Erdafitinib for intravesical administration for use in the treatment of bladder cancer

Abstract

Provided herein are methods for treating bladder cancer with one or more FGFR alterations, including locally delivering erdafitinib to the patient's bladder, erdafitinib for use, and uses of erdafitinib for treatment.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION FIELD OF THE DISCLOSURE The present disclosure is generally in the field of methods of treating bladder cancer, including methods of treating bladder cancers with one or more FGFR alterations.

[0002] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 485,831, filed February 17, 2023, and U.S. Provisional Patent Application No. 63 / 623,191, filed January 19, 2024, the contents of which are incorporated herein by reference in their entireties.

[0003] (Reference to the Electronic Sequence Listing) The contents of the electronic sequence listing (761662002340SEQLIST.xml, size: 53,281 bytes, and created on February 7, 2024) are incorporated herein by reference in their entirety. [Background technology]

[0004] Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) is a potent pan-FGFR kinase inhibitor that binds to and inhibits the enzymatic activity of FGFR1, FGFR2, FGFR3, and FGFR4. Erdafitinib has been shown to inhibit FGFR phosphorylation and signaling, resulting in reduced cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. Erdafitinib has demonstrated antitumor activity in FGFR-expressing cell lines and in xenograft models derived from tumor types, including bladder cancer.

[0005] Erdafitinib (BALVERSA®) is currently available as a film-coated tablet for oral administration and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma that harbors a susceptible fibroblast growth factor receptor FGFR3 or FGFR2 genetic alteration and has progressed during or after at least one prior line of platinum-containing chemotherapy, where the at least one prior line of platinum-containing chemotherapy includes neoadjuvant (preoperative adjuvant) or adjuvant (immunoadjuvant) platinum-containing chemotherapy within the past 12 months.

[0006] U.S. Patent No. 10,898,482 to Broggini and International Patent Application Publication No. 2020 / 201138 to De Porre describe certain erdafitinib formulations and methods of treatment.

[0007] Examples of intravesical drug delivery systems are described in U.S. Patent No. 8,679,094 to Cima et al., U.S. Patent No. 9,017,312 to Lee et al., U.S. Patent No. 9,107,816 to Lee et al., and U.S. Patent No. 9,457,176 to Lee et al. In some embodiments, the intravesical system includes a water-permeable housing defining a drug reservoir lumen containing a solid or semi-solid drug formulation, and in vivo release of the drug occurs when water from the bladder diffuses into the drug reservoir lumen, solubilizing the drug, and then the osmotic pressure built up within the drug reservoir lumen releases the solubilized drug from the drug reservoir lumen through a release opening.

[0008] U.S. Patent No. 10,286,199 to Lee et al. discloses a system in which a drug is released from a housing, the housing being made from a first wall structure and a hydrophilic second wall structure, the first wall structure being impermeable to the drug and the second wall structure being permeable to the drug. U.S. Patent No. 10,894,150 to Lee also discloses a system in which a drug is released from a housing, the housing being made from a first wall structure that is impermeable to the drug and a second wall structure that is permeable to the drug. Summary of the Invention [Means for solving the problem]

[0009] The present disclosure is generally in the field of methods of treating bladder cancer with erdafitinib, erdafitinib for use, and uses of erdafitinib for treatment, of bladder cancer having one or more FGFR alterations, comprising locally delivering erdafitinib to the bladder of a patient, including such methods and uses using erdafitinib-based pharmaceutical formulations and drug-device combination products, more particularly using erdafitinib-based formulations and systems for intravesical administration of such formulations.

[0010] In certain embodiments, a method for treating bladder cancer having one or more FGFR gene alterations is provided, comprising locally delivering an amount of erdafitinib effective for treating bladder cancer to the bladder of a patient in need thereof, wherein the one or more FGFR gene alterations are detected in a urine sample from the patient, particularly where the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR assay or NGS assay. In certain embodiments, a method for treating bladder cancer having one or more FGFR gene alterations is provided, comprising, consisting of, or consisting essentially of: (a) evaluating a urine sample from a patient with bladder cancer for the presence of one or more FGFR gene alterations, particularly using a urine-based PCR assay or NGS assay to evaluate a urine sample from a patient with bladder cancer for the presence of one or more FGFR gene alterations; and (b) locally delivering erdafitinib if one or more FGFR gene alterations are present in the sample. In certain embodiments, there is provided a method for treating bladder cancer having one or more FGFR gene alterations, comprising locally delivering a therapeutically effective amount of erdafitinib to the bladder of a patient in need thereof, wherein the patient is selected for treatment based on detection of one or more FGFR gene alterations in a urine sample from the patient, particularly where the patient is selected for treatment based on detection of one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay. In certain embodiments, there is provided a method for treating bladder cancer having one or more FGFR gene alterations, comprising locally delivering a therapeutically effective amount of erdafitinib to the bladder of a patient in need thereof, wherein the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient, particularly where the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay.In certain embodiments, there is provided erdafitinib for use in treating bladder cancer in a patient with one or more FGFR gene alterations, wherein the erdafitinib is delivered locally to the patient's bladder, and wherein the one or more FGFR gene alterations are detected in a urine sample from the patient, particularly wherein the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR assay or an NGS assay. In certain embodiments, there is provided erdafitinib for use in treating bladder cancer in a patient with one or more FGFR gene alterations, the use comprising, consisting of, or consisting essentially of: (a) evaluating a urine sample from the patient with bladder cancer for the presence of one or more FGFR gene alterations, particularly evaluating a urine sample from the patient with bladder cancer for the presence of one or more FGFR gene alterations using a urine-based PCR assay or an NGS assay; and (b) locally delivering erdafitinib to the patient if one or more FGFR gene alterations are present in the sample. In certain embodiments, there is provided erdafitinib for use in treating bladder cancer in a patient having one or more FGFR gene alterations, wherein the erdafitinib is for local delivery to the patient's bladder, and the patient is selected for treatment based on detection of one or more FGFR gene alterations in a urine sample from the patient, particularly, the patient is selected for treatment based on detection of one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay.In certain embodiments, there is provided erdafitinib for use in treating bladder cancer in a patient with one or more FGFR gene alterations, wherein the erdafitinib is locally delivered to the patient's bladder, and the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient, particularly, the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay. In certain embodiments, there is provided use of erdafitinib for the manufacture of a medicament for treating bladder cancer in a patient with one or more FGFR gene alterations, wherein the erdafitinib is locally delivered to the patient's bladder, and the one or more FGFR gene alterations are detected in a urine sample from the patient, particularly, the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR assay or an NGS assay. In certain embodiments, there is provided a use of erdafitinib for the manufacture of a medicament for treating bladder cancer in a patient with one or more FGFR gene alterations, comprising, consisting of, or consisting essentially of: (a) evaluating a urine sample from a patient with bladder cancer for the presence of one or more FGFR gene alterations, particularly evaluating a urine sample from a patient with bladder cancer for the presence of one or more FGFR gene alterations using a urine-based PCR assay or an NGS assay; and (b) locally delivering erdafitinib if one or more FGFR gene alterations are present in the sample.In certain embodiments, there is provided a use of erdafitinib for the manufacture of a medicament for treating bladder cancer in a patient with one or more FGFR gene alterations, wherein the erdafitinib is locally delivered to the patient's bladder, and the patient is selected for treatment based on detection of one or more FGFR gene alterations in a urine sample from the patient, particularly, the patient is selected for treatment based on detection of one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay. In certain embodiments, there is provided a use of erdafitinib for the manufacture of a medicament for treating bladder cancer in a patient with one or more FGFR gene alterations, wherein the erdafitinib is locally delivered to the patient's bladder, and the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient, particularly, the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay. The method or use may include locally delivering or administering erdafitinib (e.g., as in any of the formulations or drug delivery systems described herein) to the bladder of a patient in need of treatment, particularly a cancer patient, in an effective amount for treating bladder cancer (e.g., about 1-10 mg / day, as described herein). For example, the treatment may be effective in treating muscle-invasive bladder cancer (MIBC), non-muscle-invasive bladder cancer (NMIBC), and / or bacillus calmette-guerin (BCG)-naive bladder cancer. In one embodiment, the patient, particularly a human, is a BCG-experienced bladder, NMIBC, or MIBC cancer patient. In one embodiment, the patient, particularly a human, is a BCG-naive bladder, NMIBC, or MIBC cancer patient.In one embodiment, the patient, particularly a human, is a recurrent Mycobacterium bovis Bacillus Calmette-Guérin (BCG)-experienced, high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient who refuses or is ineligible for radical cystectomy (RCy). In one embodiment, the patient, particularly a human, is a recurrent BCG-experienced, high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient scheduled for RCy. In one embodiment, the patient, particularly a human, is a recurrent intermediate-risk NMIBC (Ta and T1) cancer patient with a history of only low-grade disease. In one embodiment, the patient, particularly a human, is a MIBC cancer patient scheduled for RCy who refuses or is ineligible for cisplatin-based neoadjuvant chemotherapy.

[0011] In certain embodiments, a method of treating bladder cancer having one or more FGFR gene alterations is provided, comprising locally delivering an amount of erdafitinib effective to treat bladder cancer to the bladder of a patient in need thereof, wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient, particularly, the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or the one or more FGFR gene alterations are detected in a histopathology image of the tumor tissue via digital histopathology analysis. In certain embodiments, methods are provided for treating bladder cancer with one or more FGFR genetic alterations, comprising, consisting of, or consisting essentially of: (a) evaluating a tumor tissue sample from a patient with bladder cancer for the presence of one or more FGFR genetic alterations, particularly using a tissue-based PCR assay or an NGS assay to evaluate a tumor tissue sample from a patient with bladder cancer for the presence of one or more FGFR genetic alterations, or evaluating histopathology images of tumor tissue from a patient with bladder cancer for the presence of one or more FGFR genetic alterations via digital histopathology analysis; and (b) locally delivering erdafitinib if one or more FGFR genetic alterations are present in the sample. In certain embodiments, provided is a method of treating bladder cancer harboring one or more FGFR gene alterations, comprising locally delivering a therapeutically effective amount of erdafitinib to the bladder of a patient in need thereof, wherein the patient is selected for treatment based on detection of one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly, the patient is selected for treatment based on detection of one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or the patient is selected for treatment based on detection of one or more FGFR gene alterations in histopathology images of tumor tissue via digital histopathology analysis.In certain embodiments, methods are provided for treating bladder cancer harboring one or more FGFR gene alterations, comprising locally delivering a therapeutically effective amount of erdafitinib to the bladder of a patient in need thereof, wherein the patient's eligibility for the treatment is determined by detecting one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly, the patient's eligibility for the treatment is determined by detecting one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or the patient's eligibility for the treatment is determined by detecting one or more FGFR gene alterations in a histopathology image of the tumor tissue via digital histopathology analysis. In certain embodiments, there is provided erdafitinib for use in treating bladder cancer in a patient with one or more FGFR gene alterations, wherein the erdafitinib is delivered locally to the patient's bladder, and the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient, particularly, the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or the one or more FGFR alterations are detected in a histopathology image of the tumor tissue via digital histopathology analysis. In certain embodiments, there is provided erdafitinib for use in treating bladder cancer in a patient with one or more FGFR gene alterations, comprising, consisting of, or consisting essentially of: (a) evaluating a tumor tissue sample from the patient with bladder cancer for the presence of one or more FGFR gene alterations, in particular evaluating a tumor tissue sample from the patient with bladder cancer for the presence of one or more FGFR gene alterations using a tissue-based PCR assay or an NGS assay, or evaluating histopathology images of tumor tissue from the patient with bladder cancer for the presence of one or more FGFR gene alterations via digital histopathology analysis; and (b) locally delivering erdafitinib to the patient if one or more FGFR gene alterations are present in the sample.In certain embodiments, there is provided erdafitinib for use in treating bladder cancer in a patient having one or more FGFR gene alterations, wherein the erdafitinib is for local delivery to the patient's bladder, and the patient is selected for treatment based on detection of one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly, the patient is selected for treatment based on detection of one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or the patient is selected for treatment based on detection of one or more FGFR gene alterations in histopathology images of the tumor tissue via digital histopathology analysis. In certain embodiments, there is provided erdafitinib for use in treating bladder cancer in a patient with one or more FGFR gene alterations, wherein the erdafitinib is for local delivery to the patient's bladder, and wherein the patient's eligibility for the treatment is determined by detecting one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly wherein the patient's eligibility for the treatment is determined by detecting one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or wherein the patient's eligibility for the treatment is determined by detecting one or more FGFR gene alterations in a histopathology image of the tumor tissue via digital histopathology analysis. In certain embodiments, there is provided a use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer in a patient having one or more FGFR gene alterations, wherein the erdafitinib is for local delivery to the patient's bladder, and the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient, particularly, the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or the one or more FGFR alterations are detected in a histopathology image of the tumor tissue via digital histopathology analysis.In certain embodiments, there is provided a use of erdafitinib for the manufacture of a medicament for treating bladder cancer in a patient with one or more FGFR gene alterations, comprising, consisting of, or consisting essentially of: (a) evaluating a tumor tissue sample from the patient with bladder cancer for the presence of one or more FGFR gene alterations, in particular evaluating a tumor tissue sample from the patient with bladder cancer for the presence of one or more FGFR gene alterations using a tissue-based PCR assay or an NGS assay, or evaluating histopathology images of tumor tissue from the patient with bladder cancer for the presence of one or more FGFR gene alterations via digital histopathology analysis; and (b) locally delivering erdafitinib if one or more FGFR gene alterations are present in the sample. In certain embodiments, there is provided a use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer having one or more FGFR gene alterations in a patient, wherein the erdafitinib is for local delivery to the patient's bladder, and the patient is selected for treatment based on detection of one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly, the patient is selected for treatment based on detection of one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or the patient is selected for treatment based on detection of one or more FGFR gene alterations in a histopathology image of the tumor tissue via digital histopathology analysis.In certain embodiments, there is provided a use of erdafitinib for the manufacture of a medicament for treating a patient with bladder cancer having one or more FGFR gene alterations, wherein the erdafitinib is locally delivered to the patient's bladder, and the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly by detecting one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or by detecting one or more FGFR gene alterations in a histopathology image of the tumor tissue via digital histopathology analysis. The method or use may include locally delivering or locally administering erdafitinib (e.g., in any of the formulations or drug delivery systems described herein) to the bladder of a patient in need of treatment, particularly a cancer patient, in an effective amount for treating bladder cancer (e.g., about 1 to 10 mg / day, as described herein). For example, the treatment may be effective in treating muscle-invasive bladder cancer (MIBC), non-muscle-invasive bladder cancer (NMIBC), and / or Bacillus Calmette-Guerin (BCG)-naïve bladder cancer. In one embodiment, the patient, particularly a human, is a BCG-experienced bladder, NMIBC, or MIBC cancer patient. In one embodiment, the patient, particularly a human, is a BCG-naïve bladder, NMIBC, or MIBC cancer patient. In one embodiment, the patient, particularly a human, is a recurrent Mycobacterium bovis Bacillus Calmette-Guerin (BCG)-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient who refuses or is ineligible for radical cystectomy (RCy). In one embodiment, the patient, particularly a human, is a recurrent BCG-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient scheduled for RCy. In one aspect, the patient, particularly a human, is a recurrent intermediate-risk NMIBC (Ta and T1) cancer patient with a history of only low-grade disease.In one embodiment, the patient, particularly a human, is an MIBC cancer patient scheduled for RCy who has refused or is ineligible for cisplatin-based neoadjuvant chemotherapy.

[0012] In one aspect, provided herein is an intravesical drug delivery system comprising: an elongate body configured for intravesical insertion into a patient; and a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine). In some embodiments, the drug delivery system is configured to be osmotically driven to release erdafitinib from one or more openings in the elongate body. In some embodiments, erdafitinib is present as the mono-L-lactate salt. In some embodiments, the elongate body comprises a biocompatible elastomer. In some embodiments, the biocompatible elastomer comprises silicone or thermoplastic polyurethane. In some embodiments, the biocompatible elastomer comprises silicone. In some embodiments, the biocompatible elastomer comprises a platinum-cured silicone elastomer. In some embodiments, at least one of the one or more openings in the elongate body is located in a sidewall of the elongate body. In some embodiments, at least one of the one or more openings in the elongate body is located at a first end and / or an opposing second end of the elongate body. In some embodiments, the drug delivery system has a single opening located in a sidewall of the elongate body between the first end and the opposing second end of the elongate body. In some embodiments, the one or more openings have a diameter of about 100 μm to about 200 μm. In some embodiments, the one or more openings have a diameter of about 150 μm.

[0013] In some embodiments, the drug delivery system is configured to release erdafitinib by osmotic pressure through one or more openings in the elongate body. In some embodiments, the elongate body comprises an annular wall structure defining a drug reservoir lumen in which the drug formulation is disposed. In some embodiments, the annular wall structure has a thickness of about 0.1 mm to about 0.5 mm. In some embodiments, the annular wall structure has a thickness of about 0.2 mm.

[0014] In some embodiments, the drug delivery system further comprises a first end plug disposed at a first end of the annular wall structure and a second end plug disposed at a second end of the annular wall structure. In some embodiments, the one or more openings in the elongate body of the drug delivery system comprise a single opening in the annular wall structure, and the elongate body is configured to release erdafitinib through the opening. In some embodiments, the elongate body is configured to release erdafitinib through temporary microchannels formed in one or both end regions of the annular wall structure. In some embodiments, the system is configured to release erdafitinib at an average rate of 1 mg / day to 10 mg / day, particularly 1 mg / day to 10 mg / day of erdafitinib free base equivalent. In some embodiments, the system is configured to release erdafitinib at an average rate of 1 mg / day to 6 mg / day. In some embodiments, the system is configured to release erdafitinib at an average rate of 2 mg / day to 4 mg / day. In some embodiments, the system is configured to release erdafitinib at an average rate of 4 mg / day. In some embodiments, the system is configured to release erdafitinib at an average rate of 2 mg / day. In some embodiments, the system is configured to release erdafitinib in a zero-order release profile. In some embodiments, the system is configured to release erdafitinib for up to about 30 days. In some embodiments, the system is configured to release erdafitinib for up to about 90 days. In some embodiments, the system comprises 500 mg of erdafitinib (free base equivalent).

[0015] In some embodiments, the drug delivery system is elastically deformable between a relatively straightened deployed configuration suitable for insertion through the patient's urethra into the patient's bladder and a retained configuration suitable for retaining the system within the bladder. In some embodiments, the system comprises an elastically deformable tube having two opposing free ends that are oriented away from each other when the system is in the low-profile deployed configuration and toward each other when the system is in the relatively expanded retained configuration. In some embodiments, the system comprises an elastically deformable elongate body having two opposing free ends that are within the boundary of the bi-elliptical expanded retained configuration. In some embodiments, the elongate body further comprises a retaining frame lumen. In some embodiments, the system further comprises a nitinol wire disposed in the retaining frame lumen.

[0016] In another aspect, provided herein is a pharmaceutical composition, or a drug delivery system comprising the pharmaceutical composition, comprising a lactate salt of erdafitinib, particularly the L-lactate salt of erdafitinib, and at least one pharmaceutical excipient. In some embodiments, the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, an osmotic agent, or any combination thereof. In some embodiments, the at least one pharmaceutical excipient comprises or is selected from a binder, a diluent (filler), a glidant, a lubricant, or any combination thereof.

[0017] In some embodiments, the binder comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate (PVP-VA), or a combination thereof. In some embodiments, the binder is present in the drug formulation at a total concentration of about 1% to about 30% by weight, about 5% to about 20% by weight, or about 10% to about 15% by weight.

[0018] In some embodiments, the diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, calcium hydrogen phosphate, or a combination thereof. In some embodiments, the diluent (filler) is present in the drug formulation at a total concentration of about 5% to about 30% by weight, about 10% to about 30% by weight, or about 10% to about 20% by weight.

[0019] In some embodiments, the glidant comprises hydrophilic colloidal silicon dioxide or hydrophobic colloidal silicon dioxide. In some embodiments, the glidant is present in the drug formulation at a total concentration of about 0.05% to about 1% by weight, about 0.1% to about 0.5% by weight, or about 0.25% by weight.

[0020] In some embodiments, the lubricant comprises magnesium stearate or sodium stearyl fumarate or polyethylene glycol. In some embodiments, the lubricant comprises magnesium stearate or sodium stearyl fumarate. In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the lubricant is present in the drug formulation at a total concentration of about 0.05% to about 5% by weight, about 1% to about 5% by weight, or about 2.5% by weight.

[0021] In some embodiments, the pharmaceutical composition, or a drug delivery system comprising the pharmaceutical composition, comprises an intragranular composition or fraction and an extragranular composition or fraction. In some embodiments, the intragranular composition or fraction comprises erdafitinib or a pharmaceutically acceptable salt thereof, particularly a lactate salt of erdafitinib, e.g., erdafitinib L-lactate. In some embodiments, the intragranular composition or fraction comprises erdafitinib or a pharmaceutically acceptable salt thereof, particularly a lactate salt of erdafitinib, e.g., erdafitinib L-lactate, and at least one intragranular excipient, and the extragranular composition or fraction comprises at least one extragranular excipient. In some embodiments, the at least one intragranular excipient and the at least one extragranular excipient do not share a common pharmaceutical excipient. In some embodiments, the at least one intragranular excipient comprises an intragranular binder. In some embodiments, the intragranular binder comprises hydroxypropyl methylcellulose. In some embodiments, the at least one extragranular excipient comprises one or more of an extragranular binder, an extragranular filler (diluent), an extragranular glidant, and an extragranular lubricant. In some embodiments, the extragranular binder comprises vinylpyrrolidone-vinyl acetate. In some embodiments, the extragranular diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof. In some embodiments, the extragranular glidant comprises or is colloidal silicon dioxide (hydrophilic). In some embodiments, the extragranular lubricant comprises magnesium stearate or sodium stearyl fumarate or polyethylene glycol. In some embodiments, the extragranular lubricant comprises magnesium stearate or sodium stearyl fumarate. In some embodiments, the extragranular lubricant comprises or is magnesium stearate. In some embodiments, the at least one extragranular excipient comprises a filler and a binder, particularly microcrystalline cellulose and vinyl vinyl pyrrolidone-vinyl acetate, particularly in a weight:weight ratio of filler to binder of 1:1.

[0022] In some embodiments, the pharmaceutical composition or drug delivery system comprising the pharmaceutical composition comprises erdafitinib L-lactate at a concentration of 60% to 91% by weight. In some embodiments, the pharmaceutical composition or drug delivery system comprising the pharmaceutical composition comprises erdafitinib L-lactate at a concentration of 60% to 80% by weight. In some embodiments, erdafitinib L-lactate is present in the drug formulation at a concentration of 70% by weight.

[0023] In some embodiments, the pharmaceutical composition, or a drug delivery system comprising the pharmaceutical composition, comprises erdafitinib L-lactate in the form of a plurality of mini-tablets. In some embodiments, the pharmaceutical composition is in the form of about 10 to about 100 mini-tablets. In some embodiments, the pharmaceutical composition comprises mini-tablets having a total length of about 14.5 cm to about 15 cm, and / or the (b) formulation comprises mini-tablets having a weight of about 920 mg to about 965 mg. In some embodiments, the pharmaceutical composition comprises mini-tablets having a total length of about 14.5 cm to about 15 cm, and / or the (b) formulation comprises mini-tablets having a weight of about 920 mg to about 950 mg.

[0024] In some embodiments, the pharmaceutical composition comprising erdafitinib L-lactate is in the form of a tablet having a hardness of at least about 100 N. In some embodiments, the tablet has a hardness of about 150 N to about 250 N. In some embodiments, the tablet has a hardness of about 175 N to about 225 N. In some embodiments, the tablet has a thickness of about 3.2 mm to about 3.6 mm. In some embodiments, the tablet is a mini-tablet in the form of a solid cylinder having a cylindrical axis, a cylindrical side surface, a circular end surface perpendicular to the cylindrical axis, a diameter across the circular end surface, and a length along the cylindrical side surface. In some embodiments, the length of the mini-tablet exceeds the diameter of the mini-tablet, providing a mini-tablet with an aspect ratio (length:diameter) of greater than 1:1. In some embodiments, the mini-tablet has a diameter of 1.0 mm to 3.2 mm, or 1.5 mm to 3.1 mm. In some embodiments, the mini-tablet has a diameter of 2.5 mm to 2.7 mm. In some embodiments, the mini-tablet has a length of 3.0 mm to 3.5 mm. In some embodiments, the mini-tablets have a mass of 22 mg to 24 mg.

[0025] In another aspect, a process for making the pharmaceutical composition in the form of a tablet is provided, the process comprising: (a) preparing an intragranular solid composition comprising erdafitinib-L-lactate and at least one intragranular pharmaceutical excipient; (b) combining the intragranular solid composition with at least one extragranular pharmaceutical excipient to form a blend; and (c) compressing the blend to form a solid pharmaceutical composition. In some embodiments, (a) the at least one intragranular pharmaceutical excipient comprises at least one intragranular binder, and (b) the at least one extragranular pharmaceutical excipient comprises an extragranular binder, an extragranular filler (diluent), an extragranular glidant, and an extragranular lubricant. In some embodiments, the intragranular solid composition is prepared by a fluidized bed granulation process. In some embodiments, the at least one intragranular binder comprises hydroxypropyl methylcellulose. In some embodiments, the at least one extragranular binder comprises vinylpyrrolidone-vinyl acetate (PVP VA). In some embodiments, the at least one extragranular filler (diluent) comprises microcrystalline cellulose. In some embodiments, the extragranular filler (diluent) further comprises a second extragranular filler (diluent) comprising silicified microcrystalline cellulose. In some embodiments, the extragranular glidant comprises or is colloidal silicon dioxide (hydrophilic). In some embodiments, the extragranular lubricant comprises or is magnesium stearate. In some embodiments, the extragranular lubricant comprises sodium stearyl fumarate. In some embodiments, the extragranular lubricant comprises polyethylene glycol. In some embodiments, the at least one extragranular excipient comprises a filler and binder, particularly microcrystalline cellulose and vinylvinylpyrrolidone-vinyl acetate, particularly where the weight:weight ratio of filler to binder is 1:1. In some embodiments, the ejection force is less than about 1000N. [Brief explanation of the drawings]

[0026] The detailed description is set forth with reference to the accompanying drawings. The use of the same reference numbers may indicate similar or identical items. Various embodiments may utilize elements and / or components other than those illustrated in the drawings, and some elements and / or components may not be present in various embodiments. The elements and / or components shown in the drawings are not necessarily drawn to scale. [Figure 1A] FIG. 1 is a plan view of one embodiment of a drug delivery system in a coiled retention configuration in accordance with the present disclosure. [Figure 1B] 1B is a cross-sectional view of one embodiment of the drug delivery system shown in FIG. 1A taken along line BB. [Figure 2] 1 is a schematic illustration of the operation of one embodiment of an osmotic drug delivery system according to the present disclosure. [Figure 3] FIG. 1 is a perspective view of one embodiment of a mini-tablet form of a drug formulation according to the present disclosure. [Figure 4] Figure 1 shows single-dose erdafitinib exposure in plasma from nude rats bearing subcutaneous or orthotopic UM-UC-1 tumors. Exposure levels were measured in plasma from nude rats bearing naive orthotopic bladder or scUM-UC-1 tumors. Rats were dosed with a single IVES (1-hour infusion) or po dose of erdafitinib at the indicated dose levels. Individual data points are shown, and the mean is represented by the horizontal line at each time point. IVES, intravesical; PO or po, oral; sc, subcutaneous. [Figure 5]The effect of erdafitinib on ERK1 / 2 phosphorylation in orthotopic bladder UM-UC-1 tumors is shown. Nude rats were administered a single dose of vehicle or the indicated doses of erdafitinib via intravenous infusion (IVS) or p.o. to UM-UC-1 orthotopic bladder tumors, and individual pERK and total ERK levels were measured. pERK and total ERK levels are reported as the ratio to the mean value of the vehicle group at the corresponding time point (pERK / ERK). Except for the 120-hour time point, values ​​were normalized to the 48-hour vehicle group. Individual data points are shown, and the mean is represented by the horizontal line at each time point. N = 2–6 per group. ERK, extracellular signal-regulated kinase; IVES, intravesical; pERK, phosphorylated extracellular signal-regulated kinase; PO or PO, oral. [Figure 6] The size of orthotopic bladder UC tumor samples relative to control bladders at 14 days after implantation is shown. Formalin was used to fix tissue samples after autopsy. UC, urothelial carcinoma; NBTII, rat Nara bladder tumor No. 2 cells; T24, human bladder cancer cells. [Figure 7] FIG. 1 is a schematic diagram of a perfusion experiment in athymic rats with UM-UC-1 implanted within the bladder wall. [Figure 8] Figure 1 shows the percentage change in body weight of bladder-cannulated athymic rats bearing orthotopic UM-UC-1 bladder tumors. Graph values ​​are expressed as the mean ± SEM of 10–13 animals in each group. Concentrations indicated at the bottom of the figure are nominal target urinary concentrations. Statistical analysis was performed using Graph Pad Prism (version 8.3.0) by two-way ANOVA followed by Bonferroni's multiple comparison test. There was no statistically significant difference when the percentage change in body weight of the erdafitinib (0.5, 1.0, and 5.0 μg / mL)-treated groups was compared with the percentage change in body weight of the vehicle control group. SEM, standard error of the mean. [Figure 9]The mean percentage tumor weight reduction after accounting for tumor-free bladder weight is shown. Values ​​(Groups 1-4) are expressed as the mean ± SEM of 10-13 animals in each group. Statistical analysis was performed using Graph Pad Prism (version 8.3.0) by one-way ANOVA followed by Dunnett's multiple comparison test. Conc, concentration; SEM, standard error of the mean. [Figure 10] Figure 1 shows the percentage change in body weight of bladder-cannulated athymic nude rats bearing orthotopic RT-112 bladder tumors. Values ​​are expressed as the mean = SEM of 2-14 animals in each group. Concentrations indicated in the figure index are nominal target urinary concentrations. Statistical analysis was performed by two-way ANOVA followed by Bonferroni's multiple comparison test using Graph Pad Prism (version 8.3.0). When the percentage change in body weight of the erdafitinib (0.5, 1.0, and 5.0 μg / mL)-treated groups was compared with the percentage change in body weight of the vehicle control group, there was no statistically significant difference, except for Group 4 at day 11 (*p<0.05). SEM, standard error of the mean. [Figure 11] Figure 1 shows the effect of intravesical erdafitinib exposure on tumor growth, as determined by changes in total bladder weight in athymic rats bearing orthotopic RT-112 bladder tumors. Values ​​(Groups 1-5) are expressed as the mean ± SEM of 2-14 animals in each group. Statistical analysis was performed by one-way ANOVA followed by Dunnett's multiple comparison test using Graph Pad Prism (version 8.3.0). *p<0.05. Conc, concentration; SEM, standard error of the mean; ns, not significant. [Figure 12A]

[0023] Figure 1 shows plasma concentrations of erdafitinib in rats after bladder irrigation. Bladder irrigation with erdafitinib solution (0.1 mg / mL, 0.1 mL / hour, cumulative dose of 0.72 mg) was performed for 72 hours. Concentrations are expressed as mean daily urinary concentrations in ng / mL. [Figure 12B]

[0033] Figure 1 shows the intravesical concentration of erdafitinib in rats after bladder irrigation. Bladder irrigation with erdafitinib solution (0.1 mg / mL, 0.1 mL / hour, cumulative dose of 0.72 mg) was performed for 72 hours. Concentrations are expressed as the mean daily urinary concentration in ng / mL. [Figure 13] Figure 1 shows the mean erdafitinib urinary concentrations in pigs after intravesical infusion of erdafitinib at a constant rate of 12.5 mL / h for 6 consecutive days in two animals and 8 consecutive days in three animals. Total voided urine was collected at 24-hour intervals over 6 or 8 days. Conc., concentration; SD, standard deviation. [Figure 14] Figure 1 shows the mean erdafitinib plasma concentrations in pigs after intravesical infusion of erdafitinib at a constant rate of 12.5 mL / h for 6 consecutive days in two animals and 8 consecutive days in three animals. Blood samples were collected daily on study days 1-8. SD, standard deviation. [Figure 15] Screening results for material permeability are shown. O is permeable, Δ is practically impermeable, × is impermeable. a High variability between replicates. [Figure 16A] 1 shows a schematic of an osmotic system design with an orifice + end plug. FIG. 2 provides a cross-sectional side view of one embodiment of a device with a pre-formed sidewall orifice and two constraining end plugs. [Figure 16B] 1 shows a schematic of an osmotic system design with an orifice + end plug. FIG. 2 provides a top view of one embodiment of a device with a pre-formed sidewall orifice and two constraining end plugs. [Figure 16C] 1 shows a schematic of an osmotic system design with an orifice + end plug. FIG. 2 provides a cross-sectional side view of an end portion of one embodiment of a device with a constraining end plug and a microchannel formed through the end plug. [Figure 17]IVR profile for Prototype 4, Osmolality (Orifice + End Plug), 0.2 mm Wall, Erdafitinib L-Lactate, Tablet (20% wt. water-insoluble excipients). Erda, erdafitinib; IVR, in vitro release; SU, simulated urine; FBE, free base equivalent. [Figure 18] IVR profile for Prototype 5, Osmolality (Orifice + End Plug), 0.2 mm Wall, Erdafitinib L-Lactate, Tablet (Water Soluble Excipients). Erda, erdafitinib; IVR, in vitro release; SU, simulated urine; FBE, free base equivalent. [Figure 19] The mean urinary concentration versus time profiles in minipigs for prototypes 4 and 5 are summarized. [Figure 20A] Figure 20A shows the solubility of erdafitinib L-lactate as a function of pH in water at 37°C with the pH adjusted using HCl / NaOH solution (Figure 20A), and the solubility mg / mL of erdafitinib L-lactate as a function of pH in simulated urine at 37°C (Figure 20B). [Figure 20B] Figure 20A shows the solubility of erdafitinib L-lactate as a function of pH in water at 37°C with the pH adjusted using HCl / NaOH solution (Figure 20A), and the solubility mg / mL of erdafitinib L-lactate as a function of pH in simulated urine at 37°C (Figure 20B). [Figure 21] 1 shows an outline of the synthesis reaction of erdafitinib mono-L-lactate (JNJ-42756493-AFK) from erdafitinib (JNJ-42756493-AAA). [Figure 22] FIG. 1 is a schematic diagram of a concordance study of tissue and urine assays using paired samples from bladder cancer patients from the German Bladder BRIDGister clinical trial. [Figure 23-1] Heatmap of genetic alterations identified in matched urine NGS and FFPE tissue RT-PCR samples (bladder cancer patients from the German Bladder BRIDGister clinical trial). [Figure 23-2]Heatmap of genetic alterations identified in matched urine NGS and FFPE tissue RT-PCR samples (bladder cancer patients from the German Bladder BRIDGister clinical trial). [Figure 23-3] Heatmap of genetic alterations identified in matched urine NGS and FFPE tissue RT-PCR samples (bladder cancer patients from the German Bladder BRIDGister clinical trial). [Figure 23-4] Heatmap of genetic alterations identified in matched urine NGS and FFPE tissue RT-PCR samples (bladder cancer patients from the German Bladder BRIDGister clinical trial). [Figure 24A] Scatter plot of variant allele frequency (VAF) between matched urine NGS (X-axis) and tissue (FFPE) RT-PCR (Y-axis) variants for all identified genetic alterations, including somatic and germline variants. [Figure 24B] Scatter plot of variant allele frequencies (VAF) between matched urine NGS (X-axis) and tissue (FFPE) RT-PCR (Y-axis) variants for somatic FGFR3 alterations. DETAILED DESCRIPTION OF THE INVENTION

[0027] In some embodiments, a solid formulation of erdafitinib containing high concentrations of erdafitinib is provided, which is designed for intravesical drug delivery and controlled and extended drug release when deployed in the bladder. In some embodiments, the solid erdafitinib formulation is further adapted for large-scale manufacturing and is further adapted to provide the structural and chemical integrity of solid formulations, particularly tablets, when used in an intravesical drug delivery system. Improved intravesical drug delivery systems and drug delivery methods are also provided. In certain embodiments, the system is configured for intravesical insertion and sustained drug delivery, preferably configured to provide a zero-order release rate of a therapeutically effective amount of drug, particularly erdafitinib.

[0028] To utilize this administration route, erdafitinib formulations and release systems adapted for intravesical drug delivery are described herein.When formulated in solid form and administered in a suitable intravesical drug delivery system, such formulations can provide controlled drug release rates and extended drug release profiles.Further provided is a system that can deliver erdafitinib at a release rate effective for the local treatment of bladder cancer.

[0029] In certain embodiments, the drug delivery system described herein is a drug-device combination consisting of a device component, particularly an intravesical device, and a drug component, particularly an erdafitinib formulation, e.g., an erdafitinib tablet.

[0030] Erdafitinib formulations and tablets In one aspect, erdafitinib lactate, particularly erdafitinib L-lactate, particularly erdafitinib mono-L-lactate, is disclosed.This is useful, for example, in the local delivery / administration of erdafitinib to patients.In an embodiment, a pharmaceutical composition is provided, comprising erdafitinib lactate, particularly erdafitinib L-lactate, and one or more excipients.In an embodiment, the pharmaceutical composition is in the form of a tablet, particularly a mini-tablet.

[0031] In one aspect, the present disclosure provides an erdafitinib formulation, particularly an erdafitinib tablet, suitable for use in the disclosed intravesical drug delivery system. In particular, a drug tablet comprising a salt form of erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) is provided. After the drug delivery system is inserted into the bladder, the drug is released from the system into the bladder. In one aspect, for example, the drug delivery system can operate as an osmotic pump, which provides continuous release of the drug into the bladder over an extended period of time as the drug is released from the tablet in the system.

[0032] To increase or maximize the amount of drug that can be stored in and released from the disclosed drug delivery system, the drug tablet may have a relatively high erdafitinib content by weight. This relatively high weight fraction of erdafitinib in the drug tablet is accompanied by a reduced or low weight fraction of excipients that may be required for tablet manufacturing and system assembly and drug use considerations. For purposes of this disclosure, terms such as "weight fraction," "weight percentage," and "percentage by weight" with respect to any drug or API (active pharmaceutical ingredient) refer to the drug or API in the form used, regardless of whether it is in free base form, free acid form, salt form, or hydrate form. For example, a drug tablet having 90% by weight (90 wt%) of a drug or excipient in salt form may contain less than 90% by weight of the drug in free base form.

[0033] The erdafitinib drug tablet of the present disclosure includes an erdafitinib content and an excipient content. The drug content can include one or more forms of erdafitinib, such as a free base or a salt form, while the excipient content can include one or more excipients. Certain embodiments include a salt of erdafitinib, more specifically, an erdafitinib lactate salt, such as erdafitinib mono-L-lactic acid. The term "excipient" is well known in the art, and representative examples of excipients useful in the disclosed drug tablets may include, but are not limited to, ingredients such as binders, lubricants, glidants, disintegrants, solubilizers, colorants, fillers or diluents, wetting agents, stabilizers, formaldehyde scavengers, coating agents, and preservatives, or any combination thereof, as well as other ingredients to facilitate the manufacture, storage, or administration of the drug tablet.

[0034] In an embodiment, the erdafitinib drug tablet comprises erdafitinib in a salt form. In one aspect, the erdafitinib drug tablet may comprise 50% or more by weight of erdafitinib L-lactate, with the remainder of the weight comprising excipients that facilitate the manufacture and use of the drug tablet, such as lubricants, binders, and stabilizers. In an embodiment, the erdafitinib drug tablet comprises erdafitinib in a salt form. In one aspect, the erdafitinib drug tablet may comprise 50% or more by weight of erdafitinib L-lactate, with the remainder of the weight comprising excipients that facilitate the manufacture and use of the drug tablet, such as lubricants, fillers, binders, and glidants. Alternatively, the erdafitinib pharmaceutical tablet may comprise 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, or 90% or more by weight of erdafitinib L-lactate. In one embodiment, the pharmaceutical tablet may comprise 50% to 90%, 65% to 85%, 70% to 80%, e.g., 70%, 75%, or 80% by weight of erdafitinib in its L-lactic acid form, based on the total weight of the tablet.

[0035] In embodiments, the erdafitinib in the erdafitinib drug tablet is in the form of erdafitinib L-lactate. The properties of erdafitinib L-lactate are advantageous for use in the disclosed osmotic systems, including its high solubility, its stability, and its ability to function as an osmotic agent without the need for an added osmotic agent.

[0036] Erdafitinib formulations with a range of excipient combinations, both intragranular and extragranular, are provided in Example Tables 2, 9, 13, and 16. In particular, Table 16 shows formulation concepts 1-5. Concepts 1-5 are formulation embodiments encompassed by the present disclosure.

[0037] In some embodiments, the solid pharmaceutical composition comprises (a) 70% by weight of erdafitinib-L-lactate, (b) 1.43% by weight of hydroxypropyl methylcellulose, (c) 9.30% by weight of microcrystalline cellulose, (d) 7.22% by weight of silicified microcrystalline cellulose, (e) 9.30% by weight of vinylpyrrolidone-vinyl acetate (PVP VA), (f) 0.25% by weight of colloidal silicon dioxide (hydrophilic), and (g) 2.5% by weight of magnesium stearate, wherein the weight percentages are based on the total solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition comprises: (a) 70% by weight of erdafitinib-L-lactate (intragranular); (b) 1.43% by weight of hydroxypropyl methylcellulose (intragranular); (c) 9.30% by weight of microcrystalline cellulose (extragranular); (d) 7.22% by weight of silicified microcrystalline cellulose (extragranular); (e) 9.30% by weight of vinylpyrrolidone-vinyl acetate (PVP VA) (extragranular); (f) 0.25% by weight of colloidal silicon dioxide (hydrophilic) (extragranular); and (g) 2.5% by weight of magnesium stearate (extragranular). In some embodiments, the solid pharmaceutical composition is a tablet. In some embodiments, the formulation is Concept 1.

[0038] In some embodiments, the solid pharmaceutical composition comprises (a) 70% by weight of erdafitinib-L-lactate, (b) 1.43% by weight of hydroxypropyl methylcellulose, (c) 12.91% by weight of microcrystalline cellulose, (d) 12.91% by weight of vinylpyrrolidone-vinyl acetate (PVP VA), (e) 0.25% by weight of colloidal silicon dioxide (hydrophilic), and (f) 2.5% by weight of magnesium stearate, wherein the weight percentages are based on the total solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition comprises: (a) 70% by weight erdafitinib-L-lactate (intragranular); (b) 1.43% by weight hydroxypropyl methylcellulose (intragranular); (c) 12.91% by weight microcrystalline cellulose (extragranular); (d) 12.91% by weight vinylpyrrolidone-vinyl acetate (PVP VA) (extragranular); (e) 0.25% by weight colloidal silicon dioxide (hydrophilic) (extragranular); and (f) 2.5% by weight magnesium stearate (extragranular). In some embodiments, the solid pharmaceutical composition is a tablet. In some embodiments, the formulation is Concept 2.

[0039] In some embodiments, the solid pharmaceutical composition comprises (a) 70% by weight of erdafitinib-L-lactate, (b) 1.43% by weight of hydroxypropyl methylcellulose, (c) 12.91% by weight of microcrystalline cellulose, (d) 12.91% by weight of vinylpyrrolidone-vinyl acetate (PVP VA), (e) 0.25% by weight of colloidal silicon dioxide (hydrophilic), and (f) 2.5% by weight of sodium stearyl fumarate, wherein the weight percentages are based on the total solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition comprises: (a) 70% by weight of erdafitinib-L-lactate (intragranular); (b) 1.43% by weight of hydroxypropyl methylcellulose (intragranular); (c) 12.91% by weight of microcrystalline cellulose (extragranular); (d) 12.91% by weight of vinylpyrrolidone-vinyl acetate (PVP VA) (intragranular); (e) 0.25% by weight of colloidal silicon dioxide (hydrophilic) (extragranular); and (f) 2.5% by weight of sodium stearyl fumarate (extragranular). In some embodiments, the solid pharmaceutical composition is a tablet. In some embodiments, the formulation is Concept 3.

[0040] In some embodiments, the solid pharmaceutical composition comprises (a) 60% by weight of erdafitinib-L-lactate, (b) 1.23% by weight of hydroxypropyl methylcellulose, (c) 18.01% by weight of microcrystalline cellulose, (d) 18.01% by weight of vinylpyrrolidone-vinyl acetate (PVP VA), (e) 0.25% by weight of colloidal silicon dioxide (hydrophilic), and (f) 2.5% by weight of magnesium stearate, wherein the weight percentages are based on the total solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition comprises: (a) 60% by weight of erdafitinib-L-lactate (intragranular); (b) 1.23% by weight of hydroxypropyl methylcellulose (intragranular); (c) 18.01% by weight of microcrystalline cellulose (extragranular); (d) 18.01% by weight of vinylpyrrolidone-vinyl acetate (PVP VA) (extragranular); (e) 0.25% by weight of colloidal silicon dioxide (hydrophilic) (extragranular); and (f) 2.5% by weight of magnesium stearate (extragranular). In some embodiments, the solid pharmaceutical composition is a tablet. In some embodiments, the formulation is Concept 4.

[0041] In some embodiments, the solid pharmaceutical composition comprises (a) 80% by weight of erdafitinib-L-lactate, (b) 1.63% by weight of hydroxypropyl methylcellulose, (c) 7.81% by weight of microcrystalline cellulose, (d) 7.81% by weight of vinylpyrrolidone-vinyl acetate (PVP VA), (e) 0.25% by weight of colloidal silicon dioxide (hydrophilic), and (f) 2.5% by weight of magnesium stearate, wherein the weight percentages are based on the total solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition comprises: (a) 80% by weight erdafitinib-L-lactate (intragranular), (b) 1.63% by weight hydroxypropyl methylcellulose (intragranular), (c) 7.81% by weight microcrystalline cellulose (extragranular), (d) 7.81% by weight vinylpyrrolidone-vinyl acetate (PVP VA) (extragranular), (e) 0.25% by weight colloidal silicon dioxide (hydrophilic) (extragranular), and (f) 2.5% by weight magnesium stearate (extragranular). In some embodiments, the solid pharmaceutical composition is a tablet. In some embodiments, the formulation is Concept 5.

[0042] In embodiments, the erdafitinib drug and excipients are selected to enable drug release from the tablet, and the tablet is formulated in such a manner. In embodiments, the erdafitinib is formulated in a pharmaceutical composition so that it can be sterilized either within or outside the drug delivery system without substantial or adverse changes to the chemical or physical composition of the drug tablet that would otherwise render the drug tablet unsuitable for delivery of erdafitinib as described herein. In one aspect, the erdafitinib drug and excipients are selected for their compatibility with the sterilization process. In one embodiment, the drug delivery system including the drug tablet is sterilized as a whole. In particular, the drug delivery system including the drug tablet is sterilized by gamma irradiation.

[0043] In one aspect, erdafitinib drug tablets can be sized and shaped to be used with an indwelling drug delivery system, including the intravesical drug delivery system disclosed herein.For example, erdafitinib drug tablets can be "mini-tablets," which are generally smaller than conventional tablets, and mini-tablets can allow the drug tablets contained in the system to be inserted through a specific body cavity, such as the urethra, into a cavity, such as the bladder.Erdafitinib tablets can be coated or uncoated.In particular, uncoated tablets can work well in combination with the disclosed delivery system.

[0044] An example of a mini-tablet is shown in FIG. 3, which shows a mini-tablet 312 having a circular flat end face 326 and a cylindrical side wall 328 .

[0045] In embodiments, pharmaceutical tablets for intravesical insertion may be in the form of a solid cylinder having a cylinder axis, cylinder sides, a circular end surface perpendicular to the cylinder axis, a diameter across the circular end surface, and a length along the cylinder side. In the cylindrical form, each mini-tablet may have a length (L) that exceeds its diameter (D), such that the mini-tablet has an aspect ratio (L:D) of greater than 1:1. For example, the aspect ratio (L:D) of each mini-tablet may be 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, or a range of values ​​between these aspect ratios. Mini-tablet embodiments may have a cylinder diameter of 1.0 mm to 3.2 mm, or 1.5 mm to 3.1 mm, or 2.0 mm to 2.7 mm, or 2.5 mm to 2.7 mm. In some aspects, the mini-tablets may have a diameter of 2.4 mm to 2.8 mm. In some embodiments, the mini-tablets may have a length of 1.7 mm to 4.8 mm, or 2.0 mm to 4.5 mm, or 2.8 mm to 4 mm, or 3 mm to 3.5 mm. In some embodiments, the mini-tablets may have a length of 3.0 mm to 3.4 mm.

[0046] The API used in the solid tablet formulation may be erdafitinib, which is N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, the chemical structure of which is shown below. Erdafitinib tablets for use in the disclosed intravesical systems may be formulated using a salt of erdafitinib. In some specific embodiments, erdafitinib tablets for use in the disclosed intravesical systems may include a lactate salt of erdafitinib. In certain embodiments, erdafitinib tablets for use in the disclosed intravesical systems may be an L-lactate salt of erdafitinib, particularly the mono-L-lactate salt of erdafitinib.

[0047] [ka]

[0048] A general reference to a compound includes all stereoisomers unless expressly indicated otherwise, and a reference to a general structure or name, where the context permits or requires, includes all enantiomers, diastereomers, and other optical isomers, whether enantiomeric or racemic, as well as mixtures of stereoisomers. For any specific formula or name provided, any general formula or name provided also includes all stereoisomers that can result from a particular set of substituents. Thus, for example, as used herein, a reference to "lactate" includes both the D and L isomers.

[0049] In embodiments, the erdafitinib drug tablet may incorporate various excipients, including but not limited to at least one solubilizer, at least one binder, at least one wetting agent, at least one disintegrant, at least one stabilizer, at least one diluent, at least one glidant, at least one lubricant, at least one osmotic agent (osmogen), etc., or any combination thereof. In embodiments, the erdafitinib drug tablet may be free of various excipients or combinations of excipients, including but not limited to solubilizers, wetting agents, at least one stabilizer, at least one disintegrant, at least one osmotic agent (osmogen), or combinations thereof. In embodiments, the erdafitinib drug tablet comprises at least one binder, at least one filler (excipient), at least one glidant, at least one lubricant, or any combination thereof. Any excipient or any combination of excipients can be present in the intragranular composition, the extragranular composition, or both the intragranular and extragranular compositions. In one aspect, the at least one intragranular pharmaceutical excipient and the at least one extragranular pharmaceutical excipient can be the same, i.e., selected from at least one common (present in both) pharmaceutical excipient. In a further aspect, the intragranular pharmaceutical excipient and the extragranular pharmaceutical excipient do not include a common (present in both) pharmaceutical excipient, whereby the intragranular excipient and the extragranular excipient are mutually exclusive. In embodiments, an erdafitinib drug tablet, particularly an erdafitinib lactate drug tablet comprising 50% to 90%, 60% to 80%, 65% to 75%, e.g., 70% by weight of erdafitinib in its lactate salt form, particularly its L-lactic acid form, comprises at least one binder, at least one diluent, at least one glidant, at least one lubricant, or any combination thereof.

[0050] It will be understood that these functional descriptions of various excipients are generally used as follows: Solubilizers may improve or enhance the solubility of the API within the drug lumen of the disclosed system after in vivo insertion; Binders may hold solid particles of the composition together for physical stability; Wetting agents may reduce the surface tension between the drug and the medium in which the drug is generated, helping to maintain the drug's solubility; Disintegrants may aid in mini-tablet disintegration upon contact with water (urine) and release the drug substance; Stabilizers may improve the chemical stability, e.g., thermal stability, of a formulation containing the API, or protect the API from degradation; Diluents may function as bulking agents to increase the volume or weight of the composition, which may help to provide a tablet of a desired size; Glidants may improve the flow properties of (granulated) particles of tablet components or powder blends being compressed; Lubricants may prevent particles of the composition from adhering to components of manufacturing equipment, such as the dies and punches of a tablet press. The osmotic agent dissolves in the aqueous fluid in the delivery system, causing an increase in osmotic pressure therein.

[0051] In embodiments, the erdafitinib L-lactate formulation may contain all or only some of these excipients. For example, in one aspect, the erdafitinib L-lactate formulation may be free of solubilizers, wetting agents, disintegrants, stabilizers (e.g., meglumine), osmotic agents, or any combination of these excipients. For example, in another aspect, the drug itself, such as the lactate salt of erdafitinib, may function as the osmotic agent. In one aspect, the drug itself, such as the lactate salt of erdafitinib, functions as the osmotic agent, and the erdafitinib lactate formulation does not contain any other osmotic agents. In one aspect, the excipients may be water-soluble. In another aspect, the excipients may be colloidal in water. According to another aspect, the excipients may be soluble under the conditions of their development in a patient, for example, in the bladder. These and other excipients are described in more detail below.

[0052] stabilizers such as formaldehyde scavengers In one embodiment, erdafitinib API may be susceptible to degradation under certain conditions when incorporated into a solid formulation.For example, erdafitinib can decompose or be converted in the presence of formaldehyde to form the cyclization product 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine.Formaldehyde can come into contact with erdafitinib from various sources in the environment, such as from packaging materials or as contaminants in excipients or other components of the formulation.

[0053] Therefore, in one embodiment, the erdafitinib pharmaceutical formulation can contain a formaldehyde scavenger to improve the stability or shelf life of the formulation.Various formaldehyde scavengers can be used, and the formaldehyde scavenger can prevent, slow down, reduce, or postpone the formation of degradation products when erdafitinib comes into contact with formaldehyde.Therefore, the stability of the erdafitinib pharmaceutical formulation, for example, its chemical stability, can be increased in the presence of a formaldehyde scavenger compared to the erdafitinib pharmaceutical formulation in the absence of a formaldehyde scavenger.In one embodiment, the formaldehyde scavenger can be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular compositions.In one embodiment, the formaldehyde scavenger, particularly meglumine, can be present in the solid pharmaceutical composition as a component of the intragranular solid composition.

[0054] Formaldehyde scavengers may include or be selected from compounds containing reactive nitrogen centers, such as compounds containing amine or amide groups. Without being bound by theory, it is believed that these compounds react with formaldehyde to form Schiff base imines (R 1 R 2 C=NR 3 , where R 3is not hydrogen), and it is believed that the Schiff base imine itself can bind formaldehyde. Examples of such formaldehyde scavengers include, but are not limited to, amino acids, amino sugars, alpha-(α-)amine compounds, their conjugates and derivatives, and mixtures thereof. Such formaldehyde scavenger compounds can contain two or more amine and / or amide moieties capable of scavenging formaldehyde.

[0055] In one embodiment, the formaldehyde scavenger may comprise or be selected from, for example, meglumine, glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, aspartic acid, glutamic acid, arginine, lysine, ornithine, taurine, histidine, aspartame, proline, tryptophan, citrulline, pyrrolidine, asparagine, glutamine, tris(hydroxymethyl)aminomethane, conjugates thereof, pharmaceutically acceptable salts thereof, or any combination thereof. According to one embodiment, the formaldehyde scavenger may comprise or be selected from meglumine or a pharmaceutically acceptable salt thereof, in particular meglumine base.

[0056] Therefore, one aspect of the present disclosure is to use a formaldehyde scavenger, particularly meglumine, in an erdafitinib pharmaceutical formulation, such as a pharmaceutical tablet, to increase the stability of any form of erdafitinib, including erdafitinib salt forms such as erdafitinib L-lactate.The chemical stability of the erdafitinib pharmaceutical formulation is increased compared to an erdafitinib pharmaceutical formulation or composition that does not contain a formaldehyde scavenger.One aspect of the present disclosure is a method for preventing, slowing down, reducing, or postponing the formation of degradation products that may be formed from erdafitinib in the presence of formaldehyde, such as the following compounds:

[0057] [ka]

[0058] In one aspect, decomposition products, such as those described above, can occur in solid tablet compositions, such as minitablet formulations, particularly the minitablets disclosed herein.

[0059] When present in an erdafitinib solid pharmaceutical composition, the formaldehyde scavenger may be present in the solid pharmaceutical composition at a concentration of 0.01% to 5% by weight, 0.05% to 3% by weight, 0.1% to 2% by weight, 0.5% to 1.5% by weight, or about 1% by weight.When present in an erdafitinib solid pharmaceutical composition, the formaldehyde scavenger may be present in the solid pharmaceutical composition at a concentration of 5% to 10% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight.

[0060] In one aspect, the pharmaceutical compositions described herein, particularly the erdafitinib drug tablets, do not contain stabilizers or formaldehyde scavengers.

[0061] solubilizer In one aspect, the erdafitinib formulation may include a solubilizer. The solubilizer may be in the intragranular component, the extragranular component, or both the intragranular and extragranular components of the formulation. In embodiments, the solubilizer may include or be selected from, for example, (a) cyclic oligosaccharides, (b) cellulose functionalized with methoxy, 2-hydroxypropoxy, acetyl, or succinoyl moieties, or a combination thereof, or (c) a salt thereof. In one embodiment, the solubilizer is present in the intragranular component. In other aspects, the erdafitinib formulation may not include a solubilizer.

[0062] In embodiments, the solubilizer for erdafitinib tablet formulations may include or be selected from oligosaccharides. In embodiments, the solubilizer may include or be selected from cyclic oligosaccharides, such as cyclodextrins. Cyclodextrin solubilizers suitable for erdafitinib tablet formulations include, but are not limited to, hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfobutylether-beta-cyclodextrin sodium salt, or any combination thereof. In other embodiments, the solubilizer may include or be hydroxypropyl methylcellulose E5 (HPMC-E5). In other embodiments, the solubilizer for erdafitinib tablet formulations may include or be hydroxypropyl methylcellulose acetate succinate.

[0063] The oligosaccharide solubilizer may be present in an erdafitinib tablet form at a concentration of 1% to 20% by weight, alternatively 3% to 18% by weight, alternatively 5% to 15% by weight, alternatively 7% to 12% by weight, or alternatively 10% by weight or about 10% by weight. The cyclodextrin solubilizer may be present in an erdafitinib tablet formulation, e.g., an erdafitinib salt formulation, at a concentration of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight, or any range between any of these weight percentages.

[0064] In one aspect, the solubilizer for the erdafitinib tablet formulation disclosed herein can include or be hydroxypropyl-beta-cyclodextrin. One embodiment of the erdafitinib formulation includes a hydroxypropyl-beta-cyclodextrin solubilizer, which may be present in the intragranular composition. In one aspect, the pharmaceutical compositions described herein, particularly the erdafitinib drug tablets, do not contain a solubilizer.

[0065] Binder Pharmaceutical excipients for erdafitinib solid pharmaceutical compositions may include one or more binders. One or more binders may be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular solid composition and the extragranular solid composition. Suitable binders may be water-soluble, water-insoluble, slightly water-soluble, or a combination thereof. In certain embodiments, the binder is an aspect, and the binder may include a water-soluble binder, such as a water-soluble polymer binder. The polymer binder may include a non-ionic polymer that is pH-stable in aqueous solution.

[0066] Those skilled in the art will understand that binders can also function as diluents (also called fillers) in pharmaceutical compositions. Thus, the binders provided in this disclosure can also be used for these diluent functions, if desired, unless otherwise specified.

[0067] In one aspect, suitable binders include polyvinylpyrrolidone (PVP, also known as polyvidone, povidone, or poly(1-vinyl-2-pyrrolidinone)), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO, also known as poly(ethylene glycol) or poly(ethylene glycol, PEG), polypropylene oxide (PPO, also known as poly(propylene glycol) or poly(propylene glycol, PPG), ethylene glycol-propylene glycol copolymer, poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (hydroxypropyl methylcellulose), and the like. In one aspect, suitable binders may include or be selected from, but are not limited to, polyvinylpyrrolidone (PVP, also known as polyvidone, povidone, or poly(1-vinyl-2-pyrrolidinone)), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO, also known as poly(ethylene glycol) or PEG), polypropylene oxide (PPO, also known as poly(propylene glycol) or PPG), ethylene glycol-propylene glycol The binder may comprise or be selected from copolymers, poloxamers, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, or a combination thereof. In one aspect, a suitable binder may comprise or be selected from hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, vinylpyrrolidone-vinyl acetate copolymer, or a combination thereof. In one aspect, a suitable binder may comprise or be selected from hydroxypropyl methylcellulose (HPMC), vinylpyrrolidone-vinyl acetate copolymer (copovidone), or a combination thereof.

[0068] In a further aspect, suitable binders may include or be selected from polymers or copolymers of vinylpyrrolidone (VP, also 1-vinyl-2-pyrrolidinone) and vinyl acetate (VA). Suitable binders may also include or be selected from polymers or copolymers of ethylene oxide (EO) and propylene oxide (PO). Likewise, these binders may be used in combination with other binders, for example, in combination with microcrystalline cellulose, hydroxypropyl cellulose (HPC), or hydroxypropyl methylcellulose (HPMC).

[0069] In one embodiment, the total concentration of the at least one binder in the solid pharmaceutical composition can be 5% to 30% by weight, 10% to 25% by weight, 12% to 22% by weight, or 14% to 19% by weight. In one embodiment, the total concentration of the at least one binder in the solid pharmaceutical composition can be about 1% to about 30% by weight, about 5% to about 20% by weight, or about 10% to about 15% by weight.

[0070] In another aspect, a suitable polymeric binder may include or be selected from a copolymer of vinylpyrrolidone and vinyl acetate, which may be referred to as poly(vinylpyrrolidone-co-vinyl acetate) or poly(VP-co-VA). Examples of suitable binders include Kollidon® VA64 and Kollidon® VA64 Fine (BASF, Ludwigshafen am Rhein, Germany), which have a molecular weight (Mw) range of 45,000 g / mol to 70,000 g / mol based on solution light scattering measurements. Another suitable binder is Kollidon® K30.

[0071] In embodiments, the polymer binder, e.g., vinylpyrrolidone-vinyl acetate copolymer, can be present in the disclosed erdafitinib tablet formulation at a concentration of 2% to 15% by weight, alternatively 4% to 12% by weight, alternatively 6% to 10% by weight, or alternatively 8% or about 8% by weight. For example, the vinylpyrrolidone-vinyl acetate copolymer binder can be present in the erdafitinib tablet formulation at a concentration of 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 11% by weight, 12% by weight, 13% by weight, 14% by weight, 15% by weight, or any range between any of these weight percentages. In one aspect, the vinylpyrrolidone-vinyl acetate copolymer is present in an intragranular composition. In one aspect, the vinylpyrrolidone-vinyl acetate copolymer is present in an intragranular composition, and the intragranular composition is prepared by roller compaction. In one embodiment, vinylpyrrolidone-vinyl acetate copolymer is present in the extragranular composition. In one embodiment, vinylpyrrolidone-vinyl acetate copolymer is present in the extragranular composition at a concentration of 8% to 14% by weight, alternatively 7.5% to 18.5% by weight. In one embodiment, vinylpyrrolidone-vinyl acetate copolymer is present in the extragranular composition at a concentration of 8% to 14% by weight, alternatively 9% to 13% by weight.

[0072] In one aspect, the binder may include or be microcrystalline cellulose. For example, the microcrystalline cellulose may be present in the solid pharmaceutical composition at a concentration of 5% to 20%, 6% to 15%, or 7% to 12% by weight.

[0073] In another embodiment, the binder may include or be silicified microcrystalline cellulose. For example, the silicified microcrystalline cellulose may be present in the solid pharmaceutical composition at a concentration of 3% to 18%, 4% to 15%, or 5% to 12% by weight.

[0074] In another embodiment, the binder can include or be hydroxypropyl methylcellulose. For example, hydroxypropyl methylcellulose, e.g., HPMC 290 15 mPa.s, can be present in the solid pharmaceutical composition at a concentration of 0.5% to 5% by weight, or 0.5% to 2% by weight, or 1% to 2% by weight.

[0075] Wetting agent Pharmaceutical excipients for erdafitinib solid pharmaceutical compositions may include one or more wetting agents. One or more wetting agents may be present in the solid pharmaceutical composition in the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular solid compositions. In exemplary embodiments, the wetting agents may include or be independently selected from anionic surfactants or nonionic surfactants, particularly anionic surfactants. For example, the wetting agents may include or be independently selected from sodium lauryl sulfate, sodium stearyl fumarate, polysorbate 80, docusate sodium, or any combination thereof. In embodiments, the total concentration of the wetting agent in the solid pharmaceutical composition may be 0.01% to 2.5% by weight, 0.05% to 1.0% by weight, or 0.1% to 0.5% by weight. In one embodiment, the wetting agent is present in the intragranular composition.

[0076] In one embodiment, the erdafitinib solid pharmaceutical composition does not include one or more humectants.

[0077] Disintegrant Pharmaceutical excipients for erdafitinib solid pharmaceutical compositions may include one or more disintegrants. One or more disintegrants may be present in the solid pharmaceutical composition in the intragranular solid composition, the extragranular solid composition, or both the intragranular solid composition and the extragranular solid composition. In one embodiment, the disintegrant is present in the intragranular composition. In one embodiment, the disintegrant is present in the intragranular composition, and the intragranular composition is prepared by roller compaction.

[0078] In exemplary embodiments, the disintegrant may comprise or be independently selected from a functionalized polysaccharide or cross-linked polymer. For example, in one aspect, the disintegrant may comprise or be selected from, for example, (a) a cellulose functionalized with methoxy, 2-hydroxypropoxy, or carboxymethoxy moieties, a salt thereof, or a combination thereof, (b) a carboxymethylated starch, or (c) a cross-linked polymer.

[0079] In embodiments, the disintegrant may comprise or be independently selected from hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, crospovidone (cross-linked polyvinylpyrrolidone), croscarmellose sodium (cross-linked sodium carboxymethylcellulose), sodium starch glycolate, or any combination thereof.

[0080] When present, disintegrants can be present in a range of concentrations, hi embodiments, the total concentration of disintegrant in the solid pharmaceutical composition can be 0.1% to 10%, 0.2% to 8%, 0.5% to 7%, 1% to 5%, or 2% to 3% by weight.

[0081] In one embodiment, the erdafitinib solid pharmaceutical composition does not include one or more disintegrants.

[0082] Diluents or fillers Pharmaceutical excipients for erdafitinib solid pharmaceutical compositions may include one or more diluents. One or more diluents may be present in the solid pharmaceutical composition as components of the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular solid compositions.

[0083] In exemplary embodiments, the diluent may comprise or be selected from sugars, starches, microcrystalline cellulose, sugar alcohols, hydrogen phosphates, dihydrogen phosphates, carbonates, or combinations thereof. In one aspect, the diluent may comprise or be selected from lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium carbonate, sucrose, or any combination thereof. In one aspect, the diluent may comprise or be selected from microcrystalline cellulose, silicified microcrystalline cellulose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, or any combination thereof. In one aspect, the diluent may comprise or be selected from microcrystalline cellulose and silicified microcrystalline cellulose, or any combination thereof.

[0084] In embodiments, the total concentration of the diluent in the solid pharmaceutical composition can be 10% to 30% by weight, 12% to 30% by weight, 15% to 25% by weight, 18% to 22% by weight, 10% to 25% by weight, 10% to 20% by weight, or 10% to 15% by weight. In embodiments, the total concentration of the diluent in the solid pharmaceutical composition can be 5% to 30% by weight, 10% to 30% by weight, or 10% to 20% by weight. In some embodiments, the diluent comprises microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof. For example, in some aspects, the diluent can comprise or be selected from microcrystalline cellulose at a concentration of 15% to 25% by weight, or 20% to 22% by weight. For example, in some aspects, the diluent may comprise or be selected from microcrystalline cellulose at a concentration of 5% to 20% by weight, or 7.5% to 18.5% by weight, or 5% to 15% by weight, or 8% to 14% by weight, and / or silicified microcrystalline cellulose at a concentration of 5% to 10% by weight, or 7% to 8% by weight. In some embodiments, the diluent does not comprise silicified microcrystalline cellulose. In further aspects, the diluent may comprise or be selected from anhydrous calcium hydrogen phosphate at a concentration of 18% to 20% by weight.

[0085] Those skilled in the art will appreciate that some of the diluents / fillers disclosed herein may also function as binders in pharmaceutical compositions. Accordingly, some compounds or materials may be described herein as providing a binder function and as providing a diluent function.

[0086] Glidants Pharmaceutical excipients for erdafitinib solid pharmaceutical compositions may include one or more glidants. One or more glidants may be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular solid compositions. In one embodiment, the glidant is present in the extragranular composition. As used in this disclosure, glidant refers to a pharmaceutical excipient that improves or optimizes the particle flow properties of granulated or powdered tablet components in particulate form by reducing interparticle interaction, attraction, cohesion, or friction.

[0087] In one aspect, the glidant may comprise or be selected from colloidal silicon dioxide, colloidal anhydrous silicon dioxide, talc, or any combination thereof. In embodiments, the total concentration of the glidant in the solid pharmaceutical composition may be 0.01% to 5% by weight, 0.05% to 3% by weight, 0.1% to 1% by weight, or about 0.2% by weight, or about 0.25% by weight, or about 0.3% by weight, or about 0.35% by weight, or about 0.4% by weight, or about 0.45% by weight, or about 0.5% by weight. In embodiments, the total concentration of the glidant in the solid pharmaceutical composition may be about 0.05% to about 1% by weight, or about 0.1% to about 0.5% by weight, or about 0.25% by weight. In one embodiment, the glidant is colloidal silicon dioxide. In some embodiments, the glidant is colloidal silicon dioxide (hydrophilic). In some embodiments, the glidant is colloidal silicon dioxide (hydrophobic).

[0088] lubricant Pharmaceutical excipients for erdafitinib solid pharmaceutical compositions may include one or more lubricants. One or more lubricants may be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular compositions. In one aspect, the lubricant is present in the extragranular composition. In one aspect, the lubricant is present in the intragranular composition, and the intragranular composition is prepared by roller compaction. As used herein, a lubricant refers to a pharmaceutical excipient added to a tablet formulation to reduce friction at the tablet surface. In embodiments, a lubricant may reduce friction between the tablet surface and processing equipment, for example, between the tablet surface and the wall of the die cavity in which the tablet is formed. Thus, a lubricant may reduce friction between the die wall and the granules of the formulation as the tablet is formed and ejected. A pharmaceutically acceptable lubricant is a non-toxic and pharmacologically inactive substance. Furthermore, the lubricant may be water-soluble or water-insoluble, but is preferably water-soluble in the drug delivery system of the present disclosure.

[0089] In one embodiment, the lubricant includes or is magnesium stearate. In some embodiments, the lubricant includes or is sodium stearyl fumarate. In some embodiments, the lubricant includes or is polyethylene glycol (e.g., PEG8K).

[0090] In one aspect, the lubricant may comprise or be selected from, for example, a fatty acid, a fatty acid salt, a fatty acid ester, talc, a glyceride ester, a metal silicate, or any combination thereof. In embodiments, the lubricant may comprise or be selected from magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactylate, sodium stearoyl fumarate, titanium dioxide, or a combination thereof. Examples of water-soluble lubricants include, but are not limited to, leucine, sodium lauryl sulfate, sucrose stearate, boric acid, sodium acetate, sodium oleate, sodium stearyl fumarate, and PEG. In another aspect, the total concentration of the lubricant in the solid pharmaceutical composition may be 0.05% to 5% by weight, 0.1% to 3% by weight, 1% to 2% by weight, or about 1.5% by weight, or about 2.5% by weight. In another embodiment, the total concentration of the lubricant in the solid pharmaceutical composition can be 0.05% to about 5% by weight, about 1% to about 5% by weight, or about 2.5% by weight.

[0091] osmotic agents A drug or a certain salt form of a drug may itself function as an osmotic agent, and a drug formulation containing such a drug or its salt form may optionally contain one or more additional pharmaceutically acceptable osmotic agents that are pharmacologically inactive substances. Pharmaceutical excipients for erdafitinib solid pharmaceutical compositions may contain one or more osmotic agents. One or more osmotic agents may be present in the solid pharmaceutical composition as components of the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular solid compositions. Examples of osmotic agents include, but are not limited to, inorganic salts and carbohydrates, such as urea, potassium chloride, sodium chloride, sucrose, fructose, lactose, and mannitol.

[0092] In one embodiment, the drug itself, particularly erdafitinib lactic acid, especially erdafitinib mono-L-lactic acid, functions as an osmotic agent.

[0093] Method for preparing a tablet composition In one aspect, a process for making solid pharmaceutical compositions such as tablets, particularly minitablets, is provided. In some embodiments, the process comprises preparing an intragranular solid composition comprising erdafitinib L-lactate and at least one intragranular pharmaceutical excipient. In some embodiments, the intragranular pharmaceutical excipient comprises a binder. The binder may be any binder described herein. For example, the binder may be hydroxypropyl methylcellulose. In some embodiments, the process comprises combining the intragranular solid composition with at least one extragranular pharmaceutical excipient to form a blend. In some embodiments, the intragranular excipient and the extragranular excipient do not share a common excipient. In some embodiments, the extragranular excipient comprises one or more of a binder, a filler, a glidant, and / or a lubricant. Each of the extragranular binder, filler, glidant, and / or lubricant may be any binder, filler, glidant, and / or lubricant described herein, respectively. In some embodiments, the extragranular binder comprises vinylpyrrolidone-vinyl acetate (PVP VA). In some embodiments, the extragranular filler comprises microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof. In some embodiments, the extragranular filler comprises microcrystalline cellulose. In some embodiments, the extragranular filler comprises a combination of microcrystalline cellulose and silicified microcrystalline cellulose. In some embodiments, the extragranular glidant may be any glidant described herein. In some embodiments, the extragranular glidant comprises colloidal silicon dioxide (hydrophilic). In some embodiments, the extragranular lubricant may be any lubricant described herein. In some embodiments, the extragranular lubricant comprises magnesium stearate. In some embodiments, the extragranular lubricant comprises sodium stearyl fumarate. In some embodiments, the extragranular lubricant comprises polyethylene glycol. In some embodiments, the process comprises tableting the blend to form a solid pharmaceutical composition. In some embodiments, the tableting is characterized by an ejection force of less than about 1000 N.

[0094] Osmotic Drug Delivery Systems Drug delivery systems particularly suitable for the effective release of drug formulations containing erdafitinib, such as those detailed above, are described herein. These particular systems utilize osmotic pressure to drive the controlled release of the drug through one or more openings in the system housing. The terms "aperture" and "orifice" may be used interchangeably with "opening."

[0095] In certain embodiments, the system includes a water-permeable, drug-impermeable polymeric component forming a housing. For example, the polymeric component may be formed from a biocompatible elastomeric composition, such as a silicone or thermoplastic polyurethane composition, that has desired mechanical properties (e.g., soft, resiliently flexible). The polymeric component may have a tubular structure, e.g., a dual-lumen tube.

[0096] In one aspect, as shown in FIGS. 1A-1B, a drug delivery system 100 includes a flexible device body 102 defining a drug reservoir lumen 104 and a retaining frame lumen 106. The drug reservoir lumen 104 contains a plurality of solid drug tablets 108 disposed end-to-end within the drug reservoir lumen. In some embodiments, including the one shown, the drug tablets 108 have circular flat end faces and cylindrical sidewalls. The retaining frame lumen 106 houses an elastic wire or retaining frame 110. The retaining frame may be a superelastic alloy such as nitinol. Silicone spacers 120 are secured to the ends of the drug reservoir lumen 104, for example, using a silicone adhesive, to close / occlude the drug reservoir lumen 104 at its ends and retain the drug tablets 108 therein.

[0097] 1B, device body 102 includes a tubular wall structure 112 that defines drug reservoir lumen 104 and a smaller tubular wall structure 114 that defines retaining frame lumen 106. Wall structures 112, 114 and lumens 104, 106 are substantially cylindrical as shown, although other variations in shape are possible.

[0098] In a preferred embodiment, the tubular wall structures 112, 114 are formed from silicone (MED-4750), and the tubular wall structure 112 has a wall thickness of 0.1 mm to 0.5 mm, or 0.15 mm to 0.4 mm, or 0.18 mm to 0.3 mm, or 0.2 mm. In some embodiments, the tubular wall structure 112 defining the drug reservoir lumen 104 may be formed from another elastomeric material that is impermeable to the drug. As used herein, the terms "drug-impermeable" or "drug-impermeable" refer to a housing that is substantially impermeable to a solubilized drug, e.g., erdafitinib, over the course of a therapeutic period in which the system is deployed in vivo, such that a substantial amount of the solubilized drug cannot diffuse therethrough.

[0099] The device body 102 includes an opening 130 extending through the sidewall of the tubular wall structure 112 that defines the drug reservoir lumen 104. In the illustrated embodiment, the device body has a single drug release opening. In exemplary embodiments, the opening has a diameter of about 20 μm to about 500 μm, e.g., about 25 μm to about 300 μm, and more specifically, about 30 μm to about 200 μm. In one example, the opening has a diameter of about 100 μm to about 200 μm, e.g., about 150 μm. In some other embodiments, the device body may have two or more openings.

[0100] 2, the drug delivery system 100 operates in vivo as an osmotic pump. Water or urine from the patient's body diffuses through the tubular wall structure 112, contacts and solubilizes the drug tablet 108, and creates osmotic pressure that drives the solubilized drug out of the drug delivery system through the orifice 130.

[0101] In some embodiments, the system includes a single opening, i.e., a through-hole, located in the sidewall of the tubular housing.

[0102] In some embodiments, the system is a closed structure configured to release a drug through the temporary formation of microchannels defined between and at the interface of two surfaces and / or two components within the system, as described in U.S. Pat. No. 9,814,671, the entire contents of which are incorporated herein by reference.

[0103] In some specific embodiments, the system includes both a tubular housing and through-holes in the housing structure configured to release a drug through the temporary formation of microchannels defined between and at two surfaces and / or interfaces of two components, as described in U.S. Pat. No. 11,020,575, the entire contents of which are incorporated herein by reference. In some embodiments, the microchannels are formed in response to hydrostatic pressure building up within the permeable body due to osmotically driven water influx. When the hydrostatic pressure increases beyond a certain threshold, the microchannels are formed, thereby forcing at least a portion of the drug out of the device and relieving the hydrostatic pressure buildup within the drug reservoir. The microchannels may at least partially collapse when the hydrostatic pressure is released. This process repeats itself until all or a substantial portion of the drug is released or until the osmotically driven water influx is insufficient to continue the process. As shown in FIGS. 16A and 16C , drug delivery device 50 includes a device body 52 having a water-permeable wall portion 64 that bounds a reservoir 60 (also referred to herein as a “reservoir lumen” or “drug reservoir lumen”) containing a payload 58, such as a drug formulation (e.g., minitablets). Water-permeable wall portion 64 may generally be configured to allow water to enter the device and contact the drug formulation (i.e., payload) 58 located within reservoir 60 to facilitate release of fluidized drug 58A from the device. For example, osmotically driven influx of water into reservoir 60 may create pressure within reservoir 60 that drives release of fluidized drug 58A from reservoir 60 via one or more mechanisms. For example, in embodiments described herein, release of fluidized drug 58A from the device may occur through one or more preformed sidewall orifices 66 and / or through temporary formation of one or more microchannels 62 that lead to an opening in the end of the device. For example, device 50 may further include a resilient portion 54 that surrounds restraining plug 56 and controls drug release from the device through the temporary formation of one or more microchannels 62 between 54 and 56 .As indicated by the dashed arrow, water diffuses through the water-permeable wall 64 of the body 52 and enters the drug reservoir 60, forming a fluidized drug solution 58A, which may be, for example, an aqueous solution containing the drug provided in the payload 58 initially loaded in the reservoir 60. The hydrostatic pressure within the reservoir 60 forces the fluidized drug 58A out of the reservoir 60 between the elastic portion 54 and the restraining plug 56 through the microchannel 62 formed therebetween, for example, by elastic deformation of one or both of the interfaces. In certain embodiments described herein, a combination of these release mechanisms is used to provide a desired drug release profile.

[0104] As shown in FIG. 16B, device 50 of FIG. 16A is shown in plan view in a relatively expanded configuration suitable for retention within the body, e.g., the bladder. The device includes a water-permeable body 52 having a drug reservoir portion 78 and a retention frame portion 76. Retention frame portion 76 may include a retention frame 74 that is deformable between a relatively expanded configuration and a relatively low-profile configuration suitable for insertion into the bladder via a catheter. In some embodiments, retention frame 74 includes or is made of elastic wire. For example, retention frame 74 is an elastic wire formed from a superelastic alloy such as nitinol. The drug reservoir lumen may be loaded with multiple drug units 158 in a serial arrangement. The drug units may be tablets, such as mini-tablets. As used herein, the term "drug reservoir portion" refers to the portion of the device that forms and defines the "drug reservoir" or "drug reservoir lumen." For purposes of this disclosure, the term "retention shape" generally refers to any shape suitable for retaining a device within the bladder, including, but not limited to, a coiled or "pretzel" shape as shown in FIG. 16B. This retention shape prevents the device from being entrapped in urine and expelled when the patient urinates. The terms "relatively expanded shape" and "relatively higher profile shape" may be used interchangeably with "retention shape."

[0105] 2, device body 102 can be formed by a molding or extrusion process, or an additive manufacturing process. In some embodiments, where the drug and device components are produced separately and then combined, the drug component (e.g., a tablet) is loaded into the drug reservoir lumen, and the drug reservoir lumen is then closed at its ends, for example, with a silicone spacer and / or adhesive. In some other embodiments, the drug and device components are manufactured together in an additive manufacturing process, such as a 3D printing process known in the art.

[0106] In embodiments, the system is configured for intravesical insertion and retention in a patient. In preferred embodiments, the system is elastically deformable between a low-profile deployed configuration (e.g., a relatively straightened configuration) suitable for insertion through the patient's urethra and into the patient's bladder, and a relatively expanded retention configuration (e.g., a pretzel shape, a bi-elliptical coil shape, an S-shape, etc.) suitable for retention within the bladder. For example, the housing or tube of the system may have two opposing free ends that are oriented away from each other when the system is in the low-profile deployed configuration and toward each other when the system is in the relatively expanded retention configuration. The relatively expanded configuration may include a pair of overlapping coils, often referred to as a "pretzel" shape. In certain embodiments, the extended system ends are generally within the boundaries of the bi-elliptical expanded retention configuration.

[0107] Within the bladder, the system should be compliant (i.e., easily flexed and soft-feeling) during detrusor contraction to avoid or reduce discomfort and irritation to the patient. For example, the system may be configured for tolerability based on bladder characteristics and design considerations described in U.S. Pat. No. 11,065,426 (incorporated herein by reference).

[0108] In some embodiments, the system includes a support frame lumen, and in some of these embodiments, the support frame lumen includes a support frame, i.e., a resilient wire, such as a nitinol wire. In certain other embodiments, the support frame lumen is filled with a shape-set resilient polymer. In some other embodiments, the system does not include a support frame lumen or a support frame or wire. Instead, the housing material is configured to be resiliently deformable between a straightened shape and a support shape in the absence of a support frame or wire. For example, in certain embodiments, the tubular housing is heat-shaped to have a coiled or other support shape.

[0109] In embodiments, the tubular housing may be formed from a water-permeable material. In preferred embodiments, as described above with respect to erdafitinib solid formulations, the drug is in solid form (e.g., a tablet or multiple tablets), and the tubular body is water-permeable to allow in vivo solubilization of the drug while within the drug reservoir lumen. In some other embodiments, the solid formulation may be in a free-flowing particulate form, such as beads, granules, or a powder.

[0110] In some embodiments, the material for the wall structure of the system is selected from silicones and suitable thermoplastic polyurethane (TPU) based materials known in the art, hi some embodiments, the material for the wall structure is a platinum-cured silicone elastomer.

[0111] In one aspect, the system housing is in the form of a ring, i.e., a cylindrical tube. In one embodiment, the inner diameter of the cylindrical tube may be 1.0 mm to 3.0 mm, or 2.0 mm to 3.0 mm, or 2.2 mm to 2.8 mm, or 2.6 mm to 2.7 mm, or 2.64 mm. In one embodiment, the outer diameter of the cylindrical tube is about 2.0 mm to about 4.1 mm. In one embodiment, the wall structure (annulus) of the cylindrical tube has a thickness of about 0.2 mm to about 1.0 mm.

[0112] In embodiments, the systems described herein are configured to release a therapeutically effective amount of drug, wherein the rate of release of the drug from the drug delivery system is zero order over a period of at least 36 hours. In one embodiment, the rate of release of the drug from the drug delivery system is essentially zero order over a period of at least 7 days. In embodiments, the systems are configured to release a therapeutically effective amount of drug over a period of 2 days to 6 months, e.g., 2 days to 90 days, 7 days to 30 days, or 7 days to 14 days. Desirably, the rate of release of the drug from the drug delivery system is zero order over a period of at least 7 days, e.g., 7 to 14 days or more, e.g., up to 3 months or 90 days. In certain embodiments, the systems are configured to begin releasing the drug after a lag time.

[0113] In some embodiments, the system is configured to release erdafitinib at an average rate of 1 mg / day to 10 mg / day, depending on the desired treatment regimen. In some embodiments, the system is configured to release erdafitinib at an average rate of 1 mg / day to 2 mg / day. In some embodiments, the system is configured to release erdafitinib at an average rate of 4 mg / day to 6 mg / day. In some embodiments, the system is configured to release erdafitinib at an average rate of 2 mg / day or 4 mg / day. In some embodiments, the system is configured to release erdafitinib in a zero-order release profile.

[0114] The osmotic drug delivery system may be loaded with a solid form of erdafitinib salt, such as a tablet, as described throughout this disclosure. For example, the system may have a drug reservoir lumen configured to hold a plurality of the disclosed drug tablets in an elongated configuration, arranged end-to-end in series. In some embodiments, the system holds about 10 to 100 cylindrical drug tablets (e.g., 44 tablets), e.g., mini-tablets, which may be sequentially loaded within the drug reservoir lumen. In some embodiments, the system holds about 10 to 100 cylindrical drug tablets (e.g., about 40 to about 50 tablets), e.g., mini-tablets, which may be sequentially loaded within the drug reservoir lumen. In some embodiments, each mini-tablet has a mass of about 20 mg to about 30 mg, or about 22 mg to about 24 mg. In some embodiments, the formulation comprises mini-tablets having a total length of about 14 cm to about 16 cm, about 14.5 cm to about 15.5 cm, or about 14.7 cm to about 14.8 cm. In some embodiments, the total tablet mass loaded into the system is about 900 mg to about 1000 mg. In some embodiments, the total tablet mass loaded into the system is about 920 mg to about 965 mg. In some embodiments, the total tablet mass loaded into the system is about 920 mg to about 950 mg. In some embodiments, the system comprises about 500 mg to about 750 mg of erdafitinib (free base equivalent).

[0115] In some embodiments, the drug delivery system comprises a dual lumen system comprising a silicone tube having a wall thickness of 0.2 mm, the dual lumen system comprising: (i) a retention frame lumen (the "small lumen") that encapsulates a wireform as a retention feature; and (ii) a drug reservoir lumen (the "large lumen") having an inner diameter of 2.64 mm that is filled with multiple mini-tablets, wherein the silicone tube surrounding the drug reservoir lumen comprises a single 150 μm orifice, and the drug reservoir lumen is sealed by two end plugs (e.g., parylene-coated end plugs) that are sealed (e.g., using silicone adhesive) to the silicone tube surrounding the drug reservoir lumen and capable of forming temporary microchannels. The multiple mini-tablets may have, for example, a total mini-tablet length of about 15.0 cm and a total tablet mass of about 932 mg (e.g., 620 mg of erdafitinib (free base equivalent) when the mini-tablets comprise 80 wt% erdafitinib mono-L-lactic acid, 18 wt% microcrystalline cellulose, 0.5 wt% hydrophilic colloidal silicon dioxide, and 1.5 wt% magnesium stearate). The multiple mini-tablets may have a total mini-tablet length of about 15.0 cm and a total tablet mass of about 932 mg (e.g., 620 mg erdafitinib (free base equivalent)), for example, when the mini-tablets contain 80 wt% erdafitinib mono-L-lactic acid intragranularly, 18 wt% microcrystalline cellulose (intragranularly), 0.5 wt% hydrophilic colloidal silicon dioxide (e.g., 0.3 wt% intragranular + 0.2 wt% extragranularly), and 1.5 wt% magnesium stearate (e.g., 0.75 wt% intragranular and 0.75 wt% extragranularly). In some embodiments, the drug delivery system exists in two shapes: one having a wire form with a low-profile (e.g., straightened) deployed shape, and the other having a relatively expanded (e.g., pretzel) retained shape. In some embodiments, the drug delivery system is Prototype 4.

[0116] In some embodiments, the drug delivery system comprises a dual lumen system comprising a silicone tube having a wall thickness of 0.2 mm, the dual lumen system comprising: (i) a retention frame lumen (the "small lumen") that encapsulates a wireform as a retention feature; and (ii) a drug reservoir lumen (the "large lumen") having an inner diameter of 2.64 mm that is filled with multiple mini-tablets, wherein the silicone tube surrounding the drug reservoir lumen comprises a single 150 μm orifice, and the drug reservoir lumen is sealed by two end plugs (e.g., parylene-coated end plugs) that are sealed (e.g., using silicone adhesive) to the silicone tube surrounding the drug reservoir lumen and capable of forming temporary microchannels. The mini-tablets may have, for example, a total mini-tablet length of about 15.0 cm and a total tablet mass of about 961 mg (e.g., 726 mg of erdafitinib (free base equivalent) when the mini-tablets comprise 90.8 wt% erdafitinib mono-L-lactic acid, 4.5 wt% polyethylene glycol (e.g., PEG8K), and 4.7 wt% polyvinylpyrrolidone). The mini-tablets may have, for example, a total mini-tablet length of about 15.0 cm and a total tablet mass of about 961 mg (e.g., 726 mg of erdafitinib (free base equivalent) when the mini-tablets comprise 90.8 wt% erdafitinib mono-L-lactic acid intragranularly, 4.5 wt% polyethylene glycol (e.g., PEG8K) (extragranular), and 4.7 wt% polyvinylpyrrolidone (intragranular). In some embodiments, the drug delivery system exists in two shapes, one with a low-profile (e.g., straightened) deployed wire form and the other with a relatively expanded (e.g., pretzel) retained shape. In some embodiments, the drug delivery system is Prototype 5.

[0117] Variations of Prototype 4 and Prototype 5, in which the mini-tablets may comprise any of the pharmaceutical formulations described herein, are also encompassed by the present disclosure. In some embodiments, Prototype 4 comprises a mini-tablet comprising 20% ​​by weight of a water-insoluble excipient. In some embodiments, Prototype 5 comprises a mini-tablet comprising only water-soluble excipients. In some embodiments, Prototype 4 or Prototype 5 may comprise any of the pharmaceutical formulations described herein, including Concept 1, Concept 2, Concept 3, Concept 4, or Concept 5.

[0118] As discussed herein with respect to the erdafitinib pharmaceutical formulation, the drug may be provided in a solid form suitable for loading into the drug reservoir lumen of the system. In some embodiments, the individual drug tablets may essentially have any selected shape and dimensions that fit within the systems described herein. In one embodiment, the drug unit is sized and shaped so that the drug reservoir lumen in the housing is substantially filled with a selected number of drug tablets. Each tablet may have a cross-sectional shape that substantially corresponds to the cross-sectional shape of the drug reservoir lumen of a particular housing. For example, the tablet may be substantially cylindrical for positioning within a substantially cylindrical drug reservoir lumen.

[0119] In one embodiment, the drug units (tablets) are shaped to align when the system is in its deployed configuration. For example, each drug unit may have a cross-sectional shape corresponding to the cross-sectional shape of the drug reservoir lumen in the housing, and each drug unit may have an end face shape corresponding to the end face of an adjacent drug unit. Gaps or interruptions between the drug units may accommodate deformation or movement of the drug delivery system, for example, during deployment, while allowing each drug unit to retain its solid form. Thus, the drug delivery system may be relatively flexible or deformable despite being loaded with solid drug, allowing each drug unit to move relative to adjacent drug units.

[0120] In embodiments, the drug unit is a "mini-tablet" sized and shaped to be suitable for insertion through a natural body lumen, such as the urethra. For purposes of this disclosure, the term "mini-tablet" generally refers to a solid drug unit that is substantially cylindrical in shape, having end faces and substantially cylindrical sides. Mini-tablets have a diameter extending along the end faces ranging from about 1.0 to about 3.2 mm, e.g., about 1.5 to about 3.1 mm. Mini-tablets have a length extending along the sides ranging from about 1.7 mm to about 4.8 mm, e.g., about 2.0 mm to about 4.5 mm. The friability of the tablets may be less than about 2%.

[0121] Drug Delivery and Treatment Methods The systems and methods disclosed herein may be adapted for use in humans or in veterinary or livestock applications. Accordingly, the term "patient" may refer to a human or other mammalian subject. In one embodiment, the patient is a human subject. The patient may be a cancer patient.

[0122] In certain embodiments, provided herein are methods for treating urothelial cancer, e.g., bladder cancer. In certain embodiments, provided herein are uses of the drug delivery systems described herein for the manufacture of medicaments for treating urothelial cancer, e.g., bladder cancer. In certain embodiments, provided herein are drug delivery systems described herein for use in treating urothelial cancer, e.g., bladder cancer. In certain embodiments, provided herein are erdafitinib for use in the drug delivery systems described herein for treating urothelial cancer, e.g., bladder cancer. The method or use may include locally delivering or administering erdafitinib (e.g., erdafitinib in any of the formulations described herein) to the bladder of a patient in need of treatment, particularly a cancer patient, in an amount effective for treating bladder cancer (e.g., about 1-10 mg / day, as described herein). For example, the treatment may be effective in treating muscle-invasive bladder cancer (MIBC), non-muscle-invasive bladder cancer (NMIBC), and / or Mycobacterium bovis Bacillus Calmette-Guerin (BCG)-naïve bladder cancer. In one embodiment, the patient, particularly a human, is a BCG-experienced bladder or NMIBC or MIBC cancer patient. In one embodiment, the patient, particularly a human, is a BCG-naïve bladder or NMIBC or MIBC cancer patient. In one embodiment, the patient, particularly a human, is a recurrent Mycobacterium bovis Bacillus Calmette-Guerin (BCG)-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient who refuses or is ineligible for radical cystectomy (RCy). In one embodiment, the patient, particularly a human, is a recurrent BCG-experienced, high-risk, papillary-only NMIBC (high-grade Ta / T1) cancer patient scheduled for RCy. In one embodiment, the patient, particularly a human, is a recurrent, intermediate-risk NMIBC (Ta and T1) cancer patient with a history of only low-grade disease. In one embodiment, the patient, particularly a human, is a MIBC cancer patient scheduled for RCy who has refused or is ineligible for cisplatin-based neoadjuvant chemotherapy.

[0123] In certain embodiments, a method for treating bladder cancer having one or more FGFR gene alterations is provided, comprising locally delivering an amount of erdafitinib effective for treating bladder cancer to the bladder of a patient in need thereof, wherein the one or more FGFR gene alterations are detected in a urine sample from the patient, particularly where the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR assay or NGS assay. In certain embodiments, a method for treating bladder cancer having one or more FGFR gene alterations is provided, comprising, consisting of, or consisting essentially of: (a) evaluating a urine sample from a patient with bladder cancer for the presence of one or more FGFR gene alterations, particularly using a urine-based PCR assay or NGS assay to evaluate a urine sample from a patient with bladder cancer for the presence of one or more FGFR gene alterations; and (b) locally delivering erdafitinib if one or more FGFR gene alterations are present in the sample. In certain embodiments, there is provided a method for treating bladder cancer having one or more FGFR gene alterations, comprising locally delivering a therapeutically effective amount of erdafitinib to the bladder of a patient in need thereof, wherein the patient is selected for treatment based on detection of one or more FGFR gene alterations in a urine sample from the patient, particularly where the patient is selected for treatment based on detection of one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay. In certain embodiments, there is provided a method for treating bladder cancer having one or more FGFR gene alterations, comprising locally delivering a therapeutically effective amount of erdafitinib to the bladder of a patient in need thereof, wherein the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient, particularly where the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay.In certain embodiments, there is provided erdafitinib for use in treating bladder cancer in a patient with one or more FGFR gene alterations, wherein the erdafitinib is delivered locally to the patient's bladder, and wherein the one or more FGFR gene alterations are detected in a urine sample from the patient, particularly wherein the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR assay or an NGS assay. In certain embodiments, there is provided erdafitinib for use in treating bladder cancer in a patient with one or more FGFR gene alterations, the use comprising, consisting of, or consisting essentially of: (a) evaluating a urine sample from the patient with bladder cancer for the presence of one or more FGFR gene alterations, particularly evaluating a urine sample from the patient with bladder cancer for the presence of one or more FGFR gene alterations using a urine-based PCR assay or an NGS assay; and (b) locally delivering erdafitinib to the patient if one or more FGFR gene alterations are present in the sample. In certain embodiments, there is provided erdafitinib for use in treating bladder cancer in a patient having one or more FGFR gene alterations, wherein the erdafitinib is for local delivery to the patient's bladder, and the patient is selected for treatment based on detection of one or more FGFR gene alterations in a urine sample from the patient, particularly, the patient is selected for treatment based on detection of one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay.In certain embodiments, there is provided erdafitinib for use in treating bladder cancer in a patient with one or more FGFR gene alterations, wherein the erdafitinib is locally delivered to the patient's bladder, and the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient, particularly, the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay. In certain embodiments, there is provided use of erdafitinib for the manufacture of a medicament for treating bladder cancer in a patient with one or more FGFR gene alterations, wherein the erdafitinib is locally delivered to the patient's bladder, and the one or more FGFR gene alterations are detected in a urine sample from the patient, particularly, the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR assay or an NGS assay. In certain embodiments, there is provided a use of erdafitinib for the manufacture of a medicament for treating bladder cancer in a patient with one or more FGFR gene alterations, comprising, consisting of, or consisting essentially of: (a) evaluating a urine sample from a patient with bladder cancer for the presence of one or more FGFR gene alterations, particularly evaluating a urine sample from a patient with bladder cancer for the presence of one or more FGFR gene alterations using a urine-based PCR assay or an NGS assay; and (b) locally delivering erdafitinib if one or more FGFR gene alterations are present in the sample.In certain embodiments, there is provided a use of erdafitinib for the manufacture of a medicament for treating bladder cancer in a patient with one or more FGFR gene alterations, wherein the erdafitinib is locally delivered to the patient's bladder, and the patient is selected for treatment based on detection of one or more FGFR gene alterations in a urine sample from the patient, particularly, the patient is selected for treatment based on detection of one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay. In certain embodiments, there is provided a use of erdafitinib for the manufacture of a medicament for treating bladder cancer in a patient with one or more FGFR gene alterations, wherein the erdafitinib is locally delivered to the patient's bladder, and the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient, particularly, the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay. The method or use may include locally delivering or administering erdafitinib (e.g., as in any of the formulations described herein) to the bladder of a patient, particularly a cancer patient, in need of treatment, in an amount effective for treating bladder cancer (e.g., about 1-10 mg / day, as described herein). For example, the treatment may be effective in treating muscle-invasive bladder cancer (MIBC), non-muscle-invasive bladder cancer (NMIBC), and / or Bacillus Calmette-Guérin (BCG)-naïve bladder cancer. In one embodiment, the patient, particularly a human, is a BCG-experienced bladder or NMIBC or MIBC cancer patient. In one embodiment, the patient, particularly a human, is a BCG-naïve bladder or NMIBC or MIBC cancer patient. In one aspect, the patient, particularly a human, is a recurrent Mycobacterium bovis Bacille Calmette-Guérin (BCG)-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient who refuses or is ineligible for radical cystectomy (RCy).In one embodiment, the patient, particularly a human, is a recurrent BCG-experienced, high-risk, papillary-only NMIBC (high-grade Ta / T1) cancer patient scheduled for RCy. In one embodiment, the patient, particularly a human, is a recurrent, intermediate-risk NMIBC (Ta and T1) cancer patient with a history of only low-grade disease. In one embodiment, the patient, particularly a human, is a MIBC cancer patient scheduled for RCy who has refused or is ineligible for cisplatin-based neoadjuvant chemotherapy.

[0124] In certain embodiments, a method of treating bladder cancer having one or more FGFR gene alterations is provided, comprising locally delivering an amount of erdafitinib effective to treat bladder cancer to the bladder of a patient in need thereof, wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient, particularly, the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or the one or more FGFR gene alterations are detected in a histopathology image of the tumor tissue via digital histopathology analysis. In certain embodiments, methods are provided for treating bladder cancer with one or more FGFR genetic alterations, comprising, consisting of, or consisting essentially of: (a) evaluating a tumor tissue sample from a patient with bladder cancer for the presence of one or more FGFR genetic alterations, particularly using a tissue-based PCR assay or an NGS assay to evaluate a tumor tissue sample from a patient with bladder cancer for the presence of one or more FGFR genetic alterations, or evaluating histopathology images of tumor tissue from a patient with bladder cancer for the presence of one or more FGFR genetic alterations via digital histopathology analysis; and (b) locally delivering erdafitinib if one or more FGFR genetic alterations are present in the sample. In certain embodiments, provided is a method of treating bladder cancer harboring one or more FGFR gene alterations, comprising locally delivering a therapeutically effective amount of erdafitinib to the bladder of a patient in need thereof, wherein the patient is selected for treatment based on detection of one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly, the patient is selected for treatment based on detection of one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or the patient is selected for treatment based on detection of one or more FGFR gene alterations in histopathology images of tumor tissue via digital histopathology analysis.In certain embodiments, methods are provided for treating bladder cancer harboring one or more FGFR gene alterations, comprising locally delivering a therapeutically effective amount of erdafitinib to the bladder of a patient in need thereof, wherein the patient's eligibility for the treatment is determined by detecting one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly, the patient's eligibility for the treatment is determined by detecting one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or the patient's eligibility for the treatment is determined by detecting one or more FGFR gene alterations in a histopathology image of the tumor tissue via digital histopathology analysis. In certain embodiments, there is provided erdafitinib for use in treating bladder cancer in a patient with one or more FGFR gene alterations, wherein the erdafitinib is delivered locally to the patient's bladder, and the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient, particularly, the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or the one or more FGFR alterations are detected in a histopathology image of the tumor tissue via digital histopathology analysis. In certain embodiments, there is provided erdafitinib for use in treating bladder cancer in a patient with one or more FGFR gene alterations, comprising, consisting of, or consisting essentially of: (a) evaluating a tumor tissue sample from the patient with bladder cancer for the presence of one or more FGFR gene alterations, in particular evaluating a tumor tissue sample from the patient with bladder cancer for the presence of one or more FGFR gene alterations using a tissue-based PCR assay or an NGS assay, or evaluating histopathology images of tumor tissue from the patient with bladder cancer for the presence of one or more FGFR gene alterations via digital histopathology analysis; and (b) locally delivering erdafitinib to the patient if one or more FGFR gene alterations are present in the sample.In certain embodiments, there is provided erdafitinib for use in treating bladder cancer in a patient having one or more FGFR gene alterations, wherein the erdafitinib is for local delivery to the patient's bladder, and the patient is selected for treatment based on detection of one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly, the patient is selected for treatment based on detection of one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or the patient is selected for treatment based on detection of one or more FGFR gene alterations in histopathology images of the tumor tissue via digital histopathology analysis. In certain embodiments, there is provided erdafitinib for use in treating bladder cancer in a patient with one or more FGFR gene alterations, wherein the erdafitinib is for local delivery to the patient's bladder, and wherein the patient's eligibility for the treatment is determined by detecting one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly wherein the patient's eligibility for the treatment is determined by detecting one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or wherein the patient's eligibility for the treatment is determined by detecting one or more FGFR gene alterations in a histopathology image of the tumor tissue via digital histopathology analysis. In certain embodiments, there is provided a use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer in a patient having one or more FGFR gene alterations, wherein the erdafitinib is for local delivery to the patient's bladder, and the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient, particularly, the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or the one or more FGFR alterations are detected in a histopathology image of the tumor tissue via digital histopathology analysis.In certain embodiments, there is provided a use of erdafitinib for the manufacture of a medicament for treating bladder cancer in a patient with one or more FGFR gene alterations, comprising, consisting of, or consisting essentially of: (a) evaluating a tumor tissue sample from the patient with bladder cancer for the presence of one or more FGFR gene alterations, in particular evaluating a tumor tissue sample from the patient with bladder cancer for the presence of one or more FGFR gene alterations using a tissue-based PCR assay or an NGS assay, or evaluating histopathology images of tumor tissue from the patient with bladder cancer for the presence of one or more FGFR gene alterations via digital histopathology analysis; and (b) locally delivering erdafitinib if one or more FGFR gene alterations are present in the sample. In certain embodiments, there is provided a use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer having one or more FGFR gene alterations in a patient, wherein the erdafitinib is for local delivery to the patient's bladder, and the patient is selected for treatment based on detection of one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly, the patient is selected for treatment based on detection of one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or the patient is selected for treatment based on detection of one or more FGFR gene alterations in a histopathology image of the tumor tissue via digital histopathology analysis.In certain embodiments, there is provided a use of erdafitinib for the manufacture of a medicament for treating bladder cancer in a patient with one or more FGFR gene alterations, wherein the erdafitinib is locally delivered to the patient's bladder, and the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly by detecting one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or an NGS assay, or by detecting one or more FGFR gene alterations in a histopathology image of the tumor tissue via digital histopathology analysis. The method or use may include locally delivering or locally administering erdafitinib (e.g., in any of the formulations described herein) to the bladder of a patient in need of treatment, particularly a cancer patient, in an effective amount for treating bladder cancer (e.g., about 1 to 10 mg / day, as described herein). For example, the treatment may be effective in treating muscle-invasive bladder cancer (MIBC), non-muscle-invasive bladder cancer (NMIBC), and / or Bacillus Calmette-Guerin (BCG)-naïve bladder cancer. In one embodiment, the patient, particularly a human, is a BCG-experienced bladder, NMIBC, or MIBC cancer patient. In one embodiment, the patient, particularly a human, is a BCG-naïve bladder, NMIBC, or MIBC cancer patient. In one embodiment, the patient, particularly a human, is a recurrent Mycobacterium bovis Bacillus Calmette-Guerin (BCG)-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient who refuses or is ineligible for radical cystectomy (RCy). In one embodiment, the patient, particularly a human, is a recurrent BCG-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient scheduled for RCy. In one aspect, the patient, particularly a human, is a recurrent intermediate-risk NMIBC (Ta and T1) cancer patient with a history of only low-grade disease.In one embodiment, the patient, particularly a human, is an MIBC cancer patient scheduled for RCy who has refused or is ineligible for cisplatin-based neoadjuvant chemotherapy.

[0125] In certain embodiments, the urothelial cancers described herein are susceptible to FGFR2 and / or FGFR3 genetic alterations.

[0126] As used herein, "FGFR gene alteration" refers to an alteration in a wild-type FGFR gene, including, but not limited to, an FGFR fusion gene, an FGFR mutation, an FGFR amplification, or any combination thereof, particularly an FGFR fusion gene, an FGFR mutation, or any combination thereof. In certain embodiments, the FGFR2 or FGFR3 gene alteration is an FGFR gene fusion. "FGFR fusion" or "FGFR gene fusion" refers to a gene encoding a portion of an FGFR (e.g., FGRF2 or FGFR3) and one or a portion of one of the fusion partners disclosed herein, which is created by a translocation between two genes. The terms "fusion" and "translocation" are used interchangeably herein. The presence of one or more of the following FGFR fusion genes in a biological sample from a patient: FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof, can be determined using the disclosed methods or uses or by methods known to those of skill in the art. In certain embodiments, the FGFR3-TACC3 is FGFR3-TACC3 variant 1 (FGFR3-TACC3 V1) or FGFR3-TACC3 variant 3 (FGFR3-TACC3 V3). Table A provides FGFR fusion genes and fused FGFR and fusion partner exons. The sequences of individual FGFR fusion genes are disclosed in Table A2. The underlined sequences correspond to either FGFR3 or FGFR2, and the other sequences represent the fusion partners.

[0127] [Table 1]

[0128] Table 2-1

[0129] Table 2-2

[0130] Table 2-3

[0131] Table 2-4

[0132] Table 2-5

[0133] Table 2-6

[0134] Table 2-7

[0135] Table 2-8

[0136] FGFR genetic alterations include FGFR single nucleotide polymorphisms (SNPs). An "FGFR single nucleotide polymorphism" (SNP) refers to an FGFR2 or FGFR3 gene that differs between individuals by a single nucleotide. In certain embodiments, the FGFR2 or FGFR3 genetic alteration is an FGFR3 genetic mutation. In particular, an "FGFR single nucleotide polymorphism" (SNP) refers to an FGFR3 gene that differs between individuals by a single nucleotide. The presence of one or more of the following FGFR SNPs in a biological sample from a patient can be determined by methods well known to those skilled in the art or disclosed in WO 2016 / 048833. The sequences of the FGFR SNPs are provided in Table B.

[0137] [Table 3] The sequence corresponds to nucleotides 920 to 1510 of FGFR3 (Genebank identification number NM_000142.4). Bold underlined nucleotides represent SNPs. * It is sometimes erroneously referred to as Y375C in the literature.

[0138] In certain embodiments, the methods or uses for treating urothelial cancer described herein comprise, consist of, or consist essentially of administering a drug delivery system described herein to a patient who has been diagnosed with a urothelial cancer described herein and has at least one FGFR2 genetic alteration and / or FGFR3 genetic alteration (i.e., one or more FGFR2 genetic alterations, one or more FGFR3 genetic alterations, or a combination thereof). In certain embodiments, the FGFR2 genetic alteration and / or FGFR3 genetic alteration is an FGFR3 genetic mutation, an FGFR2 gene fusion, or an FGFR3 gene fusion. In some embodiments, the FGFR3 genetic mutation is R248C, S249C, G370C, Y373C, or any combination thereof. In still further embodiments, the FGFR2 or FGFR3 gene fusion is FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

[0139] Also described herein are methods or uses for treating urothelial cancer described herein, comprising, consisting of, or consisting essentially of: (a) assessing a biological sample from a patient having a urothelial cancer described herein for the presence of one or more FGFR genetic alterations, particularly one or more FGFR2 or FGFR3 genetic alterations; and (b) administering to the patient a drug delivery system described herein if one or more FGFR genetic alterations, particularly one or more FGFR2 or FGFR3 genetic alterations, are present in the sample.

[0140] The following methods for assessing a biological sample for the presence of one or more FGFR genetic alterations apply equally to any of the methods of treatment and uses disclosed above.

[0141] Suitable methods for assessing a biological sample for the presence of one or more FGFR genetic alterations are described herein and in WO 2016 / 048833 and U.S. Patent Application No. 16 / 723,975, which are incorporated herein in their entireties. For example, and without intending to be limiting, assessing a biological sample for the presence of one or more FGFR genetic alterations may include any combination of isolating RNA from the biological sample, synthesizing cDNA from the RNA, and amplifying the cDNA (pre-amplified or not). In some embodiments, assessing a biological sample for the presence of one or more FGFR genetic alterations may include amplifying cDNA from the patient using a primer pair that binds to and amplifies one or more FGFR genetic alterations and determining whether one or more FGFR genetic alterations are present in the sample. In some aspects, the cDNA may be pre-amplified. In some aspects, the assessing step may include isolating RNA from the sample, synthesizing cDNA from the isolated RNA, and pre-amplifying the cDNA.

[0142] Suitable primer pairs for carrying out the amplification step include, but are not limited to, those disclosed in WO 2016 / 048833, exemplified in Table C below.

[0143] [Table 4]

[0144] The presence of one or more FGFR gene alterations can be assessed at any suitable time point, including at the time of diagnosis, following tumor removal, following the first line of treatment, during clinical treatment, or any combination thereof.

[0145] The methods and uses may further comprise assessing the presence of one or more FGFR genetic alterations in the biological sample prior to the administering step.

[0146] Diagnostic tests and screening are typically performed on a biological sample selected from blood, lymph, bone marrow, a solid tumor sample, or any combination thereof. In certain embodiments, the biological sample is a solid tumor sample. In embodiments, the biological sample is a blood sample.

[0147] Methods for identifying and analyzing genetic alterations and protein upregulation are known in the art, and screening methods can include, but are not limited to, standard methods such as reverse-transcriptase polymerase chain reaction (RT PCR) or in situ hybridization, such as fluorescence in situ hybridization (FISH).

[0148] Identification of individuals carrying genetic alterations in FGFR, particularly those described herein, may mean that the patient is particularly suitable for treatment with erdafitinib. Tumors may be selectively screened for the presence of FGFR variants prior to treatment. Screening processes typically involve direct sequencing, oligonucleotide microarray analysis, or mutant-specific antibodies. Diagnosis of tumors with such genetic alterations may be performed using methods well known to those skilled in the art, such as RT-PCR and FISH, as described herein.

[0149] In addition, genetic alterations of, for example, FGFR can be identified by, for example, direct sequencing of tumor biopsies using PCR and the methods for direct sequencing of PCR products as described above. Those skilled in the art will recognize that any of these well-known techniques for detecting overexpression, activation or mutation of the above proteins can be applied in the present invention.

[0150] In RT-PCR screening, the level of mRNA in tumors is assessed by generating a cDNA copy of the mRNA and then amplifying the cDNA by PCR. PCR amplification methods, primer selection, and amplification conditions are well known to those skilled in the art. Nucleic acid manipulation and PCR are performed by standard methods described, for example, in Ausubel, FM et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc., or Innis, MA et al., eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al., (2001), 3rd Ed., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, commercially available kits for RT-PCR (e.g., Roche Molecular Biochemicals) may be used, or the methodology set forth in U.S. Patent Nos. 4,666,828, 4,683,202, 4,801,531, 5,192,659, 5,272,057, 5,882,864, and 6,218,529 may be used, which are incorporated herein by reference. An example of an in situ hybridization technique for assessing mRNA expression is fluorescence in situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152:649).

[0151] Generally, in situ hybridization involves the following major steps: (1) fixation of the tissue to be analyzed, (2) prehybridization treatment of the sample to increase the accessibility of the target nucleic acid and reduce nonspecific binding, (3) hybridization of the mixture of nucleic acids with nucleic acids in the biological structure or tissue, (4) posthybridization washes to remove nucleic acid fragments not bound by hybridization, and (5) detection of the hybridized nucleic acid fragments. Probes used in such applications are typically labeled, for example, with radioisotopes or fluorescent reporters. Preferred probes are sufficiently long, for example, from about 50, 100, or 200 nucleotides to about 1,000 nucleotides or more, to enable specific hybridization with the target nucleic acid under stringent conditions. 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 John M. S. Bartlett, Fluorescence In Situ Hybridization: Technical Overview, Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pp. 077-088; Series: Methods in Molecular Medicine.

[0152] Methods for gene expression profiling are described by DePrimo et al. (2003), BMC Cancer, 3:3. Briefly, the protocol is as follows: double-stranded cDNA is synthesized from total RNA using a (dT)24 oligomer (SEQ ID NO: 38: tttttttttt tttttttttt tttt) to prime first-strand cDNA synthesis, followed by second-strand cDNA synthesis with a random hexamer primer. This double-stranded cDNA is used as a template for in vitro transcription of cRNA using biotinylated ribonucleotides. The cRNA is then chemically fragmented according to the protocol described by Affymetrix (Santa Clara, CA, USA) and hybridized overnight on a Human Genome Array.

[0153] Alternatively, the protein products expressed from mRNA may be assayed by immunohistochemistry of tumor samples, solid-phase immunoassays using microtiter plates, Western blotting, two-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry, and other methods known in the art for detecting specific proteins. Detection methods include the use of site-specific antibodies. Those skilled in the art will recognize that any of these well-known techniques for detecting FGFR upregulation or FGFR variants or mutations may be applicable in the context of the present invention.

[0154] Abnormal levels of proteins such as FGFR can be measured using standard enzyme assays, such as those described herein. Activation or overexpression can also be detected in tissue samples, e.g., tumor tissue, by measuring tyrosine kinase activity with assays, e.g., assays from Chemicon International. The tyrosine kinase of interest is immunoprecipitated from the sample lysate and its activity is measured.

[0155] Another method for measuring the overexpression or activation of FGFR, including its isoforms, is to measure microvessel density, which can be measured, for example, using the method described by Orre and Rogers (Int J Cancer (1999), 84(2)101-8). Assay methods also include the use of markers.

[0156] Thus, all of these techniques can also be used to identify tumors that are particularly suitable for treatment with the drug delivery systems of the present invention.

[0157] According to certain embodiments, FGFR2 and / or FGFR3 genetic alterations may be identified using commercially available kits, including, but not limited to, the QIAGEN therascreen® FGFR RGQ RT-PCR kit.

[0158] In certain embodiments, FGFR2 and / or FGFR3 genetic alterations can be identified in a liquid biological sample, such as a urine sample, from a cancer patient. Exfoliated urothelial bladder cancer cells can enter the urine.

[0159] According to certain embodiments, analytes that may be used for screening or detecting FGFR genetic alterations in urine include pellet DNA, cell-free DNA (cfDNA), non-coding RNA, exfoliated tumor cells, and proteins.

[0160] According to certain embodiments, cfDNA can be analyzed in urine samples by ultracentrifugation or molecular weight-based DNA separation techniques. For example, DNA extraction from urine samples can be performed using a QIAamp DNA Blood Mini Kit (Qiagen, Valencia, CA, USA) according to the manufacturer's instructions. The extracted cfDNA can be amplified and analyzed using various procedures, including polymerase chain reaction (PCR) and / or gene sequencing.

[0161] According to certain embodiments, urine-based molecular profiling can be performed using available kits, including, but not limited to, PCR and NGS assays. Non-limiting examples of available kits include the Urodiag® PCR Kit (which includes the mutation assay MASO (Mutated Allele Specific Oligonucleotide)-PCR), AssureMDX (which is a urine-based test that studies mutations in, for example, FGFR3), and PredicineCARE™, a urine cfDNA-based targeted NGS assay.

[0162] In certain embodiments, a method of administering a drug to a patient includes inserting a drug delivery system described herein into the patient and allowing the drug to be released from the system. For example, the system may include any feature or combination of features described herein. In certain embodiments, the release profile of the drug is substantially independent of pH over a pH range of 5 to 7.

[0163] In certain embodiments, allowing the drug to be released from the system includes allowing water to be imbibed through a water-permeable wall bounding the drug reservoir lumen to contact and solubilize the drug formulation, generating osmotic pressure within the drug reservoir lumen, and then allowing the solubilized drug to be released from the system through an opening in the system, driven by osmotic pressure. That is, in certain embodiments, elution of the drug from the system occurs following dissolution of the drug within the system. Bodily fluid, such as urine, enters the system, contacts the drug, and solubilizes it, and the dissolved drug is then pumped out of the system by osmotic pumping through one or more openings in fluid communication with the drug reservoir lumen.

[0164] In certain embodiments, inserting includes deploying the system through the patient's urethra and into the patient's bladder. The system may release the drug for days, weeks, months, or longer after the insertion procedure is completed. In one embodiment, deploying the drug delivery system in the patient includes inserting the system into the patient's body cavity or lumen via a deployment instrument. For example, the system may be deployed into a natural lumen of the body, e.g., the urethra, or through a deployment instrument, e.g., a catheter or cystoscope, positioned in a body cavity, e.g., the bladder. The deployment instrument is typically removed from the body lumen, and the drug delivery system remains in the bladder or other body cavity for a prescribed treatment period.

[0165] In one example, the system is deployed by passing the drug delivery system through a deployment instrument and releasing the system from the deployment instrument into the bladder. In embodiments, the system assumes a retention shape, e.g., an expanded or higher profile shape, when the system emerges from the deployment instrument into the bladder. The deployment instrument may be a commercially available system or a system specially adapted for the present drug delivery system. In one embodiment, deploying the drug delivery system into a patient includes (i) elastically deforming the system into a relatively straightened shape, (ii) inserting the system through the patient's urethra, e.g., through a lumen of an insertion catheter driven by a stylet, and (iii) releasing the system from the insertion catheter into the patient's bladder so that the system assumes a coiled retention shape.

[0166] Upon deployment in vivo, the system then locally releases a drug (e.g., erdafitinib) for the treatment of one or more conditions or diseases to tissue at the deployment site. The release is controlled to release an effective amount of the drug over an extended period of time. In certain embodiments, the system resides in the bladder releasing the drug for a predetermined period of time, such as 2 weeks, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months, or more.

[0167] The deployed system releases a desired amount of drug over a desired, predetermined period of time. In embodiments, the system may deliver a desired dose of drug over an extended period of time, such as 2 days to 90 days (e.g., 3, 5, 7, 10, 14, 20, 21, 25, 28, 30, 40, 45, 50, 60, 70, 80, or 90 days), 1 month to 6 months (e.g., 6 weeks, 1 month, 2 months, 3 months, 4 months, or 5 months), or longer. The rate of drug delivery and dosage may be selected depending on the drug being delivered and the disease or condition being treated. In one embodiment, the rate of release of drug from the drug delivery system is zero order over a period of at least 36 hours. In one embodiment, the rate of release of drug from the drug delivery system is essentially zero order over a period of at least 7 days, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, or longer.

[0168] The system may then be retrieved from the bladder through the urethra using a cystoscope or catheter, and if needed, a freshly drug-loaded system may then be inserted during the same handling procedure as the retrieval or afterwards.

[0169] The present disclosure may be further understood with reference to the following non-limiting examples.

[0170] Enumerated Embodiments 1. A drug delivery system comprising: an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof; The drug delivery system is configured to release the erdafitinib from one or more openings in the elongate body. 2. The drug delivery system of embodiment 1, wherein the drug formulation comprises a salt form of the erdafitinib. 3. The drug delivery system of embodiment 2, wherein the salt form comprises the L-lactate salt of erdafitinib. 4. The drug delivery system of embodiment 1, wherein erdafitinib is present as the mono-L-lactate salt. 5. The drug delivery system of any one of embodiments 1 to 4, wherein the elongate body comprises a biocompatible elastomer. 6. The drug delivery system of embodiment 5, wherein the biocompatible elastomer comprises silicone or thermoplastic polyurethane. 7. A drug delivery system described in any one of embodiments 1 to 6, wherein at least one of the one or more openings in the elongate body is located in a side wall of the elongate body. 8. A drug delivery system described in any one of embodiments 1 to 7, wherein at least one of the one or more openings in the elongate body is located at a first end and / or an opposing second end of the elongate body. 9. A drug delivery system as described in any one of embodiments 1 to 6, having a single opening located in the side wall of the elongate body at a position between the first end and the opposing second end of the elongate body. 10. The drug delivery system of any one of embodiments 1 to 9, wherein the drug formulation comprises at least one pharmaceutical excipient. 11. The drug delivery system of embodiment 10, wherein the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, an osmotic agent, or any combination thereof. 12. The drug delivery system of embodiment 10, wherein the at least one pharmaceutical excipient comprises or is selected from a binder, a diluent (filler), a glidant, a lubricant, or any combination thereof. 13. The drug delivery system of any one of embodiments 1 to 12, wherein the erdafitinib is present in the drug formulation at a concentration of 60% to 80% by weight. 14. The drug delivery system of embodiment 13, wherein the erdafitinib is present in the drug formulation in a concentration of 70% by weight. 15. The drug delivery system of any one of embodiments 1-14, wherein the drug formulation is in the form of a plurality of mini-tablets. 16. The drug delivery system of any one of embodiments 1-15, wherein the drug delivery system is configured to release the erdafitinib by osmotic pressure through one or more openings in the elongate body. 17. A drug delivery system described in any one of embodiments 1 to 16, wherein the elongate body includes an annular wall structure defining a drug reservoir lumen in which the drug formulation is disposed. 18. The drug delivery system of embodiment 17, wherein the one or more openings in the elongate body comprise a single opening in the annular wall structure, and the elongate body is configured to release the erdafitinib through the opening and / or through microchannels temporarily formed in one or both end regions of the annular wall structure. 19. An intravesical drug delivery system comprising: an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, and a drug formulation comprising the L-lactate salt of erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine), An intravesical drug delivery system, wherein the drug delivery system is configured to release erdafitinib from one or more openings in the elongate body in an osmotically driven manner. 20. The system of any one of embodiments 1-19, wherein the system is configured to release the erdafitinib at an average rate of 1 mg / day to 10 mg / day. 21. The system of any one of embodiments 1-19, wherein the system is configured to release the erdafitinib at an average rate of 1 mg / day to 6 mg / day. 22. The system of any one of embodiments 1-19, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day to 4 mg / day. 23. The system of any one of embodiments 1-19, wherein the system is configured to release the erdafitinib at an average rate of 4 mg / day. 24. The system of any one of embodiments 1-19, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day. 25. The system of any one of embodiments 1 to 24, wherein the system comprises 500 mg of said erdafitinib (free base equivalent). 26. A system described in any one of embodiments 1 to 25, wherein the system is elastically deformable between a relatively straightened deployed shape suitable for insertion through the patient's urethra and into the patient's bladder, and a retained shape suitable for retaining the system within the bladder. 27. A system described in any one of embodiments 1 to 26, wherein the system comprises a tube that is elastically deformable and has two opposing free ends that are directed away from each other when the system is in a low-profile deployed shape and toward each other when the system is in a relatively expanded retained shape. 28. A system described in any one of embodiments 1 to 27, wherein the system comprises an elastically deformable elongated body having two opposing free ends within the boundaries of a bi-elliptical expanded holding shape. 29. A system described in any one of embodiments 1 to 28, wherein the elongate body further comprises a retaining frame lumen. 30. The system of embodiment 29, further comprising a nitinol wire disposed within the retaining frame lumen. 31. A method of intravesical administration of erdafitinib, comprising: deploying a drug delivery system into the bladder of a patient; and releasing erdafitinib from the drug delivery system by osmotic pressure. 32. A method for intravesical administration of erdafitinib, comprising: Deploying a system according to any one of embodiments 1 to 30 into the bladder of a patient; and releasing said erdafitinib from said system. 33. The method of embodiment 31 or 32, wherein releasing the erdafitinib from the system comprises releasing the erdafitinib from the drug reservoir lumen through the one or more openings driven by osmotic pressure within the drug reservoir lumen. 34. A method according to any one of embodiments 31 to 33, wherein the system is elastically deformed into a low-profile deployed shape, inserted through the urethra into the patient's bladder, and then assumes a relatively expanded, retained shape within the bladder. 35. The method of any one of embodiments 31-34, wherein erdafitinib is released into the bladder at an average rate of 1 mg / day to 10 mg / day for a period ranging from 7 days to 90 days. 36. A method of treating non-muscle invasive bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC) in a cancer patient, comprising: inserting a drug delivery system into the bladder of the patient; and locally delivering a therapeutically effective amount of erdafitinib from the osmotically driven drug delivery system into the patient's bladder. 37. A method of treating non-muscle invasive bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC) in a cancer patient, comprising: Inserting a system according to any one of embodiments 1 to 30 into the bladder of the patient; and locally delivering a therapeutically effective amount of erdafitinib from the system into the bladder of the patient. 38. The method of embodiment 36 or 37, wherein locally delivering the erdafitinib comprises releasing the erdafitinib from the system at a release rate of about 1 mg / day to about 6 mg / day, for example, 2 to 4 mg / day. 39. The method of any one of embodiments 36-38, wherein the system is maintained in the patient's bladder for up to 90 days and then, if desired, replaced with another erdafitinib-releasing system. 40. A method of treating (i) recurrent non-muscle-invasive or muscle-invasive urothelial carcinoma of the bladder, (ii) high- or intermediate-risk papillary urothelial carcinoma of the bladder, or (iii) stage cT2 to T3a muscle-invasive urothelial carcinoma of the bladder in a cancer patient, comprising: inserting a drug delivery system into the bladder of the patient; and locally delivering a therapeutically effective amount of erdafitinib from the drug delivery system into the bladder of the patient, particularly in an osmotically driven manner. 41. A method of treating (i) recurrent non-muscle-invasive or muscle-invasive urothelial carcinoma of the bladder, (ii) high- or intermediate-risk papillary urothelial carcinoma of the bladder, or (iii) stage cT2 to T3a muscle-invasive urothelial carcinoma of the bladder in a cancer patient, comprising: Inserting a system according to any one of embodiments 1 to 30 into the bladder of the patient; A therapeutically effective amount of erdafitinib is administered to the and locally delivering the compound to said bladder of said patient. 42. The method of embodiment 40 or 41, wherein the patient undergoes transurethral resection of bladder tumor (TURBT) to reduce the total tumor(s) size to 3 cm or less, and then the erdafitinib is delivered locally into the bladder. 43. The method of any one of embodiments 40-42, wherein locally delivering the erdafitinib comprises releasing the erdafitinib from the system at a release rate of about 1 mg / day to about 6 mg / day, for example, 2 to 4 mg / day. 44. The method of any one of embodiments 40-43, wherein the system is maintained in the patient's bladder for up to 90 days and then, if desired, replaced with another erdafitinib-releasing system. 45. A method of treating Mycobacterium bovis Bacille Calmette-Guerin (BCG)-experienced patients with recurrent high-grade Ta / T1 urothelial carcinoma of the bladder within 18 months of completing a previous BCG therapy, comprising: inserting a drug delivery system into the bladder of the patient; and locally delivering a therapeutically effective amount of erdafitinib from the drug delivery system into the bladder of the patient. 46. ​​A method of treating Mycobacterium bovis Bacille Calmette-Guerin (BCG)-experienced patients with recurrent high-grade Ta / T1 urothelial carcinoma of the bladder within 18 months of completing a previous BCG therapy, comprising: A method comprising locally delivering a therapeutically effective amount of erdafitinib into the bladder of the patient from the system, particularly from a system described in any one of embodiments 1 to 30 inserted into the bladder of the patient. 47. The method of embodiment 45 or 46, wherein locally delivering the erdafitinib comprises releasing the erdafitinib from the system at a release rate of about 1 mg / day to about 6 mg / day, for example, 2 to 4 mg / day. 48. The method of any one of embodiments 45-47, wherein the system is maintained in the patient's bladder for up to 90 days and then, if desired, replaced with another erdafitinib-releasing system. 49. The method of any one of embodiments 36 to 48, wherein the patient has at least one FGFR2 genetic alteration and / or FGFR3 genetic alteration. 50. Erdafitinib lactate, especially erdafitinib L-lactate. 51. A pharmaceutical composition comprising erdafitinib lactate, particularly erdafitinib L-lactate, and one or more excipients. 52. The pharmaceutical composition of embodiment 51, wherein the composition is in the form of a tablet, in particular a mini-tablet.

[0171] Enumerated Embodiments 1. An intravesical drug delivery system comprising: an elongate body configured for intravesical insertion into a patient; and a drug formulation disposed within the elongate body, a drug formulation comprising erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, in particular the L-lactate salt of erdafitinib; An intravesical drug delivery system, wherein the drug delivery system is configured to release erdafitinib from one or more openings in the elongate body in an osmotically driven manner. 2. The drug delivery system of claim 1, wherein erdafitinib is present as the mono-L-lactate salt. 3. The drug delivery system of claim 1 or 2, wherein the elongate body comprises a biocompatible elastomer. 4. The drug delivery system of claim 3, wherein the biocompatible elastomer comprises silicone or thermoplastic polyurethane. 5. The drug delivery system of claim 3, wherein the biocompatible elastomer comprises silicone. 6. The drug delivery system of claim 3, wherein the biocompatible elastomer comprises a platinum-cured silicone elastomer. 7. The drug delivery system of any one of claims 1 to 6, wherein at least one of the one or more openings in the elongate body is located in a side wall of the elongate body. 8. A drug delivery system according to any one of claims 1 to 7, wherein at least one of the one or more openings in the elongate body is located at a first end and / or an opposing second end of the elongate body. 9. A drug delivery system according to any one of claims 1 to 6, having a single opening located in the side wall of the elongate body at a position between the first end and the opposing second end of the elongate body. 10. The drug delivery system of any one of claims 1 to 9, wherein the one or more openings have a diameter of about 100 μm to about 200 μm. 11. The drug delivery system of claim 10, wherein the one or more openings have a diameter of about 150 μm. 12. The drug delivery system of any one of claims 1 to 11, wherein the drug formulation comprises at least one pharmaceutical excipient. 13. The drug delivery system of claim 12, wherein the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, an osmotic agent, or any combination thereof. 14. The drug delivery system of claim 12, wherein the at least one pharmaceutical excipient comprises or is selected from a binder, a diluent (filler), a glidant, a lubricant, or any combination thereof. 15. The drug delivery system of claim 14, wherein the binder comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate (PVP-VA), or a combination thereof. 16. The drug delivery system of claim 14 or 15, wherein the binder is present in the drug formulation at a total concentration of about 1% to about 30% by weight, about 5% to about 20% by weight, or about 10% to about 15% by weight. 17. The drug delivery system of any one of claims 14 to 16, wherein the diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, calcium hydrogen phosphate, or a combination thereof. 18. The drug delivery system of any one of claims 14 to 17, wherein the diluent (filler) is present in the drug formulation at a total concentration of about 5% by weight to about 30% by weight, about 10% by weight to about 30% by weight, or about 10% by weight to about 20% by weight. 19. A drug delivery system according to claims 14 to 18, wherein the glidant comprises hydrophilic colloidal silicon dioxide or hydrophobic colloidal silicon dioxide, in particular hydrophilic colloidal silicon dioxide. 20. The drug delivery system of any one of claims 14 to 19, wherein the glidant is present in the drug formulation at a total concentration of about 0.05% by weight to about 1% by weight, about 0.1% by weight to about 0.5% by weight, or about 0.25% by weight. 21. The drug delivery system of any one of claims 14 to 20, wherein the lubricant comprises magnesium stearate, or sodium stearyl fumarate, or polyethylene glycol. 22. The drug delivery system of any one of claims 14 to 20, wherein the lubricant comprises magnesium stearate. 23. The drug delivery system of any one of claims 14 to 22, wherein the lubricant is present in the drug formulation at a total concentration of about 0.05% to about 5% by weight, about 1% to about 5% by weight, or about 2.5%. 24. A drug delivery system according to any one of claims 1 to 23, wherein the drug formulation comprises an intragranular composition comprising erdafitinib or a pharmaceutically acceptable salt thereof, in particular the lactate salt of erdafitinib, and at least one intragranular excipient, and an extragranular composition comprising at least one extragranular excipient. 25. The drug delivery system of claim 24, wherein the at least one intragranular excipient and the at least one extragranular excipient do not comprise a common pharmaceutical excipient. 26. The drug delivery system of claim 24 or 25, wherein the at least one intragranular excipient comprises an intragranular binder. 27. The drug delivery system of any one of claims 24 to 26, wherein the intragranular binder comprises hydroxypropyl methylcellulose. 28. The drug delivery system of any one of claims 24 to 27, wherein the at least one extragranular excipient comprises one or more of an extragranular binder, an extragranular filler (diluent), an extragranular glidant, and an extragranular lubricant. 29. The drug delivery system of claim 28, wherein the extragranular binder comprises vinylpyrrolidone-vinyl acetate. 30. The drug delivery system of claim 28 or 29, wherein the extragranular diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof. 31. The drug delivery system of any one of claims 28 to 30, wherein the extragranular glidant comprises hydrophilic colloidal silicon dioxide. 32. The drug delivery system of any one of claims 28 to 31, wherein the extragranular lubricant comprises magnesium stearate, or sodium stearyl fumarate, or polyethylene glycol. 33. The drug delivery system of any one of claims 28 to 32, wherein the extragranular lubricant comprises magnesium stearate. 34. The drug delivery system of any one of claims 1 to 33, wherein erdafitinib L-lactate is present in the drug formulation at a concentration of 60% to 91% by weight, or 60% to 80% by weight. 35. The drug delivery system of claim 34, wherein the erdafitinib L-lactate is present in the drug formulation at a concentration of 70% by weight. 36. The drug delivery system of any one of claims 1 to 35, wherein the drug formulation is in the form of a plurality of mini-tablets. 37. The drug delivery system of claim 36, wherein the drug formulation is in the form of about 10 to about 100 mini-tablets. 38. The drug delivery system of claim 36 or 37, wherein (a) the formulation comprises mini-tablets having a total length of about 14.5 cm to about 15 cm, and / or (b) the formulation comprises mini-tablets of about 920 mg to about 965 mg, or mini-tablets of about 920 mg to about 950 mg. 39. The drug delivery system of any one of claims 1-38, wherein the drug delivery system is configured to release erdafitinib by osmotic pressure through one or more openings in the elongate body. 40. The drug delivery system of any one of claims 1-39, wherein the elongate body includes an annular wall structure defining a drug reservoir lumen in which the drug formulation is disposed. 41. The drug delivery system of claim 40, wherein the annular wall structure has a thickness of about 0.1 mm to about 0.5 mm. 42. The drug delivery system of claim 41, wherein the annular wall structure has a thickness of about 0.2 mm. 43. The drug delivery system of any one of claims 40-42, further comprising a first end plug positioned at a first end of the annular wall structure and a second end plug positioned at a second end of the annular wall structure. 44. The drug delivery system of any one of claims 40-43, wherein the one or more openings in the elongate body comprise a single opening in the annular wall structure, and the elongate body is configured to release erdafitinib through the opening. 45. The drug delivery system of any one of claims 40 to 44, wherein the elongate body is configured to release erdafitinib through microchannels temporarily formed in one or both end regions of the annular wall structure. 46. ​​The drug delivery system of any one of claims 1 to 45, wherein the system is configured to release erdafitinib at an average rate of 1 mg / day to 10 mg / day. 47. The drug delivery system of any one of claims 1-45, wherein the system is configured to release erdafitinib at an average rate of 1 mg / day to 6 mg / day. 48. The drug delivery system of any one of claims 1-45, wherein the system is configured to release erdafitinib at an average rate of 2 mg / day to 4 mg / day. 49. The drug delivery system of any one of claims 1-45, wherein the system is configured to release erdafitinib at an average rate of 4 mg / day. 50. The drug delivery system of any one of claims 1 to 50, wherein the system is configured to release erdafitinib at an average rate of 2 mg / day. 51. The drug delivery system of any one of claims 1 to 50, wherein the system is configured to release erdafitinib in a zero-order release profile. 52. The drug delivery system of any one of claims 46-51, wherein the system is configured to release erdafitinib for up to about 30 days. 53. The drug delivery system of any one of claims 46-51, wherein the system is configured to release erdafitinib for up to about 90 days. 54. The drug delivery system of any one of claims 1 to 53, wherein the system comprises 500 mg of erdafitinib (free base equivalent). 55. A drug delivery system according to any one of claims 1 to 54, wherein the system is elastically deformable between a relatively straightened deployed configuration suitable for insertion through the patient's urethra and into the patient's bladder, and a retained configuration suitable for retaining the system within the bladder. 56. A drug delivery system according to any one of claims 1 to 55, wherein the system comprises a tube that is elastically deformable and has two opposing free ends that are directed away from each other when the system is in a low-profile deployed configuration and that are directed towards each other when the system is in a relatively expanded retained configuration. 57. A drug delivery system according to any one of claims 1 to 56, wherein the system comprises an elastically deformable elongate body having two opposing free ends within the confines of a bi-ellipsoidal expanded retention shape. 58. The drug delivery system of any one of claims 1-57, wherein the elongate body further comprises a retaining frame lumen. 59. The drug delivery system of claim 58, further comprising a nitinol wire disposed within the retaining frame lumen. 60. A compound which is erdafitinib lactate. 61. The compound of claim 60, which is erdafitinib L-lactate. 62. The compound of claim 61, which is erdafitinib mono-L-lactate. 63. A pharmaceutical composition comprising erdafitinib L-lactate and one or more pharmaceutical excipients. 64. The pharmaceutical composition of claim 63, wherein the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, an osmotic agent, or any combination thereof. 65. The pharmaceutical composition of claim 63, wherein the at least one pharmaceutical excipient comprises or is selected from a binder, a diluent (filler), a glidant, a lubricant, or any combination thereof. 66. The pharmaceutical composition of claim 65, wherein the binder comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate (PVP-VA), or a combination thereof. 67. The pharmaceutical composition of claim 65 or 66, wherein the binder is present in the drug formulation at a total concentration of about 1% to about 30% by weight, about 5% to about 20% by weight, or about 10% to about 15% by weight. 68. The pharmaceutical composition of any one of claims 65-67, wherein the diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, calcium hydrogen phosphate, or a combination thereof. 69. The pharmaceutical composition of any one of claims 65-68, wherein the diluent (filler) is present in the drug formulation at a total concentration of about 5% to about 30% by weight, about 10% to about 30% by weight, or about 10% to about 20% by weight. 70. A pharmaceutical composition according to claims 65 to 69, wherein the glidant comprises hydrophilic colloidal silicon dioxide or hydrophobic colloidal silicon dioxide, in particular hydrophilic colloidal silicon dioxide. 71. The pharmaceutical composition of any one of claims 65-70, wherein the glidant is present in the drug formulation at a total concentration of about 0.05% to about 1% by weight, about 0.1% to about 0.5% by weight, or about 0.25% by weight. 72. The pharmaceutical composition of any one of claims 65-71, wherein the lubricant comprises magnesium stearate, or sodium stearyl fumarate, or polyethylene glycol. 73. The pharmaceutical composition of any one of claims 65-71, wherein the lubricant comprises magnesium stearate. 74. The pharmaceutical composition of any one of claims 65-73, wherein the lubricant is present in the drug formulation at a total concentration of about 0.05% to about 5% by weight, about 1% to about 5% by weight, or about 2.5%. 75. A pharmaceutical composition according to any one of claims 65 to 74, wherein the drug formulation comprises an intragranular composition comprising erdafitinib or a pharmaceutically acceptable salt thereof, in particular the lactate salt of erdafitinib, and at least one intragranular excipient, and an extragranular composition comprising at least one extragranular excipient. 76. The pharmaceutical composition of claim 75, wherein the at least one intragranular excipient and the at least one extragranular excipient do not comprise a common pharmaceutical excipient. 77. The pharmaceutical composition of claim 75 or 76, wherein the at least one intragranular excipient comprises an intragranular binder. 78. The pharmaceutical composition of claim 77, wherein the intragranular binder comprises hydroxypropyl methylcellulose. 79. The pharmaceutical composition of any one of claims 75-78, wherein the at least one extragranular excipient comprises one or more of an extragranular binder, an extragranular filler (diluent), an extragranular glidant, and an extragranular lubricant. 80. The pharmaceutical composition of claim 79, wherein the extragranular binder comprises vinylpyrrolidone-vinyl acetate. 81. The pharmaceutical composition of claim 79 or 80, wherein the extragranular diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof. 82. The pharmaceutical composition of any one of claims 79-81, wherein the extragranular glidant comprises hydrophilic colloidal silicon dioxide. 83. The pharmaceutical composition of any one of claims 79-82, wherein the extragranular lubricant comprises magnesium stearate, or sodium stearyl fumarate, or polyethylene glycol. 84. The pharmaceutical composition of any one of claims 79-83, wherein the extragranular lubricant comprises magnesium stearate. 85. The pharmaceutical composition of any one of claims 63 to 84, wherein erdafitinib L-lactate is present in the drug formulation at a concentration of 60% to 91% by weight, or 60% to 80% by weight. 86. The pharmaceutical composition of claim 85, wherein the erdafitinib L-lactate is present in the drug formulation at a concentration of 70% by weight. 87. The pharmaceutical composition of any one of claims 63 to 86, wherein the composition is in the form of a tablet. 88. The pharmaceutical composition of claim 87, wherein the tablet is a mini-tablet. 89. The pharmaceutical composition of claim 87 or 88, wherein the tablet has a hardness of at least about 100 N. 90. The pharmaceutical composition of claim 89, wherein the tablet has a hardness of about 150N to about 250N. 91. The pharmaceutical composition of claim 89, wherein the tablet has a hardness of about 175N to about 225N. 92. The pharmaceutical composition of any one of claims 87 to 91, wherein the tablet has a thickness of about 3.2 mm to about 3.6 mm. 93. A process for producing a pharmaceutical composition in the form of a tablet, comprising: (a) preparing an intragranular solid composition, (i) erdafitinib L-lactate, (ii) preparing an intragranular solid composition comprising at least one intragranular pharmaceutical excipient; (b) combining the intragranular solid composition with at least one extragranular pharmaceutical excipient to form a blend; (c) compressing the blend to form a solid pharmaceutical composition; 1. A process for making a pharmaceutical composition in the form of a tablet, comprising: 94. (a) at least one intragranular pharmaceutical excipient comprises at least one intragranular binder; (b) the at least one extragranular pharmaceutical excipient comprises an extragranular binder, an extragranular filler (diluent), an extragranular glidant, and an extragranular lubricant; 94. A process for making the solid pharmaceutical composition of claim 93. 95. A process for producing a tablet according to claim 93 or 94, wherein the intragranular solid composition is prepared by a fluid bed granulation process. 96. A process for producing a solid pharmaceutical composition according to claim 94 or 95, wherein the at least one intragranular binder comprises hydroxypropyl methylcellulose. 97. A process for making a solid pharmaceutical composition according to any one of claims 94-96, wherein at least one extragranular binder comprises vinylpyrrolidone-vinyl acetate (PVP VA). 98. A process for producing a solid pharmaceutical composition according to any one of claims 94-97, wherein the at least one extragranular filler (diluent) comprises microcrystalline cellulose. 99. A process for producing a solid pharmaceutical composition according to claim 98, further comprising a second extragranular filler (diluent) comprising silicified microcrystalline cellulose. 100. A process for producing a solid pharmaceutical composition according to any one of claims 94-99, wherein the extragranular glidant comprises hydrophilic colloidal silicon dioxide. 101. A process for producing a solid pharmaceutical composition according to any one of claims 94-100, wherein the extragranular lubricant comprises magnesium stearate. 102. A process for producing a solid pharmaceutical composition according to any one of claims 94-100, wherein the extragranular lubricant comprises sodium stearyl fumarate. 103. A process for producing a solid pharmaceutical composition according to any one of claims 93-102, wherein the expulsion force is less than about 1000 N. 103. The pharmaceutical composition of claim 88, wherein the minitablets are in the form of a solid cylinder, the solid cylinder having a cylinder axis, a cylinder side surface, a cylinder end surface perpendicular to the cylinder axis, a diameter across the cylinder end surface, and a length along the cylinder side surface. 104. The solid pharmaceutical composition of claim 103, wherein the length of the mini-tablets exceeds the diameter of the mini-tablets so as to provide mini-tablets with an aspect ratio (length:diameter) of greater than 1:1. 105. The solid pharmaceutical composition of claim 103 or 104, wherein the mini-tablets have a diameter of 1.0 mm to 3.2 mm, or 1.5 mm to 3.1 mm. 106. The solid pharmaceutical composition of claim 103 or 104, wherein the mini-tablets have a diameter of 2.5 mm to 2.7 mm. 107. The solid pharmaceutical composition of any one of claims 103 to 106, wherein the mini-tablets have a length of 3.0 mm to 3.5 mm. 108. A solid pharmaceutical composition according to any one of claims 103 to 107, wherein the mini-tablets have a mass of 22 mg to 24 mg. 109. The drug delivery system of any one of claims 44 to 59, wherein the elongate body is configured to release erdafitinib through the openings and through microchannels temporarily formed in one end region of the annular wall structure. 110. The drug delivery system of any one of claims 44 to 59, wherein the elongate body is configured to release erdafitinib through the openings and through microchannels temporarily formed in both end regions of the annular wall structure. 111. The drug delivery system of any one of claims 45, 109, or 110, wherein the microchannels form transiently when the osmotic pressure increases above a certain threshold.

[0172] Enumerated Embodiments 1. A method of treating bladder cancer having one or more FGFR gene alterations, comprising locally delivering erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, in an amount effective for said treatment of bladder cancer, wherein the one or more FGFR gene alterations are detected in a urine sample from the patient, particularly wherein the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR assay or an NGS assay, and wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib; An intravesical drug delivery system, wherein the drug delivery system is configured to release erdafitinib from one or more openings in the elongate body in an osmotically driven manner. 2. A method of treating bladder cancer having one or more FGFR gene alterations, comprising, consisting of, or consisting essentially of: (a) evaluating a urine sample from a patient with bladder cancer for the presence of said one or more FGFR gene alterations, particularly using a urine-based PCR assay or an NGS assay to evaluate a urine sample from a patient with bladder cancer for the presence of said one or more FGFR gene alterations; and (b) if said one or more FGFR gene alterations are present in the sample, locally delivering erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib; An intravesical drug delivery system, wherein the drug delivery system is configured to release erdafitinib from one or more openings in the elongate body in an osmotically driven manner. 3. A method for treating bladder cancer having one or more FGFR gene alterations, comprising locally delivering erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, in an amount effective for said treatment to the bladder of a patient in need thereof, wherein said patient is selected for said treatment based on detection of said one or more FGFR gene alterations in a urine sample from said patient, particularly wherein said patient is selected for said treatment based on said detection of said one or more FGFR gene alterations in a urine sample from said patient using a urine-based PCR assay or an NGS assay, and wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib; An intravesical drug delivery system, wherein the drug delivery system is configured to release erdafitinib from one or more openings in the elongate body in an osmotically driven manner. 4. A method for treating bladder cancer having one or more FGFR gene alterations, comprising locally delivering erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, to the bladder of a patient in need thereof in an amount effective for said treatment, wherein the patient's eligibility for said treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient, particularly wherein the patient's eligibility for said treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay, and wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib; An intravesical drug delivery system, wherein the drug delivery system is configured to release erdafitinib from one or more openings in the elongate body in an osmotically driven manner. 5. Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, for use in treating bladder cancer in a patient with one or more FGFR gene alterations, wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, is delivered locally to the bladder of the patient, and the one or more FGFR gene alterations are detected in a urine sample from the patient, particularly the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR assay or an NGS assay, and wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib; Erdafitinib or a pharmaceutically acceptable salt thereof for use, wherein the drug delivery system is configured to release erdafitinib from one or more openings in the elongate body in an osmotically driven manner. 6. Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, for use in treating bladder cancer in patients with one or more FGFR gene alterations, comprising: (a) assessing a urine sample from a patient with bladder cancer for the presence of one or more FGFR gene alterations, particularly a urine-based (b) evaluating a urine sample from a patient with bladder cancer for the presence of one or more FGFR genetic alterations using a PCR or NGS assay; and (b) if the one or more FGFR genetic alterations are present in the sample, locally delivering erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, to the patient, wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib; Erdafitinib or a pharmaceutically acceptable salt thereof for use, wherein the drug delivery system is configured to release erdafitinib from one or more openings in the elongate body in an osmotically driven manner. 7. Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, for use in treating bladder cancer with one or more FGFR genetic alterations in a patient, wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, is administered to the patient. and wherein the patient is selected for the treatment based on detection of the one or more FGFR genetic alterations in a urine sample from the patient, particularly wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay, and wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib; Erdafitinib or a pharmaceutically acceptable salt thereof for use, wherein the drug delivery system is configured to release erdafitinib from one or more openings in the elongate body in an osmotically driven manner. 8. Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, for use in treating bladder cancer with one or more FGFR genetic alterations in a patient, wherein the erdafitinib or the pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, is administered locally to the bladder of the patient. and wherein the patient's eligibility for the treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient, particularly wherein the patient's eligibility for the treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay, and wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib; Erdafitinib or a pharmaceutically acceptable salt thereof for use, wherein the drug delivery system is configured to release erdafitinib from one or more openings in the elongate body in an osmotically driven manner. 9. Use of erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, for the manufacture of a medicament for the treatment of bladder cancer in a patient with one or more FGFR gene alterations, wherein erdafitinib is delivered locally to the bladder of the patient, and the one or more FGFR gene alterations are detected in a urine sample from the patient, particularly the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR assay or an NGS assay, and erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib; An intravesical drug delivery system, wherein the drug delivery system is configured to release erdafitinib from one or more openings in the elongate body in an osmotically driven manner. 10. Use of erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, for the manufacture of a medicament for the treatment of bladder cancer in a patient having one or more FGFR gene alterations, comprising: (a) assessing a urine sample from the patient having bladder cancer for the presence of the one or more FGFR gene alterations; In particular, the method comprises, consists of, or consists essentially of: (a) assessing a urine sample from a patient with bladder cancer for the presence of said one or more FGFR genetic alterations using a urine-based PCR assay or an NGS assay; and (b) if said one or more FGFR genetic alterations are present in the sample, locally delivering erdafitinib or a pharmaceutically acceptable salt thereof, in particular the L-lactate salt of erdafitinib, an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib; An intravesical drug delivery system, wherein the drug delivery system is configured to release erdafitinib from one or more openings in the elongate body in an osmotically driven manner. 11. Use of erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, for the manufacture of a medicament for the treatment of bladder cancer having one or more FGFR gene alterations in the patient, wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, is administered to the patient. wherein the patient is selected for the treatment based on detection of the one or more FGFR gene alterations in a urine sample from the patient, particularly wherein the patient is selected for the treatment based on the detection of the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay, and wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib is an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib; An intravesical drug delivery system, wherein the drug delivery system is configured to release erdafitinib from one or more openings in the elongate body in an osmotically driven manner. 12. Use of erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, for the manufacture of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, is administered to the bladder of the patient. and wherein the patient's eligibility for the treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient, particularly wherein the patient's eligibility for the treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay, and wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib; An intravesical drug delivery system, wherein the drug delivery system is configured to release erdafitinib from one or more openings in the elongate body in an osmotically driven manner. 13. The method, use, or use of erdafitinib of any one of the preceding embodiments, wherein the one or more FGFR genetic alterations comprise one or more FGFR2 genetic alterations or FGFR3 genetic alterations. 14. The method, erdafitinib for use, or use of any one of the preceding embodiments, wherein the one or more FGFR genetic alterations comprise one or more FGFR2 point mutations or fusions or FGFR3 point mutations or fusions. 15. The method, erdafitinib for use, or use of any one of the preceding embodiments, wherein the one or more FGFR genetic alterations are detected in a urine sample of the patient prior to locally delivering erdafitinib. 16. The method, erdafitinib for use, or use of any one of the preceding embodiments, wherein erdafitinib is present in the drug delivery system as the mono-L-lactate salt. 17. The method, use, or use of any one of the preceding embodiments, wherein the elongate body comprises a biocompatible elastomer. 18. The method, use, or use of embodiment 17, wherein the biocompatible elastomer comprises silicone or thermoplastic polyurethane. 19. The method, use, or use of embodiment 17, wherein the biocompatible elastomer comprises silicone. 20. The method, use, or use according to embodiment 17, wherein the biocompatible elastomer comprises a platinum-cured silicone elastomer. 21. The method, use, or use of any one of the preceding embodiments, wherein at least one of the one or more openings in the elongate body is located in a sidewall of the elongate body. 22. The method, use, or use of any one of the preceding embodiments, wherein at least one of the one or more openings in the elongate body is located at a first end and / or an opposing second end of the elongate body. 23. The method, use, or use of any one of embodiments 1 to 20, wherein the drug delivery system has a single opening located in the sidewall of the elongate body at a location between the first end and the opposing second end of the elongate body. 24. The method, the erdafitinib for use, or the use of any one of the preceding embodiments, wherein the one or more openings have a diameter of about 100 μm to about 200 μm. 25. The method, use, or use according to embodiment 24, wherein the one or more openings have a diameter of about 150 μm. 26. The method, use, or use of erdafitinib according to any one of the preceding embodiments, wherein the drug formulation comprises at least one pharmaceutical excipient. 27. The method, the erdafitinib for use, or the use according to embodiment 26, wherein the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, an osmotic agent, or any combination thereof. 28. The method, use, or use of embodiment 26, wherein the at least one pharmaceutical excipient comprises or is selected from a binder, a diluent (filler), a glidant, a lubricant, or any combination thereof. 29. The method, use, or use according to embodiment 28, wherein the binder comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate (PVP-VA), or a combination thereof. 30. The method, use, or use of embodiment 28 or 29, wherein the binder is present in the drug formulation in a total concentration of about 1% to about 30% by weight, about 5% to about 20% by weight, or about 10% to about 15% by weight. 31. The method, use, or use of erdafitinib according to any one of embodiments 28 to 30, wherein the diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, calcium hydrogen phosphate, or a combination thereof. 32. The method, the use, or the use of any one of embodiments 28 to 31, wherein the diluent (filler) is present in the drug formulation in a total concentration of about 5% to about 30% by weight, about 10% to about 30% by weight, or about 10% to about 20% by weight. 33. The method, the use, or the use of erdafitinib according to any one of embodiments 28-32, wherein the glidant comprises hydrophilic colloidal silicon dioxide or hydrophobic colloidal silicon dioxide, in particular hydrophilic colloidal silicon dioxide. 34. The method, the erdafitinib for use, or the use according to any one of embodiments 28 to 33, wherein the glidant is present in the drug formulation at a total concentration of about 0.05% to about 1% by weight, about 0.1% to about 0.5% by weight, or about 0.25% by weight. 35. The method, use, or use of erdafitinib according to any one of embodiments 28-34, wherein the lubricant comprises magnesium stearate, or sodium stearyl fumarate, or polyethylene glycol. 36. The method, use, or use of erdafitinib according to any one of embodiments 28-34, wherein the lubricant comprises magnesium stearate. 37. The method, the erdafitinib for use, or the use according to any one of embodiments 28 to 36, wherein the lubricant is present in the drug formulation at a total concentration of about 0.05% to about 5% by weight, about 1% to about 5% by weight, or about 2.5% by weight. 38. The method, erdafitinib for use, or use of any one of the preceding embodiments, wherein the drug formulation comprises an intragranular composition comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly the lactate salt of erdafitinib, and at least one intragranular excipient, and an extragranular composition comprising at least one extragranular excipient. 39. The method, use, or use of embodiment 38, wherein the at least one intragranular excipient and the at least one extragranular excipient do not comprise a common pharmaceutical excipient. 40. The method, use, or use of embodiment 38 or 39, wherein the at least one intragranular excipient comprises an intragranular binder. 41. The method, use, or use according to any one of embodiments 38-40, wherein the intragranular binder comprises hydroxypropylmethylcellulose. 42. The method, the erdafitinib for use, or the use according to any one of embodiments 38-41, wherein the at least one extragranular excipient comprises one or more of an extragranular binder, an extragranular filler (diluent), an extragranular glidant, and an extragranular lubricant. 43. The method, use, or use according to embodiment 42, wherein the extragranular binder comprises vinylpyrrolidone-vinyl acetate. 44. The method, use, or use according to embodiment 42 or 43, wherein the extragranular diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof. 45. The method, the use, or the use of erdafitinib according to any one of embodiments 42-44, wherein the extragranular glidant comprises hydrophilic colloidal silicon dioxide. 46. ​​The method, use, or use of erdafitinib according to any one of embodiments 42-45, wherein the extragranular lubricant comprises magnesium stearate, or sodium stearyl fumarate, or polyethylene glycol. 47. The method, use, or use of erdafitinib according to any one of embodiments 42-46, wherein the extragranular lubricant comprises magnesium stearate. 48. The method, erdafitinib for use, or use of any one of the preceding embodiments, wherein the erdafitinib L-lactate salt is present in the drug formulation in a concentration of 60% to 91% by weight, or 60% to 80% by weight. 49. The method, use, or use according to embodiment 48, wherein the erdafitinib L-lactate is present in the drug formulation in a concentration of 70% by weight. 50. The method, use, or use of erdafitinib according to any one of the preceding embodiments, wherein the drug formulation is in the form of a plurality of mini-tablets. 51. The method, use, or use according to embodiment 50, wherein the drug formulation is in the form of about 10 to about 100 mini-tablets. 52. Erdafitinib for the method, use, or use according to embodiment 50 or 51, wherein (a) the formulation comprises mini-tablets having a total length of about 14.5 cm to about 15 cm, and / or (b) the formulation comprises mini-tablets of about 920 mg to about 965 mg, or mini-tablets of about 920 mg to about 950 mg. 53. The method, erdafitinib for use, or use of any one of the preceding embodiments, wherein the drug delivery system is configured to release the erdafitinib by osmotic pressure through the one or more openings in the elongate body. 54. The method, use, or use of any one of the preceding embodiments, wherein the elongate body comprises an annular wall structure defining a drug reservoir lumen in which the drug formulation is disposed. 55. The method, use, or use of erdafitinib according to embodiment 54, wherein the annular wall structure has a thickness of about 0.1 mm to about 0.5 mm. 56. The method, use, or use of erdafitinib according to embodiment 55, wherein the annular wall structure has a thickness of about 0.2 mm. 57. The method, the erdafitinib for use, or the use according to any one of embodiments 54 to 56, further comprising a first end plug positioned at a first end of the annular wall structure, and a second end plug positioned at a second end of the annular wall structure. 58. The method, erdafitinib for use, or use according to any one of embodiments 54 to 57, wherein the one or more openings in the elongate body comprise a single opening in the annular wall structure, and the elongate body is configured to release the erdafitinib through the opening. 59. The method, erdafitinib for use, or use according to any one of embodiments 54 to 58, wherein the elongate body is configured to release the erdafitinib through microchannels temporarily formed in one or both end regions of the annular wall structure. 60. The method, the erdafitinib for use, or the use of any one of the preceding embodiments, wherein the system is configured to release the erdafitinib at an average rate of between 1 mg / day and 10 mg / day. 61. The method, the use, or the use of any one of embodiments 1-59, wherein the system is configured to release the erdafitinib at an average rate of 1 mg / day to 6 mg / day. 62. The method, the use, or the use of any one of embodiments 1-59, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day to 4 mg / day. 63. The method, the use, or the use of erdafitinib according to any one of embodiments 1 to 59, wherein the system is configured to release erdafitinib at an average rate of 4 mg / day. 64. The method, the erdafitinib for use, or the use of any one of the preceding embodiments, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day. 65. The method, erdafitinib for use, or use according to any one of the preceding embodiments, wherein the system is configured to release the erdafitinib in a zero-order release profile. 66. The method, erdafitinib for use, or use according to any one of embodiments 60 to 65, wherein the system is configured to release the erdafitinib for up to about 30 days. 67. The method, erdafitinib for use, or use according to any one of embodiments 60 to 65, wherein the system is configured to release the erdafitinib for up to about 90 days. 68. The method, the erdafitinib for use, or the use according to any one of the preceding embodiments, wherein the system comprises 500 mg of said erdafitinib (free base equivalent). 69. The method, erdafitinib for use, or use of any one of the preceding embodiments, wherein the system is elastically deformable between a relatively straightened deployed configuration suitable for insertion through the patient's urethra and into the patient's bladder, and a retained configuration suitable for retaining the system within the bladder. 70. The method, erdafitinib for use, or use of any one of the preceding embodiments, wherein the system comprises a tube that is elastically deformable and has two opposing free ends that are oriented away from each other when the system is in a low-profile deployed configuration and toward each other when the system is in a relatively expanded, retained configuration. 71. The method, erdafitinib for use, or use according to any one of the preceding embodiments, wherein the system comprises an elastically deformable elongate body having two opposing free ends within the confines of a bi-elliptical expanded retention shape. 72. The method, erdafitinib for use, or use of any one of the preceding embodiments, wherein the elongate body further comprises a retaining frame lumen. 73. The method, erdafitinib for use, or use according to embodiment 72, further comprising a nitinol wire disposed within the lumen of the retaining frame. 74. The method, erdafitinib for use, or use according to any one of embodiments 1 to 15, wherein erdafitinib or a pharmaceutically acceptable salt thereof, in particular the L-lactate salt of erdafitinib, is locally delivered in the form of a pharmaceutical composition comprising erdafitinib L-lactate and one or more pharmaceutical excipients. 75. The method, use, or use of embodiment 74, wherein the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, an osmotic agent, or any combination thereof. 76. The method, erdafitinib for use, or use according to 74, wherein at least one pharmaceutical excipient comprises or is selected from a binder, a diluent (filler), a glidant, a lubricant, or any combination thereof. 77. The method, use, or use of erdafitinib according to embodiment 76, wherein the binder comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate (PVP-VA), or a combination thereof. 78. The method, use, or use of erdafitinib according to embodiment 76 or 77, wherein the binder is present in the drug formulation at a total concentration of about 1% to about 30% by weight, about 5% to about 20% by weight, or about 10% to about 15% by weight. 79. The method, use, or use of erdafitinib according to any one of embodiments 76-78, wherein the diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, calcium hydrogen phosphate, or a combination thereof. 80. The method, the use, or the use of erdafitinib according to any one of embodiments 76 to 79, wherein the diluent (filler) is present in the drug formulation in a total concentration of about 5% to about 30% by weight, about 10% to about 30% by weight, or about 10% to about 20% by weight. 81. The method, the use, or the use of erdafitinib according to any one of embodiments 76 to 80, wherein the glidant comprises hydrophilic colloidal silicon dioxide or hydrophobic colloidal silicon dioxide, in particular hydrophilic colloidal silicon dioxide. 82. The method, the erdafitinib for use, or the use according to any one of embodiments 76 to 81, wherein the glidant is present in the drug formulation at a total concentration of about 0.05% to about 1% by weight, about 0.1% to about 0.5% by weight, or about 0.25% by weight. 83. The method, use, or use of erdafitinib according to any one of embodiments 76-82, wherein the lubricant comprises magnesium stearate, or sodium stearyl fumarate, or polyethylene glycol. 84. The method, use, or use of erdafitinib according to any one of embodiments 76-82, wherein the lubricant comprises magnesium stearate. 85. The method, the erdafitinib for use, or the use according to any one of embodiments 76 to 84, wherein the lubricant is present in the drug formulation at a total concentration of about 0.05% to about 5% by weight, about 1% to about 5% by weight, or about 2.5% by weight. 86. The method, erdafitinib for use, or use according to any one of embodiments 76 to 85, wherein the drug formulation comprises an intragranular composition comprising erdafitinib or a pharmaceutically acceptable salt thereof, in particular the lactate salt of erdafitinib, and at least one intragranular excipient, and an extragranular composition comprising at least one extragranular excipient. 87. The method, use, or use of erdafitinib according to embodiment 86, wherein the at least one intragranular excipient and the at least one extragranular excipient do not comprise a common pharmaceutical excipient. 88. The method, use, or use of erdafitinib according to embodiment 86 or 87, wherein the at least one intragranular excipient comprises an intragranular binder. 89. The method, use, or use according to embodiment 88, wherein the intragranular binder comprises hydroxypropyl methylcellulose. 90. The method, the erdafitinib for use, or the use according to any one of embodiments 86-89, wherein the at least one extragranular excipient comprises one or more of an extragranular binder, an extragranular filler (diluent), an extragranular glidant, and an extragranular lubricant. 91. The method, use, or use according to embodiment 90, wherein the extragranular binder comprises vinylpyrrolidone-vinyl acetate. 92. The method, use, or use according to embodiment 90 or 91, wherein the extragranular diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof. 93. The method, use, or use of erdafitinib according to any one of embodiments 90-92, wherein the extragranular glidant comprises hydrophilic colloidal silicon dioxide. 94. The method, use, or use of erdafitinib according to any one of embodiments 90-93, wherein the extragranular lubricant comprises magnesium stearate, or sodium stearyl fumarate, or polyethylene glycol. 95. The method, use, or use of erdafitinib according to any one of embodiments 90-94, wherein the extragranular lubricant comprises magnesium stearate. 96. The method, erdafitinib for use, or use according to any one of embodiments 74 to 95, wherein the erdafitinib L-lactate is present in the drug formulation in a concentration of 60% to 91% by weight, or 60% to 80% by weight. 97. The method, use, or use of embodiment 96, wherein the erdafitinib L-lactate is present in the drug formulation in a concentration of 70% by weight. 98. The method, use, or use of erdafitinib according to any one of embodiments 74 to 97, wherein the composition is in the form of a tablet. 99. The method, use, or use according to embodiment 98, wherein the tablets are mini-tablets. 100. The method, use, or use according to embodiment 98 or 99, wherein the tablet has a hardness of at least about 100 N. 101. The method, use, or use according to embodiment 100, wherein the tablet has a hardness of about 150 N to about 250 N. 102. The method, use, or use according to embodiment 100, wherein the tablet has a hardness of about 175N to about 225N. 103. The method, use, or use according to any one of embodiments 98 to 102, wherein the tablet has a thickness of about 3.2 mm to about 3.6 mm. 104. The method, use, or use according to embodiment 99, wherein the mini-tablets are in the form of solid cylinders having a cylindrical axis, cylindrical sides, a circular end face perpendicular to the cylindrical axis, a diameter across the circular end face, and a length along the cylindrical sides. 105. The method, use, or use of erdafitinib according to embodiment 104, wherein the length of the mini-tablets exceeds the diameter of the mini-tablets so as to provide mini-tablets with an aspect ratio (length:diameter) of more than 1:1. 106. The method, use, or use according to embodiment 104 or 105, wherein the mini-tablets have a diameter of 1.0 mm to 3.2 mm, or 1.5 mm to 3.1 mm. 107. The method, use, or use according to embodiment 104 or 105, wherein the mini-tablets have a diameter of 2.5 mm to 2.7 mm. 108. The method, use, or use of erdafitinib according to any one of embodiments 104 to 107, wherein the mini-tablets have a length of 3.0 mm to 3.5 mm. 109. The method, use, or use of erdafitinib according to any one of embodiments 104 to 108, wherein the mini-tablets have a mass of 22 mg to 24 mg. 110. The method, erdafitinib for use, or use according to any one of embodiments 59 to 73, wherein the elongate body is configured to release the erdafitinib through the opening and through a microchannel temporarily formed in one end region of the annular wall structure. 111. The method, erdafitinib for use, or use according to any one of embodiments 58 to 73, wherein the elongate body is configured to release the erdafitinib through the opening and through microchannels temporarily formed in both end regions of the annular wall structure. 112. The method, erdafitinib for use, or use according to any one of embodiments 59, 110, or 111, wherein the microchannels are formed transiently when the osmotic pressure increases above a certain threshold. 113. The method, the erdafitinib for use, or the use of any one of the preceding embodiments, wherein the one or more FGFR genetic alterations are selected from FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, in particular FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof, and in particular the FGFR2 genetic alteration and / or FGFR3 genetic alteration is selected from FGFR3-TACC3 variant 1 (FGFR3-TACC3 V1), FGFR3 G370C, FGFR3 S249C, FGFR3 Y373C, and FGFR3 R248C. [Example]

[0173] Example 1. Screening of materials and API forms for erdafitinib release A number of polymeric materials were tested to determine their suitability as construction materials for the elastomeric system body for the release of various erdafitinib formulations. Materials included silicone and several thermoplastic polyurethanes (TPUs) manufactured by Lubrizol Life Sciences (Bethlehem, PA). Results are listed in Table 1.

[0174] [Table 5]

[0175] In Table 1, "O" is permeable, "Δ" is substantially impermeable, and "X" is impermeable. This information can be useful in selecting osmotic system housing materials of construction and design that can be used with various possible erdafitinib forms / formulations.

[0176] Example 2. Sample mini-tablet formulation Table 2 presents selected aspects and embodiments of mini-tablet formulations for use with the disclosed drug delivery systems. The blends in Table 2 are for tablets with a target tablet weight of 20 mg and a drug loading of 70% by weight.

[0177] [Table 6]

[0178] The erdafitinib granules were composed of 98% by weight erdafitinib mono-L-lactic acid and 2% by weight HPMC (eg, HPMC 290 15 mPa.s).

[0179] Preparation: All compounds were screened through a 600 μm sieve. Erdafitinib granules, copovidone, microcrystalline cellulose, and colloidal silica were weighed and mixed for 10 minutes. The blend was screened through a 600 μm sieve. Magnesium stearate was added and the blend was mixed for 5 minutes. The resulting blend was tableted.

[0180] Example 3. Erdafitinib metabolism and pharmacokinetic properties for intravesical delivery Erdafitinib was determined to be sufficiently stable in freshly collected human, minipig, and rat urine for 6 hours at 37°C, indicating that the drug is stable in urine between urination cycles.

[0181] In vitro protein binding studies demonstrated that erdafitinib exists primarily in the free form in urine. The percent free erdafitinib in rat, minipig, and human urine was 84%, 97%, and 95%, respectively, and was estimated to be concentration-independent. Erdafitinib was found to bind less to AGP than to albumin. Albuminuria / proteinuria had minimal effect on the percent free form in urine.

[0182] In vitro binding of erdafitinib to normal / tumor bladder tissues showed a significant free fraction. The free fraction of erdafitinib in minipig bladder tissue was 79%, which was two-fold higher than that in rats (33%) and humans (39%). In tumor tissue, the free fraction was 40%.

[0183] Bladder perfusion studies in pigs and rats showed good distribution from urine into the bladder, particularly into the urothelium. Low systemic bioavailability (approximately 5% in rats and 12% in minipigs) after localized bladder dosing was observed.

[0184] Based on these studies, erdafitinib is stable in urine and exists in a high free fraction, which should therefore provide desirable exposure to bladder tumors. Erdafitinib is believed to have favorable drug metabolism and pharmacokinetic properties for intravesical administration.

[0185] Example 4: Pharmacokinetics (PK) and pharmacodynamics (PD) of single-dose intravesical erdafitinib administration in orthotopic bladder tumor-bearing rats. The objective of Example 4 was to compare the PK and PD effects of localized bladder versus oral administration of erdafitinib in nude rats bearing human UM-UC-1 bladder xenografts. Animals received a single oral intravesical dose of erdafitinib (20 mg / kg erdafitinib in 10% weight per volume (w / v) HP-β-CD solution) or a 1-hour intravesical instillation of erdafitinib (6 mg / kg erdafitinib in 10% w / v HP-β-CD solution). Extracellular signal-regulated kinase (ERK) 1 / 2 phosphorylation was assessed at various time points after administration / implantation as a PD marker for FGFR kinase inhibition in tumors. PK analysis of tumor and plasma samples was performed 2, 7, 48, and 120 hours after a single 6 mg / kg intravesical dose of erdafitinib or a 20 mg / kg oral dose of erdafitinib. Groups of nude rats bearing subcutaneous (sc) tumors (UM-UC-1) were given erdafitinib orally, and concentrations were measured in plasma and tumors 2, 7, 48, and 120 hours after dosing.

[0186] Intravesical administration resulted in mean erdafitinib exposure levels that were equivalent to those of the 20 mg / kg oral dose (Table 3). Approximately two-fold lower exposure levels were detected in subcutaneous (sc) tumors from orally dosed rats at 2 and 7 hours compared to orthotopic tumors from orally dosed rats, reflecting the commensurately lower plasma exposures observed in the same groups of rats (Figure 4).

[0187] [Table 7] HP-β-CD, hydroxypropyl β-cyclodextrin; IVES, intravesical (bladder instillation); LLOQ, lower limit of quantitation; PO or po, oral. Values ​​are means with standard deviations in parentheses. Mean exposures for the 48 and 120 hour time points were low (less than 35 ng / g). Erdafitinib was dosed as a 10% w / v solution in HP-β-CD. a LLOQ serum=0.05ng / mL b LLOQ tumor = 2ng / g c Mean = tumor concentration (ng / g) / plasma concentration (ng / mL)

[0188] The effect of a single 20 mg / kg oral or 6 mg / kg intravesical dose of erdafitinib on ERK1 / 2 phosphorylation in orthotopic bladder UM-UC-1 tumors was assessed by capillary immunoblotting at various time points. Proteins from tumor sample lysates collected 2, 7, 48, and 120 hours after treatment with erdafitinib or vehicle were separated by capillary electrophoresis and probed with antibodies detecting phosphorylated (p)ERK1 / 2 and total ERK1 / 2. The pERK1 / 2 signal was divided by the total ERK1 / 2 signal in the same sample, and the average pERK1 / 2 value for the corresponding vehicle-treated sample was set to a relative value of 1. At each time point, the pERK / ERK ratio for each tumor sample was divided by the average pERK / ERK ratio derived from the corresponding control sample. With one exception, there were no vehicle-treated samples at the 120 hour time point, so the pERK / ERK ratio for the erdafitinib-treated samples at the 120 hour time point was divided by the mean of the 48 hour vehicle-treated group.

[0189] Both the 6 mg / kg intravesical dose and the 20 mg / kg oral dose of erdafitinib resulted in a statistically significant decrease in ERK1 / 2 phosphorylation in UM-UC-1 tumors 2 hours after dosing (Figure 5, Table 4). Although not statistically significant, pERK levels were also lower in erdafitinib-treated tumors compared with vehicle-treated tumors at 7 and 48 hours, and by 120 hours, pERK1 / 2 levels were comparable to those in vehicle-treated rats.

[0190] [Table 8] ANOVA, analysis of variance; ERK, extracellular signal-regulated kinase; IVES, intravesical; NA, not applicable; pERK, phosphorylated extracellular signal-regulated kinase; po, oral. "Zero dose" animals received vehicle. a Ratio of pERK / ERK mean group value divided by the mean of the vehicle-treated group. Standard deviation in parentheses. b One-way ANOVA, Dunnett's test for multiple comparisons. c Divided by the mean of the 48-hour vehicle-treated group.

[0191] Overall, these data indicate that intravesical administration of erdafitinib provides adequate tumor PK / PD while dramatically reducing plasma exposure, thereby reducing the potential for on-target off-tumor toxicity compared to oral therapy.

[0192] Example 5: Continuous perfusion studies in an orthotopic bladder cancer model. Perfusion studies: The bladders of study animals were cannulated on day 1 and animals were allowed to recover for 3 days. On day 5, UM-UC-1 cells (2 × 10 6 Cells (1000 cells) were injected into the lateral wall of each bladder. After a 2-day tumor growth period, erdafitinib was perfused continuously for 5 days, followed by autopsy within 24 hours. Based on the in vitro results, target urinary concentrations of 0.5, 1.0, and 5.0 μg / mL were used in the perfusion experiments. The study design is shown in Figure 7. Body weight, daily urine production, and daily water consumption were recorded. At autopsy, plasma samples, bladder photographs, and bladder weight measurements were recorded. After autopsy, the total bladder weight, consisting of normal bladder tissue plus urothelial tumor, was used to determine the effect of erdafitinib on tumor growth.

[0193] Human-derived tumor cells grew rapidly when implanted into the bladder wall of athymic rats. Within 7 days of implantation, tumors occupied most of the urothelial surface and increased total bladder weight by up to sevenfold (Figure 6). Therefore, total bladder weight is an accurate measure of drug response.

[0194] Five days of continuous erdafitinib infusion at nominal urinary concentrations of 0.5, 1.0, and 5.0 μg / mL was generally well tolerated. Body weight changes during the study are shown in Figure 8. An initial small decrease in body weight (days 1-3) of less than 5% was observed in most groups, including the vehicle control, due to the effects of the bladder cannulation surgery. Minimal weight changes were observed after intravesical tumor cell injection on day 5. Transfer to metabolic cages and initiation of bladder perfusion resulted in a second small weight loss that was not related to perfusate drug concentration. Based on cageside observations, no visible signs of abnormal behavior or clinical symptoms were observed in any of the treatment groups.

[0195] The percent reduction in relative tumor weight between the control and drug-perfused groups was determined as an initial measure of efficacy. Bladder tissue and tumor samples were also subjected to analysis of FGFR signaling activity by determining phosphorylated fibroblast growth factor receptor substrate (FRS) 2a levels and pERK-to-ERK ratios. Additional urine, plasma, and bladder samples were collected to determine erdafitinib concentrations using an established liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. The mean bladder weight changes in animals receiving different erdafitinib concentrations are shown in Figure 9. A significant dose-related reduction in bladder weight was observed in the erdafitinib-treated group (for erdafitinib at 0.5 μg / mL) when compared to the vehicle control group. ** p<0.01 for erdafitinib at nominal urinary concentrations of 1.0 and 5 μg / mL *** p<0.001),

[0196] Example 6: Dose-response evaluation of erdafitinib in bladder-perfused athymic rats with RT-112 implanted within the bladder wall. Perfusion Study: The experimental study design was the same as that described in Example 5 (Figure 7), except that perfusion was continued until necropsy on day 14. Six-day continuous perfusion treatment with erdafitinib at nominal urinary concentrations of 0.25, 0.5, and 1.0 μg / mL was well tolerated during the experimental period. Body weight changes observed during the study are shown in Figure 10. Mild weight loss was observed during the study, with maximum mean values ​​ranging up to approximately -3% in the erdafitinib-treated group on day 11.

[0197] The effect of intravesical erdafitinib exposure on tumor growth, as determined by changes in total bladder weight, is shown in Figure 11. Mean bladder weights tended to be lower with increasing erdafitinib concentration, but the reductions were not statistically significant for the 0.25 and 0.5 μg / mL dose groups relative to vehicle control animals. Significant bladder weight reductions ( * p<0.05) was observed in animals receiving a perfusate concentration of 1.0 μg / mL compared to vehicle controls.

[0198] A dose-response evaluation of erdafitinib (0.25-5 μg / mL) in bladder-perfused athymic rats with UM-UC-1 or RT-112 cell lines implanted into the bladder wall demonstrated that the erdafitinib dosing regimen was well tolerated. A significant dose-dependent decrease in bladder weight was observed in the erdafitinib-treated group compared with the vehicle control group, indicating that bladder perfusion with erdafitinib reduced tumor growth.

[0199] Example 7: Intravesical pharmacokinetic and distribution studies in rats and minipigs. Systemic and bladder PK studies were conducted after a single intravesical (bolus) administration of erdafitinib formulation in solution (HP-β-CD) to rats and minipigs. These studies were initially conducted to determine drug exposure in bladder tissue, urine, and plasma. Bladder tissue was also evaluated for macroscopic and microscopic examination to determine any local effects of the drug or formulation in the study. The goal of Example 7 was to determine the feasibility of intravesical erdafitinib therapy in the bladder placement of erdafitinib.

[0200] Single intravesical dose PK in rats: Systemic and bladder PK of erdafitinib were determined in female Sprague-Dawley rats after intravesical administration of erdafitinib solution at 2, 6, and 18 mg / kg body weight. Rats were kept under anesthesia using isoflurane (2-4%), a catheter was introduced into the bladder via the urethra, and erdafitinib solution (10% w / v HP-β-CD in pH 5.5 citrate buffer) was instilled into the rat bladder via the catheter. Solution formulations were prepared at various strengths and administered in 0.5 mL volumes to each rat bladder up to doses of 2, 6, and 18 mg / kg. The corresponding nominal doses of drug were 0.5, 1.5, and 4.5 mg, respectively. One hour after placement, rats were transferred to metabolic cages, and samples for PK determination were collected. Blood samples were collected from the tail vein (three rats per time point) at 24, 48, 72, 96, and 168 hours after the completion of the 1-hour compound exposure period following dosing. At each blood sampling time point, bladder samples were collected from each rat for drug analysis. In the 18 mg / kg dose (high dose) group, bladders collected at 96 hours were evaluated microscopically. Urine collection from all rats was restricted to the initial period of 0 to 6 hours after dosing.

[0201] In plasma, almost all samples were below the limit of quantitation (0.02 ng / mL) for the 2 and 6 mg / kg dose groups. For the 18 mg / kg dose group, some measurable concentrations were observed at 24, 48, and 72 hours (0.0303-0.106 ng / mL), but at 96 and 168 hours, all samples were below the limit of quantitation. In the bladder, concentrations could be measured up to 72 hours for the 2 and 6 mg / kg dose groups and up to 168 hours for the 18 mg / kg dose group. Concentrations were highest at 24 hours and declined thereafter. No dose-linearity could be observed. Exposure was similar among the doses tested. The percentage of compound excreted as unchanged drug in urine (within the first 6 hours) reached 23.5%, 19%, and 50.3% for the 2, 6, and 18 mg / kg dose groups, respectively.

[0202] Systemic and bladder pharmacokinetics of continuous intravesical erdafitinib in rats: Systemic and bladder pharmacokinetics of erdafitinib were determined in female Sprague-Dawley rats after continuous intravesical infusion of an aqueous solution of erdafitinib. The rat bladders (five rat groups, n = 3 per group) were surgically catheterized under anesthesia. The catheter was exposed, tunneled subcutaneously, and connected to a vascular access harness (VAH) in the neck. Rats were transferred to individual metabolic cages and allowed free access to food and water during a 1-week postoperative recovery period. On the study day, erdafitinib solution (0.1 mg / mL, 0.1 mL / hr, 5% w / v HP-β-CD in citrate buffer pH 5.5) was perfused through the rat bladders via the catheter for 72 hours. The first group (n = 3) was sacrificed 24 hours after perfusion, and two of the four remaining groups were sacrificed at 48 and 72 hours after perfusion. Perfusion was stopped for the last two groups at 72 hours, and these groups were sacrificed at 96 and 120 hours to determine the drug elimination phase from the bladder. Plasma and bladder samples were collected at all time points. Urine was collected from the third group during the 48-72 hour perfusion period for drug analysis. Plasma concentrations in rats after 72 hours of bladder perfusion of erdafitinib solution (0.1 mg / mL, 0.1 mL / hour, 0.72 mg cumulative dose) are shown in Figure 12A. Levels (below the limit of quantification, 0.2 ng / mL) were not detected in samples up to 120 hours (i.e., an additional 48 hours) after perfusion was stopped at 72 hours. Intravesical levels in rats after 72 hours of bladder irrigation with erdafitinib solution (0.1 mg / mL, 0.1 mL / hour, cumulative dose of 0.72 mg) are shown in Figure 12B. Rat bladders irrigated with 0.1 mg / mL erdafitinib solution showed no changes, and this formulation strength was considered well tolerated. Mean daily urinary concentrations were measured at approximately 10,000 ng / mL for urine collected during the 48- to 72-hour irrigation interval.

[0203] [Table 9] AUC 0~xh, area under the plasma concentration-time curve from time of administration to x hours; C xh , plasma concentration at time x; BQL, below limit of quantification a The average daily urinary concentration at this time point was approximately 10,000 ng / mL.

[0204] Results showed significant bladder tissue uptake and maintenance of high intravesical levels of erdafitinib during continuous slow-rate perfusion of erdafitinib, with minimal systemic exposure.

[0205] Systemic and bladder pharmacokinetics of continuous intravesical erdafitinib in pigs: The systemic and bladder pharmacokinetics of erdafitinib were evaluated in five female pigs (domestic Yorkshire crossbred) after continuous intravesical infusion of an aqueous erdafitinib solution. On day 7, a catheter was surgically placed into each animal's bladder. The distal end of the catheter was secured to a subcutaneous site and attached to a vascular access port (VAP). The port was secured, and the animals were allowed to recover. Each animal was then fitted with a portable infusion pump attached to the bladder catheter via the VAP. Dose formulation (22.5 μg / mL erdafitinib solution in 50 mM citrate buffer, pH 6.0) was prepared daily, sterile filtered daily, and analyzed to confirm concentration. The dose formulation was perfused into the bladder at a constant rate of 12.5 mL / h for 6 consecutive days in two animals and 8 consecutive days in three animals. Total voided urine was collected at 24-hour intervals over days 6 or 8. Blood samples were collected daily on study days 1 through 8. Bladder tissue samples were collected from each animal at necropsy. Samples obtained from all animals were analyzed for erdafitinib using a validated LC-MS / MS method. Based on formulation analysis for all days, the average daily dose administered for each animal ranged from 7.06 to 7.56 mg, with an overall average dose of 7.3 mg / day. Based on average body weight (pre-dose), the administered dose was 0.22 mg / kg / day.

[0206] Mean (±SD) erdafitinib urinary concentrations ranged from 1,255 ± 554 to 873 ± 179 ng / mL on days 2 through 8 (Figure 13). Mean (±SD) erdafitinib plasma concentrations on days 2 through 8 are shown in Figure 14 and ranged from 0.622 ± 0.250 to 0.828 ± 0.487 ng / mL (mean ±SD). Over the 7-day period of this study, mean (±SD) daily urine volume was 966 ± 253 mL. Inter- and intra-animal variability in daily urine production was observed, but no significant trends in urine production were observed over the treatment period. Erdafitinib urinary recovery was relatively consistent across all animals, averaging 910 ± 812 to 1,135 ± 760 ng / mL on days 2 through 8. Daily erdafitinib recovery averaged 15.7% ± 5.67% of the mean daily dose of erdafitinib administered.

[0207] Mean erdafitinib concentrations in full-thickness bladder tissue were measured on days 6 and 8 (end of perfusion), with values ​​ranging from 315 to 998 ng / g and 346 to 2,688 ng / g, respectively. Erdafitinib concentrations were measured in the urothelium and underlying tissue layers (i.e., muscle). These data suggest that the concentration of erdafitinib in the urothelial layer of the bladder was more than 10-fold higher compared to the underlying tissue layers, suggesting that the drug was primarily retained in the urothelium.

[0208] [Table 10] conc, concentration; Rem layer, bladder subtissue layer; Urothel layer, bladder urothelium.

[0209] Example 8: Stability and protein binding studies. Stability in Urine: As part of an equilibrium dialysis study, urine was spiked with erdafitinib at 1, 3, and 5 μg / mL and incubated at 37°C for 6 hours (in triplicate). At the end of the 6-hour post-dialysis incubation, the drug was analyzed and recovery calculated relative to the spiked concentration. The percent recovery of erdafitinib in the study ranged from 89% to 98% in human urine, 90% to 95% in rat urine, and 92% to 93% in miniature pig urine, indicating that erdafitinib is stable in urine. These results suggest that erdafitinib remains stable in urine within the bladder, providing exposure to tumor and bladder tissue.

[0210] Example 9: Prototype development. Based on experiments, including animal studies, release rates of 1 mg / day, 2 mg / day, 4 mg / day, and 6 mg / day were selected for further development. Designs enabling 30-day and 90-day durations of use were evaluated. The 30-day design was designed to provide a higher drug release rate that also exceeded the 90-day payload capacity of the device. The minimum target release rate was defined as the rate required to achieve a mean erdafitinib urinary concentration of 1 μg / mL. Higher release rates were also evaluated to increase tumor exposure and to assess local tolerability and systemic exposure trends. Additional performance metrics included urine pH, urine volume, and urine composition independence.

[0211] Erdafitinib exhibits significant pH-dependent solubility over the normal urinary pH range of 5.5 to 7. As a result, different drug formats and mini-tablet excipient combinations were evaluated to minimize the effect of urinary pH and composition on system release rate.

[0212] A factorial analysis-based screen was first completed to evaluate the full range of possible release rates and pH effects. Approximately 900 combinations of device polymers and erdafitinib drug formats were tested using a powder-filled short-core system, a 2 cm version known for precise adjustment to the full 15 cm design. Drug formats evaluated included erdafitinib free base, erdafitinib HCl salt, erdafitinib L-lactate salt, and erdafitinib free base + HP-β-CD.

[0213] Materials Screening In general, materials impermeable to the API, erdafitinib, are suitable for use in osmotic systems. Platinum-cured silicone, thermoplastic polyurethane (TPU), and ethylene vinyl acetate (EVA) materials were screened (Table 7). Test articles were filled with the formulated API (powder or tablet), sealed, placed in foil pouches, and gamma-irradiated (nominal 35 kGy). The systems were placed in simulated urine (pH 6.8), stored at 37°C, and sampled periodically. The amount of API in each sample was determined by high-performance liquid chromatography (HPLC) analysis.

[0214] [Table 11] EVA, ethylene vinyl acetate; NA, not available; TPU, thermoplastic polyurethane

[0215] The permeability screening results are shown in Figure 15. Materials suitable for use in the osmotic system were impermeable to the API. Silicone was used as the tubing material for the osmotic system and is also suitable as the osmotic tubing material for all four erdafitinib forms. Based on its impermeability, silicone was selected as the material for further development of the osmotic prototype.

[0216] Osmotic System Silicone tubing was selected for the osmotic system, and four API forms were screened with and without added osmotic agents (e.g., sodium chloride, potassium chloride, potassium bicarbonate, sodium phosphate dihydrate, sodium sulfate, and sodium L-(+)-tartrate dihydrate) capable of generating a constant water influx through the silicone tubing for at least 30 days. Short-core osmotic systems were tested with the four API forms alone and with added osmotic agents. The HCl salt form was not tested with sodium chloride or potassium chloride due to the common ion between the API and osmotic agent. The short-core system that showed the most promising release rate was the L-lactate API form without added osmotic agent.

[0217] [Table 12]

[0218] Osmotic system using erdafitinib L-lactate Two osmotic system prototypes using erdafitinib L-lactate were tested in minipigs (Prototype 4): Osmotic (orifice + end plugs), 0.2 mm wall, erdafitinib L-lactate, tablet (20% water-insoluble), and Prototype 5: Osmotic (orifice + end plugs), 0.2 mm wall, erdafitinib L-lactate, tablet (water-soluble) (see Figures 16A and 16B). The drug construct formulations are listed in Table 9. Both prototypes included dual-lumen silicone tubing (large lumen ID of 2.64 mm, 0.2 mm wall thickness), a 150 μm orifice, two end plugs, a 15 cm drug core, and wireform as a retention feature. Table 10 lists the drug construct payload for each prototype. IVR testing was performed on prototype 4 using simulated urine at three different pH ranges: pH 5, 6.8, and 8 as the release medium (n=3 systems tested in each medium). Prototype 5 was tested in simulated urine at pH 6.8 (n=2 systems tested in IVR). The IVR profile for prototype 4 showed good agreement between simulated urine at pH 5, 6.8, and 8, demonstrating near-zero-order release over 90 days (FIG. 17). The IVR profile for prototype 5 was tested with only two replicates in simulated urine at pH 6.8 (FIG. 18). This prototype also demonstrated near-zero-order release over 90 days.

[0219] [Table 13] API, active pharmaceutical ingredient; NA, not applicable; w / w, weight per weight.

[0220] [Table 14] FBE, free base equivalent.

[0221] Pharmacokinetic evaluation in minipigs The osmotic design released erdafitinib at a rate designed to achieve a target urinary concentration of ≥1 μg / mL in minipigs. The zero-order system demonstrated in vitro release rates (defined as constant release over at least 30 days) of up to 2 mg / day (for a duration of >90 days). Inter- and intra-device release rate variability was lowest for the zero-order system.

[0222] Based on the short-core data, a series of 200 full-length systems were developed and tested to confirm the short-core results. A subset of these was tested in minipigs to determine the in vivo release rate characteristics of the osmotic designs and obtain the release rates required to achieve the target urinary concentrations. The in vivo results largely confirmed the in vitro findings, demonstrating that an in vitro release rate of 2-4 mg / day was sufficient to maintain the target erdafitinib urinary concentrations. Figures 17 and 18 summarize the in vitro release characteristics of representative osmotic systems selected for minipig testing. Figure 19 summarizes the urinary concentration versus time profiles of the same systems. Prototypes 4 and 5 were representative zero-order osmotic designs utilizing the release of osmotic systems.

[0223] Example 10: Chemical properties, stability, formulation, and device development. Erdafitinib was assigned the number JNJ-42756493, with the suffix -AAA indicating the free base form and the suffix -AFK indicating the mono-L-lactate salt.

[0224] A summary of the solid-state properties of both the free base and the L-lactate salt is provided in Table 11. The physical stability of the L-lactate salt was evaluated by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and infrared (IR) after storage in open dishes at different conditions for 6 weeks. The product was found to be crystallographically stable. No evidence of dissociation or transformation was found (Table 12).

[0225] [Table 15] DVS, dynamic vapor sorption; RT, room temperature; TGA, thermogravimetric analysis; XRPD, X-ray powder diffractometry.

[0226] [Table 16] Cryst. Ref, crystalline reference; DSC, differential scanning calorimetry; IR, infrared; Max, maximum; RH, relative humidity; RT, room temperature; TGA, thermogravimetric analysis; w / w, weight / weight; XRPD, X-ray powder diffractometry.

[0227] Formulation-Device Development Formulation development focused on the erdafitinib L-lactate mini-tablet concept (see Table 13 for an exemplary concept).

[0228] [Table 17] API, active pharmaceutical ingredient; w / w, weight / weight.

[0229] An osmotic silicone system (osmotically driven, with an orifice) was evaluated.

[0230] The L-lactate salt has unexpectedly high solubility over a wide pH range and unexpected osmotic properties. Figure 20 shows the solubility of L-lactate salt as a function of pH in water (Figure 20A) and simulated urine (Figure 20B) at 37°C.

[0231] Example 11: Synthesis of Erdafitinib L-lactate. Synthesis of erdafitinib L-lactate: Erdafitinib mono-L-lactate was successfully produced via salt formation between erdafitinib free base and solid mono-L-lactic acid (Figure 21). Crystallization was performed using seeded API.

[0232] Step 1

[0233] [Table 18]

[0234] Procedure involving wet milling: Dissolution API Erdafitinib base was added to the reactor. 1.02 mol L-lactic acid / mol erdafitinib base was added. 1.006 L of isopropanol / mol erdafitinib base was added to the reactor. 0.11178 L of water / mol of erdafitinib base was added to the reactor. The solution was dissolved and held at 70° C. Complete dissolution was confirmed visually. The receiving vessel was set at a jacket temperature of 80°C. Polishing filtration was performed and maintained at at least 70°C The filter was rinsed with 1.1178 L of isopropanol / mol of erdafitinib base. Wait until the temperature of the receiver reactor stabilizes at 80°C.

[0235] Establish seeding conditions by cooling to 69 °C at 0.3 °C / min. Wait until the temperature stabilizes. 1 m% of seed material (5.4 g / mol) was seeded. I waited for four hours.

[0236] Cool to wet grinding conditions Cooled to 20°C at 0.2°C / min I waited for an hour. The suspension was wet milled in a high shear mill, configuration 2P-4M, for 60 minutes (CDMP scale). The reactor was heated to 35°C at 0.2°C / min. held for 30 minutes Cooled to 20°C at 0.2°C / min The reactor was heated to 40°C at 0.2°C / min. held for 30 minutes Cooled to 20°C at 0.2°C / min Final cooling and filtration: Cooled to 5°C at 0.2°C / min. Before filtration, the sample was held at 5°C for more than 3 hours. -HOLD point

[0237] Cake washing and drying The wet cake was washed with isopropanol: 0.54 L of isopropanol / mol JNJ-42756493-AFK (erdafitinib mono-L-lactate). The reactor was washed through and the washing solvent was slightly pre-cooled. After removing the mother liquor, wash as quickly as possible. The solid was dried in a vacuum oven at 40° C. for over 24 hours.

[0238] Step 2

[0239] [Table 19]

[0240] procedure: Dissolution API Erdafitinib base was added to the reactor. 1.02 mol L-lactic acid / mol erdafitinib base was added. 1.006 L of isopropanol / mol erdafitinib base was added to the reactor. 0.11178 L of water / mol of erdafitinib base was added to the reactor. The solution was dissolved and held at 70° C. Complete dissolution was confirmed visually. The receiving vessel was set at a jacket temperature of 80°C. Polishing filtration was performed and maintained at at least 70°C The filter was rinsed with 1.1178 L of isopropanol / mol of erdafitinib base. Wait until the temperature of the receiving reactor stabilizes at 80°C.

[0241] Establishing seeding conditions Cooled to 63°C at 0.3°C / min Wait until the temperature stabilizes. 4.5m% of micronized seed material (24.39g / mol) was seeded. I waited for four hours.

[0242] Final cooling and filtration Cooled to 5°C at 0.2°C / min Before filtration, the sample was held at 5°C for more than 3 hours. -HOLD point

[0243] Cake washing and drying The wet cake was washed with isopropanol: 0.54 L of isopropanol / mol JNJ-42756493-AFK (erdafitinib mono-L-lactic acid). The reactor was washed through and the washing solvent was slightly pre-cooled. After removing the mother liquor, wash as quickly as possible. The solid was dried in a vacuum oven at 40° C. for over 24 hours.

[0244] Example 12: Mini-tablets containing erdafitinib lactic acid Manufacturing Process The manufacturing process for minitablets can be described as follows: First, a binder solution was made by dissolving hydroxypropyl methylcellulose 2910 (HPMC) in purified water until a clear solution without lumps was obtained. Next, the screened drug substance was transferred to a granulator and fluid bed granulation (FBG) was performed: the contents were warmed while fluidizing, the complete binder solution was sprayed onto the ingredients, and finally, the granules were dried after spraying while fluidizing. After FBG, the dried granules were screened using a suitable sieve. Subsequently, the screened extragranular excipients were added to the granules and blended for 10 minutes to obtain a homogeneous blend. Next, sieved magnesium stearate was added to the blend and blended for 5 minutes. The final blend was then compressed into core tablets using a suitable tablet press, and the tablets were passed through a dust remover and metal detector.

[0245] DoE research: A design of experiment study was performed. A main compression force of 10 kN was used for the production of DoE concepts. The hardness, weight variation (RSD wt % which correlates with tablet defects) and ejection force of the different concepts were studied.

[0246] From this DoE study, it can be concluded that: 1) SMCC was preferred as a filler; 2) PVP VA, colloidal silicon dioxide (hydrophilic), and magnesium stearate were preferred as binders, glidants, and lubricants, respectively; and 3) MCC was preferred as an additional filler / binder.

[0247] [Table 20]

[0248] A summary of the in-process control (IPC) results obtained for Concepts 1-3 is presented in Table 17.

[0249] [Table 21]

[0250] When evaluating the IPC results, similar values ​​were observed for the different concepts. A comparison of hardness versus ejection force was performed. A higher standard deviation for ejection force was observed when SSF was used as the lubricant. Both hardness and ejection force were comparable for Concepts 1 and 2, with Concept 1 showing slightly better results (i.e., lower ejection force and better tablet hardness). Hardness was investigated as a function of compression force for each concept. The results demonstrated that the manufacturing processes for Concepts 1 and 2 were very robust. Promising results were also obtained for Concept 4. For Concept 4, slight flashing was observed at higher compression forces. The compression profile of Concept 5 showed comparable results to Concept 2, but more variability in the data and visually less optimal tablets were observed for Concept 5. Overall, Concept 2 was preferred as it was the most robust concept for manufacturability and upscaling.

[0251] Example 13: Evaluation of a urinary cell-free DNA (cfDNA) NGS assay for screening patients with bladder cancer This example describes a urine-based test for identifying bladder cancer biomarkers in urine samples from bladder cancer patients. The performance of the urine-based NGS assay is evaluated by comparing results with those from an FDA-approved tissue-based PCR CDx assay that detects alterations in FGFR genes.

[0252] method Paired urine and tissue samples were collected from 107 (muscle-invasive and non-muscle-invasive) bladder cancer patients from the German Bladder BRIDGister clinical trial (Figure 22). Tissue samples were analyzed using the FDA-approved Qiagen therascreen® FGFR RGQ RT-PCR kit, while matched urine samples were processed using the PredicineCARE™ urine (cell-free DNA) cfDNA next-generation sequencing (NGS) assay with a detection sensitivity of 0.3% (0.1% for hotspot mutations). 107 paired bladder cancer urine cfDNA NGS and tissue RT-PCR results were analyzed to determine the concordance (positive percent agreement, PPA, and negative percent agreement, NPA,) between these two assays. Smaller sample sets were also used to compare tissue NGS with therascreen® RT-PCR and tissue NGS with urine cfDNA NGS. A subset of discordant mutations was further validated by droplet digital PCR (ddPCR).

[0253] result The results of the concordance analysis between PredicineCARE™ urine cfDNA NGS and Qiagen therascreen® FGFR RGQ RT-PCR for 107 samples are shown in Tables 18-21 below.

[0254] [Table 22] * WT and mutant: Based on four defined SNVs and five fusions included in the Therascreen® RT-PCR assay (FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3_V1, FGFR3-TACC3_V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7) ** To measure assay performance, samples (107) were selected from a set of matched urine and tissue samples. *** Comparison between Therascreen® RT-PCR vs. PredicineCARE™ Tissue gDNA NGS Allele frequency (AF) cutoff for reportable range for urine NGS (SNVs and indels): 0.3% (hot spots: 0.1%). Allele frequency (AF) cutoff for reportable range for tissue ("FFPE") NGS (SNVs and indels): 5% (hot spots: 2%). Allele frequency (AF) cutoffs for reportable ranges for fusions: urine (0.1%) and tissue (1%)

[0255] [Table 23] NOTE: FGFR+ and FGFR- are based on four previously defined SNVs and five fusions included in the Qiagen therascreen® FGFR RGQ RT-PCR kit.

[0256] [Table 24] PPA, positive agreement percentage; NPA, negative agreement percentage; OPA, overall percent agreement.

[0257] [Table 25] PPA, positive agreement percentage; NPA, negative agreement percentage; OPA, overall percent agreement.

[0258] Three tissue FGFR-negative (FGFR-) samples by RT-PCR were FGFR-positive (FGFR+) by urine NGS testing, while zero urine NGS FGFR-negative samples were FGFR-positive by tissue RT-PCR (Table 19). Discordant samples (i.e., tissue FGFR WT or invalid but urine-positive for FGFR mutations) were further analyzed and confirmed as positive by independent orthogonal droplet digital PCR (Bio-Rad ddPCR Mutations Detection Assay), suggesting that discordance between urine and tissue results is often caused by reduced sensitivity of tissue FGFR RT-PCR testing.

[0259] A heat map of the genetic alterations identified for matched urine NGS and FFPE tissue RT-PCR samples is shown in Figure 23. Scatter plots of variant allele frequencies (VAFs) between matched urine NGS (X-axis) and tissue ("FFPE") RT-PCR (Y-axis) variants are shown for all identified genetic alterations, including somatic and germline variants (Figure 24A), and for somatic FGFR3 alterations (Figure 24B).

[0260] These results showed high concordance between FGFR alterations detected by an FDA-approved tissue companion diagnostic (CDx) assay and a urine cfDNA NGS assay, demonstrating the applicability of noninvasive urine-based testing for molecular diagnostic testing to identify biomarkers in bladder cancer, alleviating the need for tissue-based testing.

[0261] Many modifications and other implementations of the disclosure set forth herein will become apparent with the benefit of the teachings presented in the foregoing descriptions and the associated drawings. It is to be understood, therefore, that the disclosure is not limited to the particular implementations disclosed, and that modifications and other implementations are intended to be included within the scope of the appended claims.

[0262] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. 1. Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, for use in treating bladder cancer in a patient having one or more FGFR gene alterations, wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, is delivered locally to the bladder of the patient, and the one or more FGFR gene alterations are detected in a urine sample from the patient, particularly the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR assay or an NGS assay, and wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib; 1. Erdafitinib or a pharmaceutically acceptable salt thereof for use, wherein the drug delivery system is configured to be osmotically driven to release the erdafitinib from one or more openings in the elongate body.

2. 1. Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, for use in treating bladder cancer in a patient with one or more FGFR gene alterations, said treatment comprising: (a) assessing a urine sample from a patient with bladder cancer for the presence of one or more FGFR gene alterations, particularly a urine-based (b) evaluating a urine sample from a patient with bladder cancer for the presence of said one or more FGFR gene alterations using a PCR or NGS assay based on the one or more FGFR gene alterations; and (b) if said one or more FGFR gene alterations are present in said sample, locally delivering erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, to said patient, wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib; 1. Erdafitinib or a pharmaceutically acceptable salt thereof for use, wherein the drug delivery system is configured to be osmotically driven to release the erdafitinib from one or more openings in the elongate body.

3. 1. Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, for use in treating bladder cancer having one or more FGFR gene alterations in a patient, wherein the erdafitinib or the pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, is administered to the bladder of the patient. wherein the patient is selected for the treatment based on detection of the one or more FGFR gene alterations in a urine sample from the patient, particularly wherein the patient is selected for the treatment based on the detection of the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay, and wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib; 1. Erdafitinib or a pharmaceutically acceptable salt thereof for use, wherein the drug delivery system is configured to be osmotically driven to release the erdafitinib from one or more openings in the elongate body.

4. Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, for use in treating bladder cancer having one or more FGFR gene alterations in a patient, wherein the erdafitinib or the pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, is administered locally to the bladder of the patient. wherein the patient's eligibility for the treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient, particularly wherein the patient's eligibility for the treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or an NGS assay, and wherein erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib, an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly the L-lactate salt of erdafitinib; 1. Erdafitinib or a pharmaceutically acceptable salt thereof for use, wherein the drug delivery system is configured to be osmotically driven to release the erdafitinib from one or more openings in the elongate body.

5. Erdafitinib for use according to any one of claims 1 to 4, wherein the one or more FGFR gene alterations include one or more FGFR2 gene alterations or FGFR3 gene alterations.

6. Erdafitinib for use according to any one of claims 1 to 5, wherein the one or more FGFR genetic alterations comprise one or more FGFR2 point mutations or fusions or FGFR3 point mutations or fusions.

7. The erdafitinib for use according to any one of claims 1 to 6, wherein the one or more FGFR genetic alterations are detected in a urine sample of the patient prior to local delivery of erdafitinib.

8. Erdafitinib for use according to any one of claims 1 to 7, wherein erdafitinib is present in said drug delivery system as the mono-L-lactate salt.

9. Erdafitinib for use according to any one of claims 1 to 8, wherein the elongate body comprises a biocompatible elastomer.

10. Erdafitinib for use according to claim 9, wherein the biocompatible elastomer comprises silicone or thermoplastic polyurethane.

11. Erdafitinib for use according to claim 9, wherein the biocompatible elastomer comprises silicone.

12. Erdafitinib for use according to claim 9, wherein the biocompatible elastomer comprises a platinum-cured silicone elastomer.

13. Erdafitinib for use according to any one of claims 1 to 12, wherein at least one of the one or more openings in the elongate body is located in a side wall of the elongate body.

14. Erdafitinib for use according to any one of claims 1 to 13, wherein at least one of the one or more openings in the elongate body is located at a first end and / or an opposing second end of the elongate body.

15. Erdafitinib for use according to any one of claims 1 to 12, wherein the drug delivery system has a single opening located in the side wall of the elongate body at a position between a first end and an opposing second end of the elongate body.

16. Erdafitinib for use according to any one of claims 1 to 15, wherein the one or more openings have a diameter of about 100 μm to about 200 μm.

17. Erdafitinib for use according to claim 16, wherein the one or more openings have a diameter of about 150 μm.

18. Erdafitinib for use according to any one of claims 1 to 17, wherein the drug formulation comprises at least one pharmaceutical excipient.

19. Erdafitinib for use according to claim 18, wherein the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, an osmotic agent, or any combination thereof.

20. 19. Erdafitinib for use according to claim 18, wherein the at least one pharmaceutical excipient comprises or is selected from a binder, a diluent (filler), a glidant, a lubricant, or any combination thereof.

21. 21. Erdafitinib for use according to claim 20, wherein the binder comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate (PVP-VA), or a combination thereof.

22. Erdafitinib for use according to claim 20 or 21, wherein the binder is present in the drug formulation at a total concentration of about 1% to about 30% by weight, about 5% to about 20% by weight, or about 10% to about 15% by weight.

23. Erdafitinib for use according to any one of claims 20 to 22, wherein the diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, calcium hydrogen phosphate, or a combination thereof.

24. Erdafitinib for use according to any one of claims 20 to 23, wherein the diluent (filler) is present in the drug formulation at a total concentration of about 5% to about 30% by weight, about 10% to about 30% by weight, or about 10% to about 20% by weight.

25. Erdafitinib for use according to any one of claims 20 to 24, wherein the glidant comprises hydrophilic colloidal silicon dioxide or hydrophobic colloidal silicon dioxide, in particular hydrophilic colloidal silicon dioxide.

26. Erdafitinib for use according to any one of claims 20 to 25, wherein the glidant is present in the drug formulation at a total concentration of about 0.05% to about 1% by weight, about 0.1% to about 0.5% by weight, or about 0.25% by weight.

27. Erdafitinib for use according to any one of claims 20 to 26, wherein the lubricant comprises magnesium stearate, or sodium stearyl fumarate, or polyethylene glycol.

28. Erdafitinib for use according to any one of claims 20 to 26, wherein the lubricant comprises magnesium stearate.

29. Erdafitinib for use according to any one of claims 20 to 28, wherein the lubricant is present in the drug formulation at a total concentration of about 0.05% to about 5% by weight, about 1% to about 5% by weight, or about 2.5%.

30. Erdafitinib for use according to any one of claims 1 to 29, wherein the drug formulation comprises an intragranular composition comprising erdafitinib or a pharmaceutically acceptable salt thereof, in particular the lactate salt of erdafitinib, and at least one intragranular excipient, and an extragranular composition comprising at least one extragranular excipient.

31. Erdafitinib for use according to claim 30, wherein said at least one intragranular excipient and said at least one extragranular excipient do not comprise a common pharmaceutical excipient.

32. Erdafitinib for use according to claim 30 or 31, wherein the at least one intragranular excipient comprises an intragranular binder.

33. Erdafitinib for use according to any one of claims 30 to 32, wherein the intragranular binder comprises hydroxypropyl methylcellulose.

34. Erdafitinib for use according to any one of claims 30 to 33, wherein the at least one extragranular excipient comprises one or more of an extragranular binder, an extragranular filler (diluent), an extragranular glidant, and an extragranular lubricant.

35. Erdafitinib for use according to claim 34, wherein the extragranular binder comprises vinylpyrrolidone-vinyl acetate.

36. Erdafitinib for use according to claim 34 or 35, wherein the extragranular diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof.

37. Erdafitinib for use according to any one of claims 34 to 36, wherein the extragranular glidant comprises hydrophilic colloidal silicon dioxide.

38. Erdafitinib for use according to any one of claims 34 to 37, wherein the extragranular lubricant comprises magnesium stearate, or sodium stearyl fumarate, or polyethylene glycol.

39. Erdafitinib for use according to any one of claims 34 to 38, wherein the extragranular lubricant comprises magnesium stearate.

40. Erdafitinib for use according to any one of claims 1 to 39, wherein erdafitinib L-lactate is present in the drug formulation at a concentration of 60% to 91% by weight, or 60% to 80% by weight.

41. Erdafitinib for use according to claim 40, wherein the erdafitinib L-lactate is present in the drug formulation at a concentration of 70% by weight.

42. Erdafitinib for use according to any one of claims 1 to 41, wherein the drug formulation is in the form of a plurality of mini-tablets.

43. Erdafitinib for use according to claim 42, wherein the drug formulation is in the form of about 10 to about 100 mini-tablets.

44. Erdafitinib for use according to claim 42 or 43, wherein (a) the formulation comprises mini-tablets having a total length of about 14.5 cm to about 15 cm, and / or (b) the formulation comprises mini-tablets of about 920 mg to about 965 mg, or mini-tablets of about 920 mg to about 950 mg.

45. Erdafitinib for use according to any one of claims 1 to 44, wherein the drug delivery system is configured to release the erdafitinib by osmotic pressure through the one or more openings in the elongate body.

46. Erdafitinib for use according to any one of claims 1 to 45, wherein the elongate body comprises an annular wall structure defining a drug reservoir lumen in which the drug formulation is disposed.

47. Erdafitinib for use according to claim 46, wherein the annular wall structure has a thickness of about 0.1 mm to about 0.5 mm.

48. Erdafitinib for use according to claim 47, wherein the annular wall structure has a thickness of about 0.2 mm.

49. Erdafitinib for use according to any one of claims 46 to 48, further comprising a first end plug positioned at a first end of the annular wall structure and a second end plug positioned at a second end of the annular wall structure.

50. Erdafitinib for use according to any one of claims 46 to 49, wherein the one or more openings in the elongate body comprise a single opening in the annular wall structure, and the elongate body is configured to release the erdafitinib through the opening.

51. Erdafitinib for use according to any one of claims 46 to 50, wherein the elongate body is configured to release the erdafitinib through microchannels temporarily formed in one or both end regions of the annular wall structure.

52. Erdafitinib for use according to any one of claims 1 to 51, wherein the system is configured to release the erdafitinib at an average rate of 1 mg / day to 10 mg / day.

53. Erdafitinib for use according to any one of claims 1 to 51, wherein the system is configured to release the erdafitinib at an average rate of 1 mg / day to 6 mg / day.

54. Erdafitinib for use according to any one of claims 1 to 51, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day to 4 mg / day.

55. Erdafitinib for use according to any one of claims 1 to 51, wherein the system is configured to release the erdafitinib at an average rate of 4 mg / day.

56. Erdafitinib for use according to any one of claims 1 to 55, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day.

57. Erdafitinib for use according to any one of claims 1 to 56, wherein the system is configured to release the erdafitinib in a zero order release profile.

58. Erdafitinib for use according to any one of claims 52 to 57, wherein the system is configured to release the erdafitinib for up to about 30 days.

59. Erdafitinib for use according to any one of claims 52 to 57, wherein the system is configured to release the erdafitinib for up to about 90 days.

60. Erdafitinib for use according to any one of claims 1 to 59, wherein said system comprises 500 mg of said erdafitinib (free base equivalent).

61. Erdafitinib for use according to any one of claims 1 to 60, wherein the system is elastically deformable between a relatively straightened deployed configuration suitable for insertion through the patient's urethra and into the patient's bladder, and a retained configuration suitable for retaining the system within the bladder.

62. Erdafitinib for use according to any one of claims 1 to 61, wherein the system comprises a tube that is elastically deformable and has two opposing free ends that are directed away from each other when the system is in a low-profile deployed configuration and that are directed towards each other when the system is in a relatively expanded retained configuration.

63. Erdafitinib for use according to any one of claims 1 to 62, wherein the system comprises an elastically deformable elongate body having two opposing free ends within the confines of a bi-ellipsoidal expanded retention shape.

64. Erdafitinib for use according to any one of claims 1 to 63, wherein the elongate body further comprises a retaining frame lumen.

65. Erdafitinib for use according to claim 64, further comprising a nitinol wire disposed within the retaining frame lumen.

66. 8. Erdafitinib for use according to any one of claims 1 to 7, wherein erdafitinib or a pharmaceutically acceptable salt thereof, in particular the L-lactate salt of erdafitinib, is delivered locally in the form of a pharmaceutical composition comprising erdafitinib L-lactate and one or more pharmaceutical excipients.

67. Erdafitinib for use according to claim 66, wherein the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, an osmotic agent, or any combination thereof.

68. 67. Erdafitinib for use according to 66, wherein the at least one pharmaceutical excipient comprises or is selected from a binder, a diluent (filler), a glidant, a lubricant, or any combination thereof.

69. 69. Erdafitinib for use according to claim 68, wherein the binder comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate (PVP-VA), or a combination thereof.

70. 70. Erdafitinib for use according to claim 68 or 69, wherein the binder is present in the drug formulation at a total concentration of about 1% to about 30% by weight, about 5% to about 20% by weight, or about 10% to about 15% by weight.

71. Erdafitinib for use according to any one of claims 68 to 70, wherein the diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, calcium hydrogen phosphate, or a combination thereof.

72. Erdafitinib for use according to any one of claims 68 to 71, wherein the diluent (filler) is present in the drug formulation at a total concentration of about 5% to about 30% by weight, about 10% to about 30% by weight, or about 10% to about 20% by weight.

73. Erdafitinib for use according to any one of claims 68 to 72, wherein the glidant comprises hydrophilic colloidal silicon dioxide, or hydrophobic colloidal silicon dioxide, in particular hydrophilic colloidal silicon dioxide.

74. Erdafitinib for use according to any one of claims 68 to 73, wherein the glidant is present in the drug formulation at a total concentration of about 0.05% to about 1% by weight, about 0.1% to about 0.5% by weight, or about 0.25% by weight.

75. Erdafitinib for use according to any one of claims 68 to 74, wherein the lubricant comprises magnesium stearate, or sodium stearyl fumarate, or polyethylene glycol.

76. Erdafitinib for use according to any one of claims 68 to 75, wherein the lubricant comprises magnesium stearate.

77. Erdafitinib for use according to any one of claims 68 to 76, wherein the lubricant is present in the drug formulation at a total concentration of about 0.05% to about 5% by weight, about 1% to about 5% by weight, or about 2.5%.

78. Erdafitinib for use according to any one of claims 68 to 77, wherein the drug formulation comprises an intragranular composition comprising erdafitinib or a pharmaceutically acceptable salt thereof, in particular a lactate salt of erdafitinib, and at least one intragranular excipient, and an extragranular composition comprising at least one extragranular excipient.

79. Erdafitinib for use according to claim 78, wherein said at least one intragranular excipient and said at least one extragranular excipient do not comprise a common pharmaceutical excipient.

80. Erdafitinib for use according to claim 78 or 79, wherein the at least one intragranular excipient comprises an intragranular binder.

81. Erdafitinib for use according to claim 80, wherein the intragranular binder comprises hydroxypropyl methylcellulose.

82. Erdafitinib for use according to any one of claims 78 to 81, wherein the at least one extragranular excipient comprises one or more of an extragranular binder, an extragranular filler (diluent), an extragranular glidant, and an extragranular lubricant.

83. Erdafitinib for use according to claim 82, wherein the extragranular binder comprises vinylpyrrolidone-vinyl acetate.

84. Erdafitinib for use according to claim 82 or 83, wherein the extragranular diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof.

85. Erdafitinib for use according to any one of claims 82 to 84, wherein the extragranular glidant comprises hydrophilic colloidal silicon dioxide.

86. Erdafitinib for use according to any one of claims 82 to 85, wherein the extragranular lubricant comprises magnesium stearate, or sodium stearyl fumarate, or polyethylene glycol.

87. Erdafitinib for use according to any one of claims 82 to 86, wherein the extragranular lubricant comprises magnesium stearate.

88. Erdafitinib for use according to any one of claims 66 to 87, wherein erdafitinib L-lactate is present in the drug formulation at a concentration of 60% to 91% by weight, or 60% to 80% by weight.

89. Erdafitinib for use according to claim 88, wherein the erdafitinib L-lactate is present in the drug formulation at a concentration of 70% by weight.

90. Erdafitinib for use according to any one of claims 66 to 89, wherein the composition is in the form of a tablet.

91. Erdafitinib for use according to claim 90, wherein the tablet is a mini-tablet.

92. Erdafitinib for use according to claim 90 or 91, wherein the tablet has a hardness of at least about 100 N.

93. Erdafitinib for use according to claim 92, wherein the tablet has a hardness of about 150N to about 250N.

94. Erdafitinib for use according to claim 92, wherein the tablet has a hardness of about 175N to about 225N.

95. Erdafitinib for use according to any one of claims 90 to 94, wherein the tablet has a thickness of about 3.2 mm to about 3.6 mm.

96. Erdafitinib for use according to claim 91, wherein the mini-tablets are in the form of a solid cylinder having a cylindrical axis, a cylindrical side surface, a circular end surface perpendicular to the cylindrical axis, a diameter across the circular end surface, and a length along the cylindrical side surface.

97. Erdafitinib for use according to claim 96, wherein the length of said mini-tablets exceeds the diameter of said mini-tablets so as to provide said mini-tablets with an aspect ratio (length:diameter) of greater than 1:

1.

98. Erdafitinib for use according to claim 96 or 97, wherein the mini-tablets have a diameter of 1.0 mm to 3.2 mm, or 1.5 mm to 3.1 mm.

99. Erdafitinib for use according to claim 96 or 97, wherein the mini-tablets have a diameter of 2.5 mm to 2.7 mm.

100. Erdafitinib for use according to any one of claims 96 to 99, wherein said mini-tablets have a length of 3.0 mm to 3.5 mm.

101. Erdafitinib for use according to any one of claims 96 to 100, wherein said mini-tablets have a mass of 22 mg to 24 mg.

102. Erdafitinib for use according to any one of claims 51 to 65, wherein the elongate body is configured to release the erdafitinib through the opening and through a microchannel temporarily formed in one end region of the annular wall structure.

103. Erdafitinib for use according to any one of claims 50 to 65, wherein the elongate body is configured to release the erdafitinib through the opening and through microchannels temporarily formed in both end regions of the annular wall structure.

104. Erdafitinib for use according to any one of claims 51, 102 or 103, wherein the microchannels are formed transiently when osmotic pressure increases above a certain threshold.

105. Erdafitinib for use according to any one of claims 1 to 104, wherein the one or more FGFR genetic alterations are selected from FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, in particular FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof, and in particular the FGFR2 genetic alteration and / or FGFR3 genetic alteration is selected from FGFR3-TACC3 variant 1 (FGFR3-TACC3 V1), FGFR3 G370C, FGFR3 S249C, FGFR3 Y373C, and FGFR3 R248C.

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