drugs, and herbal products, should be taken into consideration by a doctor. Advise the patient to inform their healthcare provider.

[0369] Dosage instructions: Instruct the patient to take all tablets once a day, regardless of whether they have eaten or not. If vomiting occurs at any point after taking BALVERSA, take the following dose. Advise the patient to take the medication the following day. [See Dosage and Administration (2.1)] .

[0370] Missed dose: If you miss a dose, take the missed dose of medication as soon as possible. Advise the patient to follow the usual daily dose schedule for BALVERSA the following day. Restart the course. Extra tablets should not be taken to make up for missed doses. [See Dosage and Administration (2.3)].

[0371] Embryo-fetal toxicity: Advising pregnant women and women of reproductive capacity about potential risks to the fetus. Advise women to inform their healthcare provider if they know they are pregnant or suspect they are pregnant. [See Warnings and Precautions for Use (5.3) and Use in Specific Populations (8.1)] [Regarding].

[0372] In female patients of reproductive capacity, efficacy is maintained during treatment and for one month after the last dose of BALVERSA. Advise men with fertile female partners to use effective contraception. Sexually transmitted patients should use effective contraception during treatment and for one month after the last dose of BALVERSA. Advising on doing so [see Use in specific populations (8.3)].

[0373] Breastfeeding: Women should not breastfeed during treatment with BALVERSA and for one month after the last dose. Advise them to use it in specific populations (see 8.2).

[0374] [Table 38]

[0375] [Table 39]

[0376] The examples and embodiments described herein are for illustrative purposes only and may be modified in various ways. Or modifications that would be suggested to a person skilled in the art, and which are included in the spirit and scope of this application and the appended claims. They will be born.

[0377] Embodiments of therapeutic methods described herein are for the manufacture of erdafitinib It is also expressed in the form of use or in the form of erdafitinib for therapeutic use. It should be understood that one is gaining something.

[0378] The following sections describe the subject matter of the present invention.

[0379] 1. An approved formulation containing a fibroblast growth factor receptor (FGFR) inhibitor, as described above. This includes administering the formulation to patients with urothelial carcinoma in the amount indicated on the formulation label. Methods for treating urothelial carcinoma.

[0380] 2. The method according to claim 1, wherein the urothelial carcinoma is locally advanced or metastatic.

[0381] 3. Administration of FGFR inhibitors can improve urothelial carcinoma that has not been treated with FGFR inhibitors. Compared to patients with the condition, improved antitumor activity was measured by response rate or duration of response. The method according to claim 1 or 2, which provides anti-inflammatory activity.

[0382] 4. The administration of an FGFR inhibitor causes an adverse event of grade 3 or lower, according to claims 1 to 3. The method described in any one of the items.

[0383] 5. Urothelial carcinoma is sensitive to FGFR2 gene mutations or FGFR3 gene mutations. The method according to any one of claims 1 to 4.

[0384] 6. FGFR2 or FGFR3 gene mutations are caused by FGFR3 gene mutations or FGFR2 mutations. The method according to claim 5, wherein the method is an FGFR3 gene fusion.

[0385] 7. FGFR3 gene mutations include R248C, S249C, G370C, Y373C, and The method according to claim 6, which is any combination thereof.

[0386] 8. FGFR2 or FGFR3 gene fusions result in FGFR3-TACC3, FGFR3- BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any of the above. The method according to claim 6, which is a combination.

[0387] 9. Before administering FGFR inhibitors, a biological sample from the patient should be tested for one or more FGFR2 or FG Any one of claims 1 to 8 further includes evaluating the presence of FR3 gene alterations. The method described in section [section number].

[0388] 10. The biological sample is blood, lymph, bone marrow, solid tumor sample, or any combination thereof. The method according to claim 9.

[0389] 11. The patient has received at least one prior treatment for the treatment of urothelial carcinoma, claim 1 The method described in any one of the following ten items.

[0390] 12. At least one prior treatment for urothelial carcinoma with platinum-containing chemotherapy. A method according to claim 11.

[0391] 13. Urothelial carcinoma progresses during or after at least one line of platinum-containing chemotherapy. The method according to claim 12.

[0392] 14. Platinum-containing chemotherapy is neoadjuvant platinum-containing chemotherapy or adjuvant The method according to claim 13, wherein the chemotherapy is platinum-containing chemotherapy.

[0393] 15. Urothelial carcinoma treated with at least one line of neoadjuvant platinum-containing chemotherapy. If the disease progresses during or within 12 months thereafter, please contact us. The method described in item 14.

[0394] 16. The FGFR inhibitor is erdafitinib, according to any one of claims 1 to 15. Method of description.

[0395] 17. The method according to claim 16, wherein erdafitinib is administered daily.

[0396] 18. The method according to claim 16 or 17, wherein erdafitinib is administered orally.

[0397] 19. Erdafitinib is administered orally in a daily dosing schedule, as described in claim 16. The method described in any one of item 18.

[0398] 20. Erdafitinib is administered orally once daily in a dose of approximately 8 mg, claim 16. The method described in any one of items ~19.

[0399] 21. The dosage of erdafitinib is (a) The patient has blood glucose levels less than approximately 5.5 mg / dL 14 to 21 days after the start of treatment. When showing a clear phosphate (PO4) level; and (b) Administration of erdafitinib at a dose of 8 mg once daily did not cause ocular disorders. or (c) Administration of erdafitinib at a dose of 8 mg once daily causes a grade 2 or higher adverse reaction. If not woken up, The dosage was increased from 8 mg once daily to 9 mg once daily between 14 and 21 days after the start of treatment. The method according to claim 20.

[0400] 22. Any one of claims 16 to 21, wherein erdafitinib is present in a solid dosage form. Methods used.

[0401] 23. The method according to claim 22, wherein the solid dosage form is a tablet.

[0402] 24. Erdafitinib, (a) Pharmacological treatment with potent CYP2C9 inhibitors or CYP3A4 inhibitors; (b) Pharmacotherapy involving potent CYP2C9 inducers or CYP3A4 inducers; (c) Pharmacotherapy with a moderate CYP2C9 inducer or CYP3A4 inducer; or (d) Drug therapy involving serum phosphate level modifiers The method according to any one of claims 16 to 23, which is not administered in combination with [another drug].

[0403] 25. Erdafitinib, (a) Pharmacotherapy using CYP3A4 substrates; (b) Drug therapy that is an OCT2 substrate; or (c) Drugs that are substrates of P-glycoprotein (P-gp) therapy The method according to any one of claims 16 to 24, which is not administered in combination with [another drug].

[0404] 26. A method for treating urothelial carcinoma in a patient, (a) The presence of one or more fibroblast growth factor receptor (FGFR) gene alterations. Evaluating biological samples from individuals; and (b) If one or more FGFR gene mutations are present in the sample, the patient should be given the preparation. Treatment with an approved formulation containing an FGFR inhibitor in the amount indicated on the formulation label. to A method that includes this.

[0405] 27. A method of selling an approved formulation containing erdafitinib, wherein the method is such This includes selling such formulations and listing the formulation labels for such formulations on the reference list of drugs. A method that includes instructions for treating urothelial carcinoma.

[0406] 28. The formulation is an ANDA formulation, a formulation for which a change in the approved drug is requested, or a 505(b)(2) formulation. The method according to claim 27, wherein the agent is...

[0407] 29. A method for proposing an approved formulation containing erdafitinib for sale, The aforementioned method includes proposing such formulations for sale, and regarding such formulations A method in which the formulation label of the reference list drug includes instructions for treating urothelial carcinoma. .

[0408] 30. The formulation is an ANDA formulation, a formulation for which a change in the approved drug product has been requested, or a formulation under 505(b)(2). The method according to claim 29, wherein the agent is...

[0409] 31. A method that includes selling approved formulations containing erdafitinib, and such The reference list for eel preparations includes drug labels that contain response rate or duration of response data. A way to do it.

[0410] 32. Claim 31, wherein the response rate data for erdafitinib is approximately 32.2%. Method of description.

[0411] 33. Claim 31, the duration of response data for erdafitinib is approximately 5.4 months. Methods used.

[0412] 34. Compared to patients with urothelial carcinoma who have not received treatment with FGFR inhibitors, A method for improving the response rate or duration of response in patients with urothelial carcinoma, the patient A method comprising administering an approved formulation containing erdafitinib to the patient.

[0413] 35. The method according to claim 34, wherein the response rate is approximately 32.2%.

[0414] 36. The method according to claim 34, wherein the duration of response is approximately 5.4 months.

[0415] 37. The approved formulation is an ANDA formulation or a formulation for which a change in the approved drug status has been submitted. The method described in any one of items 34 to 36.

[0416] 38. Compared to patients with urothelial carcinoma who have not received treatment with FGFR inhibitors, A method for improving the response rate or duration of response in patients with urothelial carcinoma, the patient A method comprising providing an approved formulation containing erdafitinib.

[0417] 39. The method according to claim 38, wherein the response rate is approximately 32.2%.

[0418] The method according to claim 38, wherein the duration of response is approximately 5.4 months.

[0419] 40. The approved formulation is an ANDA formulation or a formulation for which a change in the approved drug status has been submitted. The method described in any one of items 38 to 40.

[0420] 41. Reference list for such preparations: The preparation label for the drug does not treat urothelial carcinoma. The method according to any one of claims 38 to 41, including instructions for treatment.

[0421] 42. An approved formulation having at least one approved efficacy, wherein the approved The approved formulations include those containing erdafitinib.

[0422] 43. Approved formulations are NDA formulations, ANDA approved formulations, and formulations for which a change in drug approval has been requested. An approved formulation according to claim 43, which is a pharmacopoeia or a 505(b)(2) formulation.

[0423] 44. A reference list of approved formulations, including a formulation label, as described in claim 43. Approved formulations.

[0424] 45. The approved formulation according to claim 45, wherein the formulation label includes response rate data.

[0425] 46. ​​Claim 46 states that the response rate data for erdafitinib is approximately 32.2%. The approved formulations listed.

[0426] 47. The approved formulation according to claim 45, wherein the formulation label includes duration of response data.

[0427] 48. Claim 48, the duration of response data for erdafitinib is approximately 5.4 months. Approved formulations as described above.

[0428] 49. Fibroblast Growth Factor Receptor (FG) for use in the treatment of urothelial carcinoma in patients. An approved formulation containing an FR) inhibitor, wherein the approved formulation has a property of the said formulation. An approved formulation administered in the amount indicated on the formulation label.

[0429] 50. Fibroblast growth factor in the manufacture of pharmaceuticals for the treatment of urothelial carcinoma in patients Use of an approved formulation containing a receptor (FGFR) inhibitor, wherein the pharmaceutical product is the formulation Use by administering the amount indicated on the product label.

[0430] 51. Eldafiti for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma Approved drugs containing nibs, which treat urothelial carcinoma, (a) Having a susceptible FGFR3 or FGFR2 gene alteration, and (b) Including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. The disease progressed during or after at least one line of prior platinum-containing chemotherapy, approved Pharmaceuticals.

Claims

1. Treatment of urothelial carcinoma, including administering erdafitinib to patients with urothelial carcinoma. A method in which erdafitinib is administered simultaneously with a P-glycoprotein (P-gp) substrate. And the administration of erdafitinib was at least 6 hours before the administration of the P-gp substrate or Later, the method was further divided, in particular, the method in which the P-gp substrate has a narrow therapeutic index.

2. Treatment of urothelial carcinoma, including administering erdafitinib to patients with urothelial carcinoma. A method in which erdafitinib is a moderate CYP2C9 or CYP3A4 inducer A method of simultaneous administration.

3. The aforementioned moderate CYP2C9 or CYP3A4 inducer is used to initiate treatment with erdafitinib. The method according to claim 2, which is sometimes administered simultaneously.

4. The urothelial carcinoma described in any one of claims 1 to 3 is locally advanced or metastatic. The method.

5. The urothelial carcinoma is sensitive to FGFR2 gene mutations or FGFR3 gene mutations. The method according to any one of claims 1 to 4.

6. The aforementioned FFFR2 or FFFR3 gene change is an FFFR3 gene mutation or an FFFR2 mutation. The method according to claim 5, or an FGFR3 gene fusion.

7. The aforementioned FGFR3 gene mutations are R248C, S249C, G370C, Y373C, and The method according to claim 6, which is any combination thereof.

8. The aforementioned FGFR2 or FGFR3 gene fusion is FGFR3-TACC3, FGFR3- BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any of the above. The method according to claim 6, which is a combination.

9. Before administering erdafitinib, a biological sample from the patient was taken to one or more FGFR2 or Any of claims 1 to 8 further includes evaluating the presence of FGFR3 gene alterations. The method described in item 1.

10. The aforementioned biological sample is blood, lymph, bone marrow, solid tumor sample, or any combination thereof. A method according to claim 9.

11. Claims 1 to 1, the patient has received at least one prior treatment for the treatment of urothelial carcinoma. The method described in any one of the ten items.

12. At least one prior treatment for urothelial carcinoma is platinum-containing chemotherapy. The method according to claim 11.

13. The urothelial carcinoma progresses during or after at least one line of platinum-containing chemotherapy. The method according to claim 11.

14. The platinum-containing chemotherapy is neoadjuvant platinum-containing chemotherapy or adjuvant chemotherapy. The method according to claim 12, which is a toplatinum-containing chemotherapy.

15. The urothelial carcinoma is a neoadjuvant platinum-containing chemical of at least one line If the disease progresses during or within 12 months thereafter of the therapy or adjuvant platinum-containing chemotherapy, The method according to claim 14.

16. The method according to any one of claims 1 to 15, wherein erdafitinib is administered daily.

17. The method according to any one of claims 1 to 16, wherein erdafitinib is administered orally.

18. Claim 16 or 17, in which erdafitinib is administered orally on a daily dosing schedule. Methods used.

19. Claim 18 describes how erdafitinib is administered orally once daily at a dose of approximately 8 mg. The method.

20. The aforementioned dose of erdafitinib is (a) The patient has a blood glucose level of less than approximately 5.5 mg / dL on the 14th to 21st day after the start of treatment. serum phosphate (PO ４ ) When indicating a level; and (b) Administration of erdafitinib at a dose of 8 mg once daily did not cause ocular disorders. or (c) Administration of erdafitinib at a dose of 8 mg once daily causes a grade 2 or higher adverse reaction. If not woken up, The dosage was increased from 8 mg once daily to 9 mg once daily between 14 and 21 days after the start of treatment. The method according to claim 19.

21. Erdafitinib is present in a solid dosage form, according to any one of claims 1 to 20. method.

22. The method according to claim 21, wherein the solid dosage form is a tablet.

23. In the manufacture of pharmaceuticals for the treatment of urothelial carcinoma in patients, The aforementioned pharmaceutical is administered simultaneously with a P-glycoprotein (P-gp) substrate, and Eldaf The administration of itinib is divided into doses at least 6 hours before or after the administration of the P-gp substrate, and The P-gp substrate is used in a manner that has a narrow therapeutic index.

24. In the manufacture of pharmaceuticals for the treatment of urothelial carcinoma in patients, In the case where the aforementioned drug is administered simultaneously with a moderate dose of a CYP2C9 or CYP3A4 inducer, For.

25. The aforementioned moderate CYP2C9 or CYP3A4 inducer is used to initiate treatment with erdafitinib. The use according to claim 24, which is administered simultaneously at times.

26. Erdafitinib for use in the treatment of urothelial carcinoma in patients, Tinib was administered co-administered with a P-glycoprotein (P-gp) substrate, and erdafitinib The administration is divided into at least 6 hours before or after the administration of the P-gp substrate, and in particular, the P - The gp substrate is erdafitinib, which has a narrow therapeutic index.

27. Erdafitinib for use in the treatment of urothelial carcinoma in patients, Tinib is administered concurrently with a moderate CYP2C9 or CYP3A4 inducer in erdafiti. Nib.

28. The aforementioned moderate CYP2C9 or CYP3A4 inducer is used to initiate treatment with erdafitinib. Erdafitinib for use according to claim 27, which is sometimes administered concurrently.

29. The urothelial carcinoma is locally advanced or metastatic, according to any one of claims 23 to 25. The use described, or the use described in any one of claims 26 to 28, of Erdafitini Bu.

30. The urothelial carcinoma is sensitive to FGFR2 gene mutations or FGFR3 gene mutations. Use as described in any one of claims 23 to 25, or as described in any one of claims 26 to 28 Erdafitinib for use as described.

31. The aforementioned FFFR2 or FFFR3 gene change is an FFFR3 gene mutation or an FFFR2 mutation. Alternatively, it is an FGFR3 gene fusion, the use or use of Eldaf according to claim 30. Ichinib.

32. The aforementioned FGFR3 gene mutations are R248C, S249C, G370C, Y373C, and Any combination thereof, the use or use for the Eldafiti described in claim 31 Nib.

33. The aforementioned FGFR2 or FGFR3 gene fusion is FGFR3-TACC3, FGFR3- BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any of the above. The combination of erdafitinib as described in claim 31 for use or for use.

34. Before administering erdafitinib, one or more biological samples from the patient were collected using FGFR2 or F Any of claims 23 to 33 further includes evaluating the presence of GFR3 gene alterations. Erdafitinib for any of the uses or purposes described in any one of the paragraphs.

35. The aforementioned biological sample is blood, lymph, bone marrow, solid tumor sample, or any combination thereof. Eldafitinib for use or for use according to claim 34.

36. Claim 23, the patient has received at least one prior treatment for the treatment of urothelial carcinoma. Erdafitinib for any use or purpose described in any one of paragraphs 35 to 35.

37. The above at least one prior treatment for the treatment of urothelial carcinoma is platinum-containing chemotherapy. Eldafitinib for use or for use as described in claim 36.

38. The urothelial carcinoma is diagnosed during or after at least one line of platinum-containing chemotherapy. The advanced use or use of erdafitinib according to claim 36.

39. The platinum-containing chemotherapy is neoadjuvant platinum-containing chemotherapy or adjuvant chemotherapy. A platinum-containing chemotherapy as described in claim 37, or for use of Eldafiti Nib.

40. The urothelial carcinoma is a neoadjuvant platinum-containing chemical of at least one line If the disease progresses during or within 12 months thereafter of the therapy or adjuvant platinum-containing chemotherapy, Erdafitinib for use or for use as described in claim 39.

41. The use of erdafitinib according to any one of claims 23 to 40, wherein erdafitinib is administered daily. Or erdafitinib for use.

42. The use of erdafitinib according to any one of claims 23 to 41, wherein erdafitinib is administered orally. Or erdafitinib for use.

43. Claim 41 or 42, erdafitinib is administered orally on a daily dosing schedule. Erdafitinib for use or use as described above.

44. Claim 43 describes how erdafitinib is administered orally once daily at a dose of approximately 8 mg. Erdafitinib for use or use.

45. The aforementioned dose of erdafitinib is (a) The patient has a blood glucose level of less than approximately 5.5 mg / dL on the 14th to 21st day after the start of treatment. serum phosphate (PO ４ ) When indicating a level; and (b) Administration of erdafitinib at a dose of 8 mg once daily did not cause ocular disorders. or (c) Administration of erdafitinib at a dose of 8 mg once daily causes a grade 2 or higher adverse reaction. If not woken up, The dosage was increased from 8 mg once daily to 9 mg once daily between 14 and 21 days after the start of treatment. Eldafitinib for use or use as described in claim 44.

46. Erdafitinib is present in a solid dosage form, as described in any one of claims 23 to 45. Erdafitinib for use or use.

47. The use or use of Eldaphyti according to claim 46, wherein the solid dosage form is a tablet. Nib.

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