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

Abstract

Provided herein are methods of treatment, erdafitinib for use and use of erdafitinib for the treatment of bladder cancer harboring one or more FGFR alterations comprising locally delivering erdafitinib into the bladder of a patient.

Description

MoFo Docket No.: 76166-20030.40 USE OF ERDAFITINIB FOR INTRAVESICAL ADMINISTRATION FIELD OF THE INVENTION

[0001] The present disclosure is generally in the field of methods of treatment for bladder cancer, including methods of treating bladder cancer harboring one or more FGFR alterations. CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority from U.S. provisional application No. 63 / 484,591, filed February 13, 2023, and U.S. provisional application No. 63 / 623,193, filed January 19, 2024, the contents of which are incorporated by reference in their entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0003] The content of the electronic sequence listing (761662003040seq.xml; Size: 53,214 bytes; and Date of Creation: February 8, 2024) is herein incorporated by reference in its entirety. BACKGROUND

[0004] Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l-methyl-1H- pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) is a potent pan FGFR kinase inhibitor that binds to and inhibits enzymatic activity of FGFR1, FGFR2, FGFR3 and FGFR4. The synthetic preparation of erdafitinib has been described in WO2011 / 135376. Erdafitinib has been found to inhibit FGFR phosphorylation and signaling and decrease 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 xenograft models derived from tumor types, including bladder cancer.

[0005] Currently, Erdafitinib (BALVERSA®) is available as film-coated tablets for oral administration, and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma that has susceptible fibroblast growth factor receptor (FGFR)3 or FGFR2 genetic alterations and progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

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

[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 1sf-5754313MoFo Docket No.: 76166-20030.40 to Lee et al., and U.S. Patent No. 9,457,176 to Lee et al. In some embodiments, the intravesical systems include a water permeable housing defining a drug reservoir lumen which contains a solid or semi-solid drug formulation, and release of the drug in vivo occurs by water from the bladder diffusing into drug reservoir lumen to solubilize the drug, and then an osmotic pressure build-up in the drug reservoir lumen drives the solubilized drug out of the drug reservoir lumen through a release aperture.

[0008] U.S. Patent No. 10,286,199 to Lee et al. discloses systems in which drug is released from a housing made of a first wall structure and a hydrophilic second wall structure, wherein the first wall structure is impermeable to the drug and the second wall structure is permeable to the drug. U.S. Patent No. 10,894,150 to Lee also discloses systems in which drug is released from a housing made of 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

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

[0010] In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment of bladder cancer, wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient with a urine based PCR or NGS assay. In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations comprising, consisting of, or consisting essential of: (a) evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations, in particular evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a urine based PCR or NGS assay; and (b) delivering locally erdafitinib if the one or more FGFR genetic alterations, is present in the sample. In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment, 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 2sf-5754313MoFo Docket No.: 76166-20030.40 patient, in particular 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 with a urine based PCR or NGS assay.

[0011] In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment, wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient with a urine based PCR or NGS assay.

[0012] In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is locally delivered into the bladder of the patient and wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient with a urine based PCR or NGS assay.

[0013] In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient comprising, consisting of, or consisting essential of (a) evaluating a urine sample from a patient with bladder cancer for the presence of one or more FGFR genetic alterations, in particular evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a urine based PCR or NGS assay; and (b) delivering locally erdafitinib to the patient if the one or more FGFR genetic alterations, is present in the sample.

[0014] In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and 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, in particular 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 with a urine based PCR or NGS assay. In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient with a urine based PCR or NGS assay. In a certain embodiment, there is provided use of 3sf-5754313MoFo Docket No.: 76166-20030.40 erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient, wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient with a urine based PCR or NGS assay.

[0015] In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient comprising, consisting of, or consisting essential of: (a) evaluating a urine sample from the patient with bladder cancer for the presence of the one or more FGFR genetic alterations, in particular evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a urine based PCR or NGS assay; and (b) delivering locally erdafitinib if the one or more FGFR genetic alterations, is present in the sample.

[0016] In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and 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, in particular 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 with a urine based PCR or NGS assay.

[0017] In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient with a urine based PCR or NGS assay. The methods or uses may include locally delivering or locally administering erdafitinib (such as in any of the formulations described herein) into the bladder of a patient in need of treatment, in particular a cancer patient, in an amount effective for the treatment of bladder cancer (e.g., from about 1-10 mg / day, as described herein). For example, the treatment may be effective at treating muscle invasive bladder cancer (MIBC), non-muscle invasive bladder cancer (NMIBC), and / or bacillus calmette-guérin (BCG)-naïve bladder cancer. In an aspect the patient, in particular a human, is a BCG-experienced bladder or NMIBC or MIBC cancer patient. In an aspect the patient, in particular a human, is a BCG- naïve bladder or NMIBC or MIBC cancer patient. In an aspect the patient, in particular a 4sf-5754313MoFo Docket No.: 76166-20030.40 human, is a recurrent, bacillus Calmette-Guerin (BCG)-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient, refusing or ineligible for radical cystectomy (RCy). In an aspect the patient, in particular a human, is a recurrent, BCG-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient, scheduled for RCy. In an aspect the patient, in particular a human, is a recurrent, intermediate-risk NMIBC (Ta and T1) cancer patient with a previous history of only low-grade disease. In an aspect the patient, in particular a human, is a MIBC cancer patient scheduled for RCy who has refused or is ineligible for cisplatin-based neoadjuvant chemotherapy.

[0018] In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment of bladder cancer, wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient with a tissue based PCR or NGS assay, or wherein the one or more FGFR genetic alterations are detected in a histopathological image of the tumor tissue via digital histopathology analysis.

[0019] In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations comprising, consisting of, or consisting essential of: (a) evaluating a tumor tissue sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations, in particular evaluating a tumor tissue sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a tissue based PCR or NGS assay, or evaluating a histopathological image of a tumor tissue from a patient with baldder cancer for the presence of one or more FGFR genetic alterations via digital histopathology analysis; and (b) delivering locally erdafitinib if the one or more FGFR genetic alterations, is present in the sample. In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment, wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a histopathological image of the tumor tissue via digital histopathology analysis.

[0020] In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment, 5sf-5754313MoFo Docket No.: 76166-20030.40 wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a histopathological image of the tumor tissue via digital histopathology analysis.

[0021] In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is locally delivered into the bladder of the patient and wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein the one or more FGFR alterations are detected in a histopathological image of the tumor tissue via digital histopathology analysis.

[0022] In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient comprising, consisting of, or consisting essential of (a) evaluating a tumor tissue sample from a patient with bladder cancer for the presence of one or more FGFR genetic alterations, in particular evaluating a tumor tissue sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a tissue based PCR or NGS assay, or evaluating a histopathological image of a tumor tissue from a patient with bladder cancer for the presence of one or more FGFR genetic alterations via digital histopathology analysis; and (b) delivering locally erdafitinib to the patient if the one or more FGFR genetic alterations, is present in the sample.

[0023] In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a histopathological image of the tumor tissue via digital histopathology analysis.

[0024] In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein eligibility of 6sf-5754313MoFo Docket No.: 76166-20030.40 the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a histopathological image of the tumor tissue via digital histopathology analysis.

[0025] In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient, wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein the one or more FGFR alterations are detected in a histopathological image of the tumor tissue via digital histopathology analysis.

[0026] In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient comprising, consisting of, or consisting essential of: (a) evaluating a tumor tissue sample from the patient with bladder cancer for the presence of the one or more FGFR genetic alterations, in particular evaluating a tumor tissue sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a tissue based PCR or NGS assay or evaluating a histopathological image of a tumor tissue from a patient with bladder cancer for the presence of one or more FGFR genetic alterations via digital histopathology analysis; and (b) delivering locally erdafitinib if the one or more FGFR genetic alterations, is present in the sample.

[0027] In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a histopathological image of the tumor tissue via digital histopathology analysis.

[0028] In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the 7sf-5754313MoFo Docket No.: 76166-20030.40 patient and wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a histopathological image of the tumor tissue via digital histopathology analysis. The methods or uses may include locally delivering or locally administering erdafitinib (such as in any of the formulations described herein) into the bladder of a patient in need of treatment, in particular a cancer patient, in an amount effective for the treatment of bladder cancer (e.g., from about 1-10 mg / day, as described herein). For example, the treatment may be effective at treating muscle invasive bladder cancer (MIBC), non-muscle invasive bladder cancer (NMIBC), and / or bacillus calmette-guérin (BCG)-naïve bladder cancer. In an aspect the patient, in particular a human, is a BCG-experienced bladder or NMIBC or MIBC cancer patient. In an aspect the patient, in particular a human, is a BCG- naïve bladder or NMIBC or MIBC cancer patient. In an aspect the patient, in particular a human, is a recurrent, bacillus Calmette-Guerin (BCG)-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient, refusing or ineligible for radical cystectomy (RCy). In an aspect the patient, in particular a human, is a recurrent, BCG-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient, scheduled for RCy. In an aspect the patient, in particular a human, is a recurrent, intermediate-risk NMIBC (Ta and T1) cancer patient with a previous history of only low-grade disease. In an aspect the patient, in particular a human, is a MIBC cancer patient scheduled for RCy who has refused or is ineligible for cisplatin- based neoadjuvant chemotherapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The detailed description is set forth with reference to the accompanying drawings. The use of the same reference numerals 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. Elements and / or components in the figures are not necessarily drawn to scale.

[0030] FIG. 1 is a longitudinal cross-sectional view of one embodiment of a drug delivery system in a coiled retention shape, in accordance with the present disclosure.

[0031] FIG. 2 is a traverse cross-sectional view of one embodiment of a drug delivery system, in accordance with the present disclosure.

[0032] FIG. 3 is a traverse cross-sectional view of one embodiment of a drug delivery system, in accordance with the present disclosure. 8sf-5754313MoFo Docket No.: 76166-20030.40

[0033] FIG. 4 is a photograph of one embodiment of a drug delivery system loaded with erdafitinib drug tablets, in accordance with the present disclosure.

[0034] FIG. 5 is a longitudinal cross-sectional view of one embodiment of a drug delivery system having an elastic retention frame and prior to loading with drug tablets, in a coiled retention shape, in accordance with the present disclosure.

[0035] FIG. 6A is a longitudinal cross-sectional view of one embodiment of an elastic retention frame in a coiled retention shape, in accordance with the present disclosure.

[0036] FIG. 6B is a partial magnified view of one end of the retention frame of FIG. 6A.

[0037] FIG. 7A is a perspective view of one embodiment of a drug delivery system, without drug disposed therein or an elastic retention frame, in a relatively straightened shape, in accordance with the present disclosure.

[0038] FIG. 7B is a longitudinal cross-sectional view of the drug delivery system shown in FIG. 7A, taken along line 7B-7B.

[0039] FIG. 7C is a traverse cross-sectional view of the drug delivery system shown in FIG. 7A, taken along line 7C-7C.

[0040] FIG. 8 is a photograph showing the cross-section of the drug reservoir lumen of a drug delivery system without drug disposed therein, in accordance with the present disclosure.

[0041] FIG. 9 shows single-dose erdafitinib exposures in plasma from nude rats bearing subcutaneous or orthotopic UM-UC-1 tumors. Exposure levels were measured in plasma from naïve, orthotopic bladder, or s.c. UM-UC-1 tumor-bearing nude rats. Rats were dosed with a single IVES (1-hour instillation) or p.o. dose of erdafitinib at the dose levels indicated. Individual data points are shown, with the mean represented by a horizontal line at each time point. IVES, intravesical; PO or p.o., oral; s.c., subcutaneous.

[0042] FIG. 10 demonstrates the effect of erdafitinib on ERK1 / 2 phosphorylation in orthotopic bladder UM-UC-1 tumors. Individual pERK and total ERK levels were measured from UM-UC-1 orthotopic bladder tumors from nude rats treated with vehicle, or a single IVES (1-hour instillation) or p.o. dose of erdafitinib at the dose levels indicated. pERK and total ERK levels are reported as a ratio (pERK / ERK) relative to the mean of the vehicle group for the corresponding timepoint, with the exception of the 120-hour timepoint, where values were normalized to the 48-hour vehicle group. Individual data points are shown, with the mean represented by a line at each time point. N=2-6 / group; ERK, extracellular signal-regulated kinase; IVES, intravesical; pERK, phosphorylated extracellular signal-regulated kinase; PO or p.o., oral.

[0043] FIG. 11 shows the size of orthotopic bladder UC tumor examples versus control bladder at 14 days post implantation. Formalin was used to fix tissue samples after necropsy. UC, urothelial carcinoma; NBTII, rat Nara Bladder Tumor No. 2 cells; T24, human bladder carcinoma cells. 9sf-5754313MoFo Docket No.: 76166-20030.40

[0044] FIG. 12 is a schematic of the perfusion experiment in athymic rats with UM-UC-1 implanted into the bladder wall.

[0045] FIG. 13 shows the percentage change in body weight of athymic, bladder- cannulated rats bearing orthotopic UM-UC-1 bladder tumors. Graph values are expressed as mean ± SEM of 10-13 animals in each group. Concentrations cited in the figure legend are nominal target urine concentrations. Statistical analysis was carried out by Two-way ANOVA followed by Bonferroni multiple comparison test using Graph Pad Prism (Version 8.3.0). Statistically non-significant difference when percentage change in body weight of erdafitinib (0.5, 1.0, and 5.0 !g / mL) treatment groups were compared with percentage change in body weight of the vehicle control group. SEM, standard error of the mean.

[0046] FIG. 14 shows the mean percentage tumor weight reduction after accounting for bladder weight without tumor. Values (Group 1-4) are expressed as mean ± SEM of 10-13 animals in each group. Statistical analysis was carried out by One-way ANOVA followed by Dunnett^s multiple comparisons test using Graph Pad Prism (Version 8.3.0). Conc, concentration; SEM, standard error of the mean.

[0047] FIG. 15 displays the percentage change in body weight of athymic, bladder- cannulated nude rats bearing orthotopic RT-112 bladder tumor. Values are expressed as mean ± SEM of 2-14 animals in each group. Concentrations cited in the figure legend are nominal target urine concentrations. Statistical analysis was carried out by Two-way ANOVA followed by Bonferroni multiple comparison test using Graph Pad Prism (Version 8.3.0). Statistically non-significant difference when percentage change in body weight of erdafitinib (0.5, 1.0, and 5.0 !g / mL) treatment groups were compared with percentage change in body weight of vehicle control group except Group 4 on Day 11 (*p<0.05). SEM, standard error of the mean.

[0048] FIG. 16 shows the mean bladder weight of athymic nude rats bearing orthotopic RT-112 bladder tumor. Values (Group 1-5) are expressed as mean ± SEM of 2-14 animals in each group. Statistical analysis was carried out by One-way ANOVA followed by Dunnett^s multiple comparisons test using Graph Pad Prism (Version 8.3.0). * p<0.05. Conc, concentration; SEM, standard error of the mean; ns, not significant.

[0049] FIGs. 17A and 17B show the plasma (FIG. 17A) and bladder (FIG. 17B) concentrations in rats following bladder perfusion of erdafitinib. Bladder perfusion of erdafitinib solution (0.1 mg / mL, 0.1 mL / hour, cumulative dose 0.72 mg) took place over 72 hours. Concentrations are expressed as average daily urine concentration in ng / mL.

[0050] FIG. 18 shows mean erdafitinib urine concentrations in pigs following bladder perfusion of erdafitinib for 7 days. Conc., concentration; SD, standard deviation.

[0051] FIG. 19 shows mean erdafitinib plasma concentrations in pigs following bladder perfusion of erdafitinib for 7 days. SD, standard deviation. 10sf-5754313MoFo Docket No.: 76166-20030.40

[0052] FIG. 20 shows the screening results of materials permeation. O, permeable; , practically impermeable; X, impermeable.aHigh variability between replicates.

[0053] FIG. 21 shows the predicted (from short core) and actual (from full-length) average release rate profiles for permeation prototypes. Erda, erdafitinib releasing intravesical system; HPbCD, hydroxypropyl !-cyclodextrin.

[0054] FIG. 22 displays the average release rate profile for erdafitinib free base + HP-!-CD permeation prototype (EG-80A stripe material). Erda, erdafitinib; HP-!-CD, hydroxypropyl !-cyclodextrin; SU, simulated urine.

[0055] FIG. 23 shows the average release rate profile for erdafitinib free base permeation prototypes, with and without HP-!-CD (HP-60D-35 stripe material). Erda, erdafitinib; HP-!-CD or HPbCD, hydroxypropyl !-cyclodextrin; SU, simulated urine.

[0056] FIG. 24 shows the IVR (in vitro release) profile for Prototype 1 (permeation, erdafitinib free base, tablets, wireform). Erda, erdafitinib; IVR, in vitro release.

[0057] FIG. 25 shows the IVR profile for Prototype 2 (permeation, erdafitinib free base + HP-!-CD (10% w / w), tablets, wireform). Erda, erdafitinib; HP-!-CD, hydroxypropyl !-cyclodextrin; IVR, in vitro release.

[0058] FIG. 26 summarizes the in vivo release rate versus time profiles in minipigs for Prototypes 1 and 2.

[0059] FIG. 27 summarizes the mean urine concentration versus time profiles in minipigs for Prototypes 1 and 2.

[0060] FIG. 28A is a diagram of an exemplary permeation system where the base material is impermeable TPU and the stripe material is permeable TPU.

[0061] FIG. 28B shows an overview of an exemplary permeation design. TPU or tPU, thermoplastic polyurethane; API, active pharmaceutical ingredient; HP-!-CD, hydroxypropyl !-cyclodextrin.

[0062] FIG. 29 provides an overview of the solubility of the erdafitinib free base drug as a function of pH at 20°C.aUSP / Ph. Eur. Terminology.

[0063] FIG. 30 demonstrates the solubility of the erdafitinib free base drug as a function of pH at 37°C using HCl to adjust the pH. Expon., exponential.

[0064] FIGs. 31A-31B shows the solubility of the erdafitinib free base drug and erdafitinib HCl salt Form 1 as a function of pH in simulated urine at 37°C (FIG. 31A), as well as the solubility of the erdafitinib free base drug as a function of pH in simulated urine at 37°C in mg / mL (FIG. 31B). HP-!-CD, hydroxypropyl !-cyclodextrin; Sim urine, simulated urine.

[0065] FIG. 32 is a schematic overview of the tissue assay and urine assay concordance study using paired samples from bladder cancer patients from the Bladder BRIDGister clinical trial in Germany. 11sf-5754313MoFo Docket No.: 76166-20030.40

[0066] FIG. 33 is a heat map of identified genetic alterations from matched urine NGS and FFPE tissue RT-PCR samples (bladder cancer patients from the Bladder BRIDGister clinical trial in Germany).

[0067] FIG. 34A is a scatter plot for the 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.

[0068] FIG. 34B is a scatter plot for the variant allele frequency (VAF) between matched urine NGS (X-axis) and tissue (^FFPE^) RT-PCR (Y-axis) variants for somatic FGFR3 alterations.

[0069] FIG. 35 shows a flow chart comparing urine test and tissue test performance from all screened patients with NMIBC (N=178) at cut-off date. Patients are from the first in human study as described in Example 9.

[0070] FIG. 36A is a swim lane plot showing clinical efficacy data (treatment duration and response) for disease-evaluable HR-NMIBC patients in Cohort 1, screened by urine sample assay and / or tumor tissue sample assay and treated with the intravesical drug delivery system TAR-210-B (about 2 mg / day erdafitinib) or TAR-210-D (about 4 mg / day erdafitinib). Patients are from the first in human study as described in Example 9. A key depicting patient enrollment (^Enrolled by^; left in the Figure) by tumor tissue sample assay (left in the key) or urine sample assay (right in the key) is included with associated check marks. Another key describing patient treatment status and milestones is included (right in the Figure).

[0071] FIG. 36B is a swim lane plot showing clinical efficacy data (treatment duration and response) for disease-evaluable IR-NMIBC patients in Cohort 3, screened by urine sample assay and / or tumor tissue sample assay and treated with the intravesical drug delivery system TAR-210-B (about 2 mg / day erdafitinib) or TAR-210-D (about 4 mg / day erdafitinib). Patients are from the first in human study as described in Example . A key depicting patient enrollment (^Enrolled by^; left in the Figure) by tumor tissue sample assay (left in the key) or urine sample assay (right in the key) is included with associated check marks. Another key describing patient treatment status and milestones is included (right in the Figure).

[0072] FIG. 37 depicts the landscape of pathogenic somatic variants for the 15 most prevalent genes detected in urine from all evaluable samples. Del = deletion; UTR = untranslated region; Ins = insertion; CNV = copy number variation. 12sf-5754313MoFo Docket No.: 76166-20030.40 DETAILED DESCRIPTION

[0073] In some embodiments, erdafitinib solid formulations are provided containing a high concentration of erdafitinib, which are designed for intravesical drug delivery and controlled and extended drug release when deployed within the bladder. In some embodiments, the solid erdafitinib formulations are further tailored for large scale manufacturing and to provide structural and chemical integrity of the solid formulations, in particular tablets, when used in an intravesical drug delivery system. Improved intravesical drug delivery systems, methods of manufacturing the same, and methods of drug delivery are also provided. In a particular embodiment, systems are configured for intravesical insertion and sustained drug delivery, preferably providing a zero order release rate of therapeutically effective amounts of the drug, in particular erdafitinib.

[0074] Described herein the development of erdafitinib formulations and release systems that are tailored for intravesical drug delivery, in order to take advantage of this route of administration. When formulated in solid form and administered in a suitable intravesical drug delivery system, such formulations might provide a controlled drug release rate and an extended drug release profile. Further provided are systems capable of delivering erdafitinib at effective release rates for the local treatment of bladder cancer.

[0075] Erdafitinib exhibits pH-dependent solubility over the normal urine pH range of 5.5 to 7. In some embodiments, the formulations and release systems are tailored to minimize the effect of urine pH and composition on system release rate.

[0076] In particular embodiments, the drug delivery system described herein is a drug device combination, consisting of a device constituent, particularly an intravesical device, and a drug constituent, particularly an erdafitinib formulation, such as erdafitinib tablets. Certain Terminology

[0077] Recurrence-Free Survival (RFS) is defined as the time from randomization to the first detection of high-grade Ta or T1 bladder cancer or positive urine cytology.

[0078] Complete Response (CR) is defined as the absence of urothelial carcinoma by cystoscopy, confirmed pathologically at first assessment, and negative urine cytology.

[0079] Duration of CR is defined as the time from first documentation of CR until the date of documented recurrence or progression, or death, whichever comes first.

[0080] Pathological Complete Response (pCR) Rate is defined as percentage of participants with no pathologic evidence of intravesical disease (pT0) and no pathologic evidence of nodal involvement (pN0).

[0081] No Pathologic Evidence of Intravesical Disease (pT0) rate is defined as percentage of participants with no Pathologic Evidence of Intravesical Disease.

[0082] Rate of downstaging to Less than (<) pT2 s defined as percentage of participants with pT stage <2. 13sf-5754313MoFo Docket No.: 76166-20030.40

[0083] When used herein wt% in relation to drug or excipient(s) refers to weight % based on the total weight of the formulation concerned, unless otherwise indicated. The Erdafitinib Formulation & Tablets

[0084] In one aspect, this disclosure provides erdafitinib formulations, in particular erdafitinib tablets suitable for use in the disclosed intravesical drug delivery system. In particular, drug tablets comprising erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'- (1-methylethyl)-N-[3-(l-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) are provided. As another example, drug tablets comprising erdafitinib HCl salt are provided. After the drug delivery system is inserted intravesically, the drug is released from the system into the bladder. In an aspect for example, the drug delivery system may operate by diffusion, which produces a continuous release of the drug into the bladder over an extended period as the drug is released from the tablets in the system.

[0085] In order to increase or maximize the amount of drug that can be stored in and released from the disclosed drug delivery system, the drug tablets can have a relatively high erdafitinib content by weight. This relatively high weight fraction of erdafitinib in the drug tablet is attended by a reduced or low weight fraction of excipients which may be required for tablet manufacturing and system assembly and drug use considerations. For the purposes of this disclosure, terms such as ^weight fraction,^ ^weight percentage,^ and ^percentage by weight^ with reference to any drug or API (active pharmaceutical ingredient) refers to the drug or API in the form employed, whether in free base form, free acid form, salt form, or hydrate form. For example, a drug tablet that has 90% by weight (90 wt%) of a drug or excipient in salt form may include less than 90% by weight of that drug in free base form. Unless otherwise specified, weight percentages are relative to the entire solid pharmaceutical composition.

[0086] The erdafitinib drug tablet of this disclosure includes an erdafitinib content and an excipient content. The drug content can include one form or more than one form of erdafitinib, such as free base or salt form, and the excipient content can include one or more excipients. Particular embodiments include erdafitinib free base API, and the example formulations presented herein comprise the erdafitinib free base API. The term ^excipient^ is 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, coatings, and preservatives, or any combination thereof, as well as other ingredients to facilitate manufacturing, storing, or administering the drug tablet.

[0087] Another aspect of this disclosure provides a process for making a solid pharmaceutical composition, in which the process can comprise: (a) preparing an intragranular solid composition comprising or consisting essentially of (i) erdafitinib free base and (ii) at least one intragranular pharmaceutical excipient; (b) combining the 14sf-5754313MoFo Docket No.: 76166-20030.40 intragranular solid composition with at least one extragranular pharmaceutical excipient to form a blend; and (c) tableting the blend to form the solid pharmaceutical composition. In embodiments, the erdafitinib free base can be present in a concentration of at least 45 wt% of the solid pharmaceutical composition. The at least one intragranular pharmaceutical excipient and at least one extragranular pharmaceutical excipient can comprise or can be selected from at least one common (mutually occurring) pharmaceutical excipient, or there can be no common (mutually occurring) pharmaceutical excipient between the intragranular excipients and the extragranular pharmaceutical excipients. The solid pharmaceutical composition can be made by a process that includes an intragranular solid composition prepared by a roller compaction process or by a fluid bed granulation process. In some embodiments, the step of (a) preparing an intragranular solid composition comprises: (1) preparing a pre-blend comprising the erdafitinib free base and one or more excipients; (2) preparing a binder solution; and (3) preparing the intragranular solid composition by combining the pre-blend and the binder solution. In some embodiments, the step of (a) preparing an intragranular solid composition comprises: (1) preparing a pre-blend comprising the erdafitinib free base and one or more excipients; (2) preparing a binder solution; and (3) preparing the intragranular solid composition by combining the pre-blend and the binder solution by a fluid bed granulation process. In some embodiments, the step of (a) preparing an intragranular solid composition comprises: (1) preparing a pre-blend comprising the erdafitinib free base with a stabilizer, a solubilizer, and a filler; (2) preparing a binder solution comprising a binder and a solvent; and (3) preparing the intragranular solid composition by combining the pre-blend and the binder solution by a fluid bed granulation process. In some embodiments, the step of (a) preparing an intragranular solid composition comprises: (1) preparing a pre-blend comprising the erdafitinib free base, meglumine, hydroxypropyl-beta-cyclodextrin, and microcrystalline cellulose; (2) preparing a binder solution comprising hydroxypropyl methylcellulose and purified water; and (3) preparing the intragranular solid composition by combining the pre-blend and the binder solution by a fluid bed granulation process. In some embodiments, the step of (a) preparing an intragranular solid composition comprises: (1) preparing a pre-blend comprising the erdafitinib free base with a solubilizer and a filler; (2) preparing a binder solution comprising a binder and a solvent; and (3) preparing the intragranular solid composition by combining the pre-blend and the binder solution by a fluid bed granulation process. In some embodiments, the step of (a) preparing an intragranular solid composition comprises: (1) preparing a pre-blend of the erdafitinib free base, hydroxypropyl-beta-cyclodextrin, and microcrystalline cellulose; (2) preparing a binder solution comprising hydroxypropyl methylcellulose and purified water; and (3) preparing the intragranular solid composition by combining the pre-blend and the binder solution by a fluid bed granulation process. 15sf-5754313MoFo Docket No.: 76166-20030.40

[0088] Another aspect of this disclosure provides a process for making a solid pharmaceutical composition, in which the process can comprise: (a) preparing an intragranular solid composition comprising or consisting essentially of (i) erdafitinib HCl salt form and (ii) 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) tableting the blend to form the solid pharmaceutical composition. In embodiments, the erdafitinib HCl salt form can be present in a concentration of at least 45 wt% of the solid pharmaceutical composition. The at least one intragranular pharmaceutical excipient and at least one extragranular pharmaceutical excipient can comprise or can be selected from at least one common (mutually occurring) pharmaceutical excipient, or there can be no common (mutually occurring) pharmaceutical excipient between the intragranular excipients and the extragranular pharmaceutical excipients. The solid pharmaceutical composition can be made by a process that includes an intragranular solid composition prepared by a roller compaction process or by a fluid bed granulation process.

[0089] In embodiments, the erdafitinib drug tablets includes erdafitinib in its free base form. Other embodiments of the erdafitinib drug tablets can include erdafitinib in a salt form. In one aspect, erdafitinib drug tablets can include greater than or equal to 40 wt% erdafitinib free base, with the remainder of the weight comprising excipients, such as lubricants, binders, and stabilizers that facilitate making and using the drug tablet. Alternatively, the erdafitinib drug tablets can include greater than or equal to 45 wt%, greater than or equal to 50 wt%, greater than or equal to 55 wt%, or greater than or equal to 60 wt% erdafitinib free base. In each of these weight percentage embodiments, the practical upper limit of erdafitinib free base in the tablet formulation is about 65 wt%, or 70 wt%. Therefore, in an aspect, the drug tablets can include from 40 wt% to 60 wt% of erdafitinib in its free base form, or from 45 wt% to 55 wt% of erdafitinib in its free base form. In some embodiments of the foregoing, the drug tablets can include between about 5% and about 15% by weight of hydroxypropyl-"-cyclodextrin (HP-"-CD). In some embodiments of the foregoing, the drug tablets can include about 10% by weight of hydroxypropyl-"- cyclodextrin (HP-"-CD). In embodiments, the drug tablets can include 50% by weight of erdafitinib in its free base form, based on the total weight of the tablet. In embodiments, the drug tablets can include 50% by weight of erdafitinib in its free base form, and between about 5% and about 15% by weight of hydroxypropyl-"-cyclodextrin (HP-"-CD) based on the total weight of the tablet. In embodiments, the drug tablets can include 50% by weight of erdafitinib in its free base form, and 10% by weight of hydroxypropyl-"-cyclodextrin (HP-"-CD) based on the total weight of the tablet.

[0090] In embodiments, the erdafitinib drug tablets includes erdafitinib in its HCl salt form. In one aspect, erdafitinib drug tablets can include greater than or equal to 40 wt% 16sf-5754313MoFo Docket No.: 76166-20030.40 erdafitinib HCl salt form, with the remainder of the weight comprising excipients, such as lubricants, binders, and stabilizers that facilitate making and using the drug tablet. Alternatively, the erdafitinib drug tablets can include greater than or equal to 45 wt%, greater than or equal to 50 wt%, greater than or equal to 55 wt%, or greater than or equal to 60 wt% erdafitinib HCl salt form. In each of these weight percentage embodiments, the practical upper limit of erdafitinib salt form in the tablet formulation is about 65 wt%, or 70 wt%. Therefore, in an aspect, the drug tablets can include from 40 wt% to 60 wt% of erdafitinib in its HCl salt form, or from 45 wt% to 55 wt% of erdafitinib in its HCl salt form. In embodiments, the drug tablets can include 50% by weight of erdafitinib in its HCl salt form, based on the total weight of the tablet.

[0091] In one embodiment, the erdafitinib drug and excipients are selected and the tablet is formulated to permit release of the drug from the tablet. In some embodiments, the erdafitinib drug and excipients are selected and the tablet is formulated to permit solubilization of the drug from the tablet. In embodiments, the erdafitinib is formulated in a pharmaceutical composition to be sterilizable, either within or outside of the drug delivery system, without resulting in substantial or detrimental changes to the chemical or physical composition of the drug tablets which would otherwise make them unsuitable for delivering the erdafitinib as described herein. In an aspect, the erdafitinib drug and excipients are selected for their suitability for sterilization processes. In an embodiment, the drug delivery system comprising the drug tablets is sterilized as a whole. In particular, the drug delivery system comprising the drug tablets is sterilized by gamma irradiation.

[0092] In an aspect, the erdafitinib drug tablets may be sized and shaped for use with an implantable drug delivery system including the intravesical drug delivery system disclosed herein. For example, the erdafitinib drug tablets may be ^mini-tablets^ that are generally smaller in size than conventional tablets, which may permit inserting the system-housed drug tablets through a lumen such as the urethra into a cavity such as the bladder. The erdafitinib tablets may be coated or uncoated. In particular, uncoated tablets formulated according to this disclosure have been found to work well in combination with the system.

[0093] In embodiments, the drug tablet for intravesical insertion or other in vivo implantation can be in the form of a solid cylinder having a cylindrical axis, a cylindrical side face, circular end faces perpendicular to the cylindrical axis, a diameter across the circular end faces, and a length along the cylindrical side face. In cylindrical form, each mini-tablet can have a length (L) exceeding its diameter (D) so 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 can be 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, or range in values between these aspect ratios. Embodiments of the mini-tablet can have a cylindrical diameter of from 1.0 mm to 3.2 mm, or from 1.5 mm to 3.1 mm, or from 2.0 mm to 2.7 mm, or from 2.5 mm to 2.7 mm. In some 17sf-5754313MoFo Docket No.: 76166-20030.40 aspects, the mini-tablet can have a length of from 1.7 mm to 4.8 mm, or from 2.0 mm to 4.5 mm, or from 2.8 mm to 4 mm, or from 3 mm to 3.5 mm.

[0094] The API used in the solid tablet formulations can be erdafitinib, which is N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l-methyl-1H-pyrazol-4-yl)quinoxalin- 6-yl]ethane-1,2-diamine, and the chemical structure of which is illustrated below. Erdafitinib tablets for use in the disclosed intravesical system can be formulated using the erdafitinib free base or a salt thereof. In an aspect, the erdafitinib tablets for use in the disclosed intravesical system can include erdafitinib free base. In an aspect, the erdafitinib tablets for use in the disclosed intravesical system can include erdafitinib HCl salt, particularly erdafitinib HCl salt which is in a crystalline form. In some embodiments of the foregoing, the erdafitinib tablets for use in the disclosed intravesical system can include erdafitinib free base which is in a crystalline form. As described herein, including certain stabilizers, solubilizers, and excipients in the erdafitinib free base formulation can provide advantageous stabilizing and dissolution properties for effective use of the free base formulation in the disclosed intravesical system.

[0095] In embodiments, the erdafitinib drug tablet can incorporate various excipients which include, but are 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, and the like, or any combination thereof. Any excipient or any combination of the excipients can be present in the intragranular solid composition, the extragranular solid composition, or both the intragranular and the extragranular solid composition. In an aspect, at least one intragranular pharmaceutical excipient and at least one extragranular pharmaceutical excipient can be the same, that is, can be selected from at least one common (mutually occurring) pharmaceutical excipient. In a further aspect, the intragranular pharmaceutical excipients and the extragranular pharmaceutical excipients do not comprise a common (mutually occurring) pharmaceutical excipient, such that the intragranular and the extragranular excipients are mutually exclusive. In embodiments, the erdafitinib drug tablet, in particular the erdafitinib drug tablet comprising from 40 wt% to 70 wt%, or from 40 wt% to 60 wt% , or from 45 wt% to 55 wt%, for example, 50 wt% of erdafitinib, includes at least one solubilizer, at least one binder, at least one stabilizer, at 18sf-5754313MoFo Docket No.: 76166-20030.40 least one diluent, at least one glidant, at least one lubricant, and the like, or any combination thereof. In embodiments, the erdafitinib drug tablet, in particular the erdafitinib drug tablet comprising from 40 wt% to 70 wt%, or from 40 wt% to 60 wt% , or from 45 wt% to 55 wt%, for example, 50 wt% of erdafitinib, includes at least one solubilizer, at least one binder, at least one diluent, at least one glidant, at least one lubricant, and the like, or any combination thereof.

[0096] It will be appreciated that these functional descriptions of various excipients are used generally as follows. A solubilizer can improve or enhance the solubility of the API such as erdafitinib free base within the drug lumen of the disclosed system or within a body cavity such as the bladder once the API is released from the system. A binder can hold the solid particles of the composition together for physical stability. A wetting agent can lower the surface tension between the drug and the medium in which it occurs and help maintain the solubility of the drug. A disintegrant can aid in the minitablet disintegration when contacting water to release the drug substance. A stabilizer can improve the chemical stability such as the thermal stability of the formulation, including the API, or protects the API against degradation. A diluent can function as a bulking agent to increase the volume or weight of the composition which may aid in providing tablet of the desired size or which may aid in tabletability of the API-excipient blend. A glidant may improve the flow properties of the (granulated) particles of tablet components or of the powder blend to be tableted. A lubricant can prevent particles of the composition from adhering to components of the manufacturing apparatus, such as dies and punches of a tablet press. In an aspect, an excipient can be water soluble. In another aspect, an excipient can be colloidal in water. According to another aspect, an excipient can be soluble under the conditions of its deployment in the patient, such as in a bladder. These and other excipients are described in more detail below. Stabilizers such as Formaldehyde Scavengers

[0097] In an aspect, erdafitinib API may be sensitive to degradation under certain conditions when incorporated into a solid formulation. For example, erdafitinib can degrade or transform in the presence of formaldehyde, to form the cyclization product 6,8-dimethoxy-4-(l-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 the erdafitinib from a variety of sources in the environment, such as from packaging materials or as a contaminant in excipients or other components of the formulation.

[0098] Accordingly, in one aspect, the erdafitinib pharmaceutical formulation can include a formaldehyde scavenger to improve the stability or shelf life of the formulation. Various formaldehyde scavengers can be employed which can prevent, slow down, diminish, or postpone the formation of degradation products when erdafitinib contacts formaldehyde. Therefore, the erdafitinib pharmaceutical formulation stability such as its 19sf-5754313MoFo Docket No.: 76166-20030.40 chemical stability can be increased in the presence of a formaldehyde scavenger as compared to a erdafitinib pharmaceutical formulations absent a formaldehyde scavenger. In an aspect, 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 solid composition. In an aspect, the formaldehyde scavenger, in particular meglumine, is present in the solid pharmaceutical composition as a component of the intragranular solid composition.

[0099] Formaldehyde scavengers can include or can be selected from compounds comprising a reactive nitrogen center, such as compounds containing amine or amide groups. Without being bound by theory, it is thought that these compounds can react with formaldehyde to form a Schiff base imine (R1R2C=NR3, where R3is not hydrogen), which itself can bind formaldehyde. Examples of such formaldehyde scavengers include but are not limited to amino acids, amino sugars, alpha-(a-)amine compounds, conjugates and derivatives thereof, and mixtures thereof. Such formaldehyde scavenger compounds can include two or more amine and / or amide moieties which can scavenge formaldehyde.

[0100] In an aspect, formaldehyde scavengers can include or can 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, pyrrolysine, asparagine, glutamine, tris(hydroxymethyl)aminomethane, conjugates thereof, pharmaceutically acceptable salts thereof, or any combination thereof. According to an aspect, the formaldehyde scavenger can include or can be selected from meglumine or a pharmaceutically acceptable salt thereof, in particular meglumine base.

[0101] Therefore, an aspect of this disclosure is the use of a formaldehyde scavenger, in particular meglumine, in an erdafitinib pharmaceutical formulation such as a drug tablet formulation, to increase the stability of erdafitinib in any of its forms, including erdafitinib free base, a salt thereof, or a solvate thereof. The chemical stability of the erdafitinib pharmaceutical formulation is increased as compared to an erdafitinib pharmaceutical formulation or composition containing no formaldehyde scavenger. An aspect of the disclosure is a method of preventing, slowing down, diminishing, or postponing the formation of degradation products such as the following compound, which can form from erdafitinib in the presence of formaldehyde:. 20sf-5754313MoFo Docket No.: 76166-20030.40 In an aspect, degradation products such as the above can occur in a solid tablet composition such as a mini-tablet formulation, in particular in a mini-tablet as disclosed herein.

[0102] When present in the erdafitinib solid pharmaceutical composition, the formaldehyde scavenger can be present in the solid pharmaceutical composition in a concentration of from 0.01 wt% to 5 wt%, from 0.05 wt% to 3 wt%, from 0.1 wt% to 2 wt%, from 0.5 wt% to 1.5 wt%, or about 1 wt%. In some embodiments, when present in the erdafitinib solid pharmaceutical composition, the formaldehyde scavenger can be present at a concentration of about 1 wt%. When present in the erdafitinib solid pharmaceutical composition, the formaldehyde scavenger can be present in the solid pharmaceutical composition in a concentration of, for example, from 5 wt% to 10 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt% or about 10 wt%. In some embodiments, the erdafitinib solid pharmaceutical composition contains erdafitinib free base, and the formaldehyde scavenger is present. In some embodiments, the erdafitinib solid pharmaceutical composition contains erdafitinib free base, and the formaldehyde scavenger is present in the solid pharmaceutical composition in a concentration of from 0.01 wt% to 5 wt%, from 0.05 wt% to 3 wt%, from 0.1 wt% to 2 wt%, from 0.5 wt% to 1.5 wt%, or about 1 wt%. In some embodiments, the erdafitinib solid pharmaceutical composition contains erdafitinib free base, and the formaldehyde scavenger is present in the solid pharmaceutical composition in a concentration of about 1 wt%. In some embodiments of any of the foregoing, the formaldehyde scavenger is meglumine.

[0103] In some embodiments, the pharmaceutical compositions as described herein, in particular the erdafitinib drug tablets, do not contain a stabilizer or formaldehyde scavenger. Solubilizers

[0104] In an aspect, the erdafitinib formulation can include a solubilizer. The solubilizer can be in the intragranular component, the extragranular component, or both the intragranular and extragranular component of the formulation. In embodiments, the solubilizer can comprise or can be selected from, for example (a) a cyclic oligosaccharide, (b) a cellulose which is functionalized with methoxy-, 2-hydroxypropoxy-, acetyl-, or succinoyl- moieties or a combination thereof, or (c) a salt thereof. In an embodiment, the solubilizer is present in the intragranular component.

[0105] In embodiments, solubilizers for the erdafitinib tablet formulation can comprise or can be selected from an oligosaccharide. In embodiments, the solubilizer can comprise or can be selected from a cyclic oligosaccharide such as a cyclodextrin. Suitable cyclodextrin solubilizers for the erdafitinib tablet formulation include, but are not limited to, hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether- beta-cyclodextrin sodium salt, , or any combination thereof. In other embodiments, the solubilizer can comprise or can be hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HPMC-E5), or a combination thereof. 21sf-5754313MoFo Docket No.: 76166-20030.40

[0106] Oligosaccharide solubilizers can be present in erdafitinib tablet formulation, for example a erdafitinib free base formulation, in a concentration of from 1 wt% to 20 wt%, alternatively from 3 wt% toalternatively from 5 wt% to 15 wt%, alternatively from 7 wt% to 12 wt%, or alternatively 10 wt% or about 10 wt%. The cyclodextrin solubilizer can be present in an erdafitinib tablet formulation, for example an erdafitinib free base formulation, in a concentration of 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, or 20 wt%, or any range between any of these weight percentages.

[0107] In an aspect, a solubilizer for the erdafitinib tablet formulation disclosed herein can comprise or can be hydroxypropyl-beta-cyclodextrin (HP-"-CD). One embodiment of an erdafitinib free base formulation includes a hydroxypropyl-beta-cyclodextrin solubilizer, in particular an erdafitinib free base formulation including hydroxypropyl-beta-cyclodextrin in from 8 wt% to 12 wt%, or alternatively, 10 wt% or about 10 wt% concentration. In some embodiments, the formulation comprises hydroxypropyl-beta-cyclodextrin at about 10 wt% concentration. In this formulation, the erdafitinib free base API can be present in a concentration of from 40 wt% to 70 wt%, or from 40 wt% to 60 wt% , or from 45 wt% to 55 wt%, for example, 50 wt%. In an embodiment, the hydroxypropyl-beta-cyclodextrin is present in the intragranular solid composition. In embodiments, the drug tablets can include 50% by weight of erdafitinib in its free base form, 1% by weight of meglumine, and hydroxypropyl-beta-cyclodextrin in from 8 wt% to 12 wt%, or alternatively, 10 wt% or about 10 wt% concentration. In embodiments, the drug tablets can include 50% by weight of erdafitinib in its free base form, 10% by weight of hydroxypropyl-"-cyclodextrin (HP-"-CD), and 1% by weight of meglumine based on the total weight of the tablet. In embodiments, the drug tablets can include at least about 45% by weight of erdafitinib in its free base form, 10% by weight of hydroxypropyl-"-cyclodextrin (HP-"-CD), and 0% by weight of meglumine based on the total weight of the tablet. In embodiments, the drug tablets can include 50% by weight of erdafitinib in its free base form, 10% by weight of hydroxypropyl-"-cyclodextrin (HP-"-CD), and 0% by weight of meglumine based on the total weight of the tablet. Binders

[0108] Pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more binders. The one or more binders 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 solid composition. Suitable binders can be water soluble, water insoluble, or slightly water soluble or combinations of these. In an aspect, binders can include polymeric binders such as water soluble polymeric binders, slightly water soluble polymeric binders, water 22sf-5754313MoFo Docket No.: 76166-20030.40 insoluble polymeric binders, or any combination thereof. Polymeric binders can include non-ionic polymers.

[0109] It will be appreciated by the person of ordinary skill that binders may also function as a diluent (also termed filler) in a pharmaceutical composition. Accordingly, binders provided in this disclosure may also be used for their diluent function as appropriate and unless otherwise indicated.

[0110] In an aspect, suitable binders can include or can be selected from polyvinyl- pyrrolidone (PVP, also termed polyvidone, povidone, or poly(1-vinyl-2-pyrrolidinone)), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO, also termed poly(ethylene glycol) or PEG), polypropylene oxide (PPO, also termed poly(propylene glycol) or PPG), an ethylene glycol-propylene glycol copolymer, a poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, silicified microcrystalline cellulose, or combinations thereof. In an aspect, suitable binders can include or can be selected from polyvinylpyrrolidone (PVP, also termed polyvidone, povidone, or poly(1-vinyl-2-pyrrolidinone)), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO, also termed poly(ethylene glycol) or PEG), polypropylene oxide (PPO, also termed poly(propylene glycol) or PPG), an ethylene glycol-propylene glycol copolymer, a poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, or combinations thereof. In an aspect, suitable binders can include or can be selected from hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, vinylpyrrolidone-vinyl acetate copolymer, or combinations thereof. In an aspect, suitable binders can include or can be selected from hydroxypropyl methylcellulose (HPMC), vinylpyrrolidone-vinyl acetate copolymer (copovidone), or combinations thereof. In some embodiments, the binder may be hydroxypropyl methylcellulose (HPMC). In some embodiments, the binder may be hydroxypropyl methylcellulose (HPMC) at a concentration of about 1.5 wt% of the solid composition. In some embodiments, the binder may be hydroxypropyl methylcellulose (HPMC) at 1.5 wt% of the solid composition, and is present in the intragranular solid composition.

[0111] In further aspects, suitable binders can include or can be selected from polymers of or copolymers of vinylpyrrolidone (VP, also 1-vinyl-2-pyrrolidinone) and vinyl acetate (VA). Such copolymers of VP and VA may also be referred to as ^copovidones^. Suitable binders also may include or may be selected from polymers of or copolymers of ethylene oxide (EO) and propylene oxide (PO). Again, these binders can be used in combinations with other binders such as in combination with microcrystalline cellulose, hydroxypropyl cellulose (HPC), or hydroxypropyl methylcellulose (HPMC).

[0112] In an aspect, the total concentration of the at least one binder in the solid pharmaceutical composition can be from 1 wt% to 30 wt%, from 2 wt% to 30 wt%, from 23sf-5754313MoFo Docket No.: 76166-20030.40 5 wt% to 30 wt%, from 5 wt% to 25 wt%, from 10 wt% to 25 wt%, from 10 wt% to 22 wt%, from 12 wt% to 22 wt%, from 14 wt% to 19 wt%, or from 12 wt% to 19 wt%.

[0113] According to another aspect, suitable polymeric binders can include or can be selected from a copolymer of vinylpyrrolidone and vinyl acetate, which can be termed poly(vinylpyrrolidone-co-vinyl acetate) or poly(VP-co-VA). Examples of suitable poly(vinylpyrrolidone-co-vinyl acetate) binders include Kollidon® VA64 and Kollidon® VA64 Fine (BASF, Ludwigshafen am Rhein, Germany), having a molecular weight (Mw) range of from 45,000 g / mol to 70,000 g / mol based on measuring the light scatter of a solution. Another suitable binder is Kollidon® K30.

[0114] In embodiments, the polymeric binders such as the vinylpyrrolidone-vinyl acetate copolymer can be present in the disclosed erdafitinib tablet formulation in a concentration of from 2 wt% to 15 wt%, alternatively from 4 wt% to 12 wt%, alternatively from 6 wt% to 10 wt%, or alternatively, 8 wt% or about 8 wt%. For example, the vinyl- pyrrolidone-vinyl acetate copolymer binder can be present in erdafitinib tablet formulation, for example a erdafitinib free base formulation, in a concentration of 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt% or any range between any of these weight percentages e.g., 7.5 wt%. In an aspect, the vinyl- pyrrolidone-vinyl acetate copolymer is present at a concentration of 8 wt% of the solid composition. In an aspect, the vinylpyrrolidone-vinyl acetate copolymer is present in the intragranular solid composition. In an aspect, the vinylpyrrolidone-vinyl acetate copolymer is present in the intragranular solid composition and said intragranular solid composition is prepared by roller compaction. In an aspect, the vinylpyrrolidone-vinyl acetate copolymer is present in the intragranular solid composition and said intragranular solid composition is prepared by fluid bed granulation. In an aspect, the vinylpyrrolidone-vinyl acetate copolymer is present in the extragranular solid composition. In an aspect, the vinyl- pyrrolidone-vinyl acetate copolymer is present at a concentration of about 7.5 wt% of the solid composition. In an aspect, the vinylpyrrolidone-vinyl acetate copolymer is present at a concentration of about 7.5 wt% of the solid composition, and is in the extragranular solid composition.

[0115] In an aspect, the binder can comprise or can be microcrystalline cellulose. For example, the microcrystalline cellulose can be present in the solid pharmaceutical composition in a concentration of from 5 wt% to 30 wt%, from 10 wt% to 20 wt%, from 5 wt% to 20 wt%, from 6 wt% to 15 wt%, or from 7 wt% to 12 wt%. For example, the microcrystalline cellulose can be present in the solid pharmaceutical composition as a filler and / or as a binder at a concentration of about 17.5 wt%. For example, the microcrystalline cellulose can be present in the solid pharmaceutical composition at a concentration of about 17.5% wt% of the solid composition and is present in the intragranular solid composition and extragranular solid composition. For example, the microcrystalline cellulose can be 24sf-5754313MoFo Docket No.: 76166-20030.40 present in the solid pharmaceutical composition as a filler in the intragranular composition, at a concentration of about 10 wt% of the solid composition, and can be present in the solid pharmaceutical composition as a binder in the extragranular composition, at a concentration of about 7.5 wt% of the solid composition.

[0116] According to another aspect, the binder can comprise or can be silicified microcrystalline cellulose. For example, the silicified microcrystalline cellulose can be present in the solid pharmaceutical composition in a concentration of from 3 wt% to 18 wt%, from 4 wt% to 15 wt%, or from 5 wt% to 12 wt%.

[0117] In a further aspect, the binder can comprise or can be hydroxypropyl methylcellulose (HPMC). For example, the hydroxypropyl methylcellulose (HPMC) can be present in the solid pharmaceutical composition in a concentration of from 0.25 wt% to 5 wt%, from 0.5 wt% to 4 wt%, or from 0.75 wt% to 3 wt%. In an aspect, the HPMC binder can be present in the solid pharmaceutical composition in the intragranular solid composition. Wetting Agents

[0118] Pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more wetting agents. The one or more wetting agents can 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 agent can comprise or can be selected independently from an anionic surfactant or a non-ionic surfactant, in particular an anionic surfactant. For example, the wetting agent can comprise or can be selected independently from sodium lauryl sulfate, sodium stearyl fumarate, a polysorbate, e.g., polysorbate 80, docusate sodium, or any combination thereof. In embodiments, the total concentration of the wetting agent in the solid pharmaceutical composition can be from 0.01 wt% to 2.5 wt%, from 0.05 wt% to 1.0 wt%, or from 0.1 wt% to 0.5 wt%. In an embodiment, the wetting agent is present in the intragranular solid composition. In an embodiment, the wetting agent is sodium lauryl sulfate.

[0119] In an embodiment, the erdafitinib solid pharmaceutical composition does not include one or more wetting agents. Disintegrants

[0120] Pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more disintegrants. The one or more disintegrants can be present in the solid pharmaceutical composition in the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular solid composition. In an embodiment, the disintegrant is present in the intragranular solid composition. In an embodiment, the disintegrant is present in the intragranular solid composition and said intragranular solid composition is prepared by roller compaction. 25sf-5754313MoFo Docket No.: 76166-20030.40

[0121] In exemplary embodiments, the disintegrant can comprise or can be selected independently from a functionalized polysaccharide or a crosslinked polymer. For example, in an aspect, the disintegrant can comprise or can be selected from, for example (a) a cellulose which is functionalized with methoxy-, 2-hydroxypropoxy-, or carboxymethoxy- moieties, a salt thereof, or a combination thereof, (b) a carboxymethylated starch, or (c) a crosslinked polymer.

[0122] In embodiments, the disintegrant can comprise or can be selected independently from hydroxypropyl methylcellulose, low-substituted hydroxypropylcellulose, crospovidone (crosslinked polyvinylpyrrolidone), croscarmellose sodium (cross-linked sodium carboxymethylcellulose), sodium starch glycolate, or any combination thereof.

[0123] When present, the disintegrant can be present in a range of concentrations. In embodiments, the total concentration of the disintegrant in the solid pharmaceutical composition can be from 0.1 wt% to 3 wt%, from 0.5 wt% to 2.5 wt%, from 1 wt% to 2 wt%, or about 1.5 wt%.

[0124] In an embodiment, the erdafitinib solid pharmaceutical composition does not include one or more disintegrants. Diluents or Fillers

[0125] Pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more diluents. The one or more diluents 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 solid composition.

[0126] In exemplary embodiments, diluents can comprise or can be selected from a sugar, starch, microcrystalline cellulose, a sugar alcohol, a hydrogen phosphate salt, a dihydrogen phosphate salt, a carbonate salt, or combinations thereof. In an aspect, diluents can comprise or can be selected from lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, anhydrous dibasic calcium phosphate, calcium carbonate, sucrose, or any combination thereof.

[0127] In embodiments, the total concentration of the diluent in the solid pharmaceutical composition can be from 10 wt% to 60 wt%, from 10 wt% to 50 wt%, from 10 wt% to 40 wt%, from 12 wt% to 30 wt%, from 15 wt% to 25 wt%, or from 18 wt% to 22 wt%, or from 20 wt% to 40 wt%, or from 20 wt% to 30 wt%, or from 25 wt% to 30 wt%. For example, in some aspects, the diluent can comprise or can be selected from microcrystalline cellulose in a concentration of from 15 wt% to 25 wt%, or from 20 wt% to 22 wt%, or from 15 wt% to 20 wt%. In a further aspect, the diluent can comprise or can be selected from anhydrous dibasic calcium phosphate in a concentration of from 18 wt% to 20 wt%. In a further aspect, the diluent can comprise or can be anhydrous dibasic calcium 26sf-5754313MoFo Docket No.: 76166-20030.40 phosphate in a concentration of about 19 wt%. In a further aspect, the diluent can comprise or can be anhydrous dibasic calcium phosphate in a concentration of about 19 wt%, which is present in the extragranular solid composition. In a further aspect, the diluent can comprise or can be selected from silicified microcrystalline cellulose in a concentration of from 10 wt% to 20 wt%, or from 10 wt% to 15 wt%, or from 10 wt% to 12 wt%. For example, the diluent can comprise silicified microcrystalline cellulose in a concentration of about 10.75 wt% or 11.75 wt% of the solid composition. For example, the diluent can comprise silicified microcrystalline cellulose in a concentration of about 10.75 wt% or 11.75 wt% of the solid composition and is present in the extragranular composition. For example, the diluent can comprise silicified microcrystalline cellulose in a concentration of about 10.75 wt% of the solid composition and is present in the extragranular composition. For example, the diluent can comprise silicified microcrystalline cellulose in a concentration of about 11.75 wt% of the solid composition and is present in the extragranular composition. In a further aspect, the diluent does not include silicified microcrystalline cellulose. In a further aspect, the diluent may comprise microcrystalline cellulose and silicified microcrystalline cellulose. In a further aspect, the diluent may comprise microcrystalline cellulose or silicified microcrystalline cellulose. In a further aspect, the diluent may comprise microcrystalline cellulose in a concentration of about 10 wt%. In a further aspect, the diluent may comprise microcrystalline cellulose in a concentration of about 10 wt%, which is present in the intragranular composition. For example, the microcrystalline cellulose can be present in the solid pharmaceutical composition as a filler and / or as a binder at a concentration of about 17.5 wt%. For example, the microcrystalline cellulose can be present in the solid pharmaceutical composition at a concentration of about 17.5% wt% of the solid composition and is present in the intragranular solid composition and extragranular solid composition. For example, the microcrystalline cellulose can be present in the solid pharmaceutical composition as a filler in the intragranular composition, at a concentration of about 10 wt% of the solid composition, and can be present in the solid pharmaceutical composition as a binder in the extragranular composition, at a concentration of about 7.5 wt% of the solid composition.

[0128] It will be appreciated by the person of ordinary skill that some of the diluents / fillers disclosed herein may also function as binders in the pharmaceutical composition. Accordingly, some compounds or materials may be described herein as providing a binder function and providing a diluent / filler function. Glidants

[0129] Pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more glidants. The one or more glidants 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 solid 27sf-5754313MoFo Docket No.: 76166-20030.40 composition. In an aspect, the glidant is present in the extragranular solid composition. As used in this disclosure, a glidant refers to a pharmaceutical excipient which improves or optimizes the particle flow properties of the granulated or powdered tablet components in particle form by decreasing the interaction, attraction, cohesion, or friction between particles. Pharmaceutically acceptable glidants are non-toxic and pharmacologically inactive substances. Further, the glidants can be water soluble or water insoluble.

[0130] In an aspect, glidants can include or can 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 can be from 0.01 wt% to 5 wt%, 0.05 wt% to 3 wt%, 0.1 wt% to 1 wt%, or about 0.2 wt%, or about 0.25 wt%, or about 0.3 wt%, about 0.35 wt%, or about 0.4 wt%, or about 0.45 wt% or about 0.5 wt%. In an embodiment, the glidant is colloidal silicon dioxide. In some embodiments, the glidant is colloidal silicon dioxide at about 0.5 wt% of the solid composition. In some embodiments, the glidant is colloidal silicon dioxide at about 0.5 wt% of the solid composition, and is present in the extragranular composition. In some embodiments, the glidant is colloidal silicon dioxide at about 0.25 wt% of the solid composition. In some embodiments, the glidant is colloidal silicon dioxide at about 0.25 wt% of the solid composition, and is present in the extragranular composition. Lubricants

[0131] Pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more lubricants. The one or more lubricants 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 solid composition. In an aspect, the lubricant is present in the extragranular solid composition. In an aspect, the lubricant is present in the intragranular solid composition, and said intragranular solid composition is prepared by roller compaction. As used in this disclosure, a lubricant refers to a pharmaceutical excipient added to a tablet formulation which reduces friction at the tablet^s surface. In embodiments, the lubricant can reduce friction between a tablet^s surface and processing equipment, e.g., between a tablet^s surface and the wall of a die cavity in which a tablet is formed. Therefore, a lubricant can reduce friction between a die wall and the granules of the formulation as the tablet is formed and ejected. Pharmaceutically acceptable lubricants are non-toxic and pharmacologically inactive substances. Further, the lubricants can be water soluble or water insoluble.

[0132] In an aspect, the lubricant can comprise or can 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 can comprise or can be selected from magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactate, sodium stearoyl fumarate, titanium 28sf-5754313MoFo Docket No.: 76166-20030.40 dioxide, or combinations thereof. Examples of 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 can be from 0.05 wt% to 5 wt%, 0.1 wt% to 3 wt%, 1 wt% to 2 wt%, or about 1.5 wt%. In an embodiment, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate, and is present in the intragranular composition or the extragranular composition. In some embodiments, the lubricant is magnesium stearate, and is present in the intragranular composition and the extragranular composition. In some embodiments, the lubricant is magnesium stearate at about 1.5 wt% of the solid composition. In some embodiments, the lubricant is magnesium stearate at about 1.5 wt% of the solid composition, and is present in the intragranular composition. In some embodiments, the lubricant is magnesium stearate at about 1.5 wt% of the solid composition, and is present in the extragranular composition. In some embodiments, the lubricant is magnesium stearate at about 1.5 wt% of the solid composition, and is present in the intragranular composition and the extragranular composition. Formulation Development

[0133] Provided herein are erdafitinib formulations, in particular erdafitinib tablets, that (a) comprise a high erdafitinib drug load, such as ranging from 40 wt% to 70 wt%, or from 40 wt% to 60 wt% , or from 45wt% to 55 wt%, or about 50 wt%, or ranging from 45wt% to 55 wt%, or about 50 wt%, (b) provide for an acceptable chemical stability of erdafitinib, (c) support high production speeds for tablet production, e.g., on an industrial scale, in particular tablets having a length (L) that exceeds its diameter (D) so that the tablet has an aspect ratio (L:D) of greater than 1:1, in particular such tablets having a cylindrical diameter of from 1.0 mm to 3.2 mm, or from 1.5 mm to 3.1 mm or from 2.0 mm to 2.7 mm or from 2.5 mm to 2.7 mm, in particular on an industrial scale, in particular for minitablets, (d) provide a tablet that is sufficiently robust physically, in particular is suitable for being included in a drug delivery system as described herein, in particular a permeation system, and / or (e) exhibits desired disintegration and / or dissolution properties.

[0134] Erdafitinib formulations with a range of excipient combinations, both intragranular and extragranular, are provided in Table 1 in the Examples which sets out Formula 4A, Formula 4B, Formula 4C, and Formula 4D. Further erdafitinib formulations with a range of excipient combinations, are provided in Table 3 and in the Examples which set forth formulations 3.2, 3.3, 3.4, and 4.1.

[0135] Provided herein are erdafitinib solid formulations, in particular erdafitinib minitablets, in particular with a high erdafitinib drug load, such as ranging from 40 wt% to 70 wt%, or from 40 wt% to 60 wt% , or from 45wt% to 55 wt%, or about 50 wt%, or ranging from 45wt% to 55 wt%, or about 50 wt%. In an embodiment the tablets are 29sf-5754313MoFo Docket No.: 76166-20030.40 obtainable by a process that comprises fluid bed granulation. In an embodiment the tablets are obtainable by a process that comprises roller compaction. In an embodiment the intragranular solid composition comprises a cyclodextrin, in particular hydroxypropyl-beta- cyclodextrin. In an embodiment the formulation does not comprise mannitol in the intragranular solid composition. In an embodiment, the intragranular solid composition does not comprise a water soluble filler. In an embodiment, the formulation comprises a water insoluble filler, such as for example microcrystalline cellulose.

[0136] In an embodiment, there is provided a fluid bed granulation process for making granules comprising erdafitinib and hydroxypropyl-beta-cyclodextrin. In an aspect, the process does not comprise using a water soluble filler such as mannitol.

[0137] Provided herein are erdafitinib solid formulations, in particular erdafitinib minitablets, in particular with a high erdafitinib drug load, such as ranging from 45wt% to 55 wt%, or about 50 wt% comprising vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose, in particular in a weight ratio ranging from 1:99 to 99:1, or from 5:95 to 95:5, or from 10:90 to 90:10, or from 20:80 to 80:20, or from 30:70 to 70:30, or from 40:60 to 60: 40 or 50:50. It was unexpectedly found that ejection forces during tableting, in particular tableting of mini-tablets, such as those described herein, were reduced in the presence of this mixture. It was found that a powder formulation comprising such a mixture had good flow properties. In an aspect the formulation further comprises hydroxypropyl-beta-cyclodextrin. In an aspect the formulation does not comprise mannitol.

[0138] In an embodiment, a process is provided for making tablets, in particular minitablets as described herein, wherein the powder blend to be tableted comprises vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose, in particular in a weight ratio ranging from 1:99 to 99:1, or from 5:95 to 95:5, or from 10:90 to 90:10, or from 20:80 to 80:20, or from 30:70 to 70:30, or from 40:60 to 60: 40 or 50:50. In an aspect, there is provided a process for making tablets, in particular minitablets as described herein, wherein the powder blend to be tableted comprises erdafitinib, vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose, in particular wherein the weight ratio of vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose ranges from 1:99 to 99:1, or from 5:95 to 95:5, or from 10:90 to 90:10, or from 20:80 to 80:20, or from 30:70 to 70:30, or from 40:60 to 60: 40 or 50:50. In an aspect, the powder blend to be tableted further comprises hydroxypropyl-beta-cyclodextrin. In an aspect, the powder blend to be tableted does not comprise mannitol.

[0139] Provided herein are erdafitinib solid formulations, in particular erdafitinib powder formulations or erdafitinib minitablets, in particular with a high erdafitinib drug load, such as ranging from 40 wt% to 70 wt%, or from 40 wt% to 60 wt% , or from 45wt% to 55 wt%, or about 50 wt%, or ranging from 45wt% to 55 wt%, or about 50 wt% having a low content of fine particles, such as for example a content of fine particles below 20%, or 30sf-5754313MoFo Docket No.: 76166-20030.40 below 10 %, or below 5 %, or about or below 3 %, or about or below 2%. Fine particles can increase the ejection forces during tableting, especially during tableting of minitablets as described herein, in particular when tableting at a high speed, such as for example 2500 tablets / minute.

[0140] In an embodiment, provided herein is a formulation, in particular a tablet or minitablet, comprising erdafitinib, in particular with a high erdafitinib drug load, such as ranging from 40 wt% to 70 wt%, or from 40 wt% to 60 wt% , or from 45wt% to 55 wt%, or about 50 wt%, or ranging from 45wt% to 55 wt%, or about 50 wt%, hydroxypropyl-beta- cyclodextrin, vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose. In an aspect, the formulation further comprises meglumine. In an aspect, the formulation does not comprise mannitol. In an aspect the formulation further comprises at least one or all of a glidant, such as for example colloidal silica, a lubricant, such as for example magnesium stearate, a binder such as for example a cellulose derivative, such as hydroxypropyl methylcellulose, a filler, such as for example silicified microcrystalline cellulose.

[0141] In an embodiment, provided herein is a formulation, in particular a tablet or minitablet, comprising erdafitinib, in particular with a high erdafitinib drug load, such as ranging from 40 wt% to 70 wt%, or from 40 wt% to 60 wt% , or from 45wt% to 55 wt%, or about 50 wt%, or ranging from 45wt% to 55 wt%, or about 50 wt%, hydroxypropyl-beta- cyclodextrin, vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose. In an aspect, the formulation further comprises at least one or all of a glidant, such as for example colloidal silica, a lubricant, such as for example magnesium stearate, a binder such as for example a cellulose derivative, such as hydroxypropyl methylcellulose, a filler, such as for example silicified microcrystalline cellulose. In an aspect, the formulation does not comprise a stabilizer, such as meglumine. In an aspect, the formulation does not comprise mannitol.

[0142] In an embodiment, the formulation is Formula 4A. In an embodiment, the formulation is Formula 4B. In an embodiment, the formulation is Formula 4C. In an embodiment, the formulation is Formula 4D.

[0143] Accordingly, Formula 4D formulation is encompassed by this disclosure, in which the solid pharmaceutical composition includes: (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 17.5 wt% microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25 wt% colloidal silicon dioxide; (h) 1.5 wt% hydroxypropyl methylcellulose; and (i) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In an aspect, this formulation can be prepared by a process comprising (a) preparing an intragranular solid composition by a fluid bed granulation process, the intragranular solid composition consisting essentially of: (i) erdafitinib free base in a concentration of 50 wt% 31sf-5754313MoFo Docket No.: 76166-20030.40 of the solid pharmaceutical composition; (ii) hydroxypropyl-beta-cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition; (iii) meglumine in a concentration of 1 wt% of the solid pharmaceutical composition; (iv) microcrystalline cellulose in a concentration of 10 wt% of the solid pharmaceutical composition; and (v) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the solid pharmaceutical composition; (b) combining the intragranular solid composition with extragranular components to form a blend, wherein the extragranular components consist essentially of: (i) microcrystalline cellulose in a concentration of 7.5 wt% of the solid pharmaceutical composition; and (ii) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.5 wt% of the solid pharmaceutical composition; (iii) silicified microcrystalline cellulose in a concentration of 10.75 wt% of the solid pharmaceutical composition; (iv) colloidal silicon dioxide in a concentration of 0.25 wt% of the solid pharmaceutical composition; and (iv) magnesium stearate in a concentration of 1.5 wt% of the solid pharmaceutical composition; and (c) tableting the blend to form of a solid pharmaceutical composition in the form of mini-tablets. In an embodiment, the tablet comprises 11.5 mg of erdafitinib.

[0144] Accordingly, Formula 4C formulation is encompassed by this disclosure, in which the solid pharmaceutical composition includes: (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 1.5 wt% hydroxypropyl methylcellulose; (e) 21.0 wt% mannitol; (f) 0.25 wt% sodium lauryl sulfate; (g) 7.25 wt% microcrystalline cellulose; (h) 7.25 wt% vinylpyrrolidone-vinyl acetate copolymer; (i) 0.25 wt% colloidal silicon dioxide; and (j) 1.50 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In an aspect, this formulation may be prepared by a process comprising (a) preparing an intragranular solid composition by a fluid bed granulation process; (b) combining the intragranular solid composition with extragranular components to form a blend; and (c) tableting the blend to form a solid pharmaceutical composition in the form of mini-tablets, in which the intragranular and the extragranular components are set out in the Examples in Table 1. In an embodiment, the tablet comprises 11.5 mg of erdafitinib.

[0145] Accordingly, Formula 4B formulation is encompassed by this disclosure, in which the solid pharmaceutical composition includes (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 24.5 wt% microcrystalline cellulose; (e) 6.0 wt% silicified microcrystalline cellulose; (f) 6.0 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 2.0 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In an aspect, this formulation may be prepared by a process comprising (a) preparing an intragranular solid composition by a fluid bed granulation process; (b) combining the intragranular solid composition with extragranular components to form a blend; and (c) tableting the blend to form of a solid pharmaceutical 32sf-5754313MoFo Docket No.: 76166-20030.40 composition in the form of mini-tablets, in which the intragranular and the extragranular components are set out in the Examples in Table 1. In an aspect, this formulation may be prepared by a process comprising (a) preparing an intragranular solid composition by a roller compaction process; (b) combining the intragranular solid composition with extragranular components to form a blend; and (c) tableting the blend to form of a solid pharmaceutical composition in the form of mini-tablets, in which the intragranular and the extragranular components are set out in the Examples in Table 1. In an embodiment, the tablet comprises 11.5 mg of erdafitinib.

[0146] Accordingly, Formula 4A formulation is encompassed by this disclosure, in which the solid pharmaceutical composition includes (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 10 wt% microcrystalline cellulose; (e) 19 wt% anhydrous dibasic calcium phosphate; (f) 8 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 1.50 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In an aspect, this formulation may be prepared by a process comprising (a) preparing an intragranular solid composition by a fluid bed granulation process; (b) combining the intragranular solid composition with extragranular components to form a blend; and (c) tableting the blend to form a solid pharmaceutical composition in the form of mini-tablets, in which the intragranular and the extragranular components are set out in the Examples in Table 1. In an aspect, this formulation may be prepared by a process comprising (a) preparing an intragranular solid composition by a roller compaction process; (b) combining the intragranular solid composition with extragranular components to form a blend; and (c) tableting the blend to form a solid pharmaceutical composition in the form of mini-tablets, in which the intragranular and the extragranular components are set out in the Examples in Table 1. In an embodiment, the tablet comprises 11.5 mg of erdafitinib.

[0147] Accordingly, Formulation 4.1 is encompassed by the disclosure, in which the solid pharmaceutical composition includes: (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In an aspect, this formulation can be prepared by a process comprising (a) preparing an intragranular solid composition by a fluid bed granulation process, the intragranular solid composition consisting essentially of: (i) erdafitinib free base in a concentration of 50 wt% of the solid pharmaceutical composition; (ii) hydroxypropyl-beta-cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition; (iii) microcrystalline cellulose in a concentration of 10 wt% of 33sf-5754313MoFo Docket No.: 76166-20030.40 the solid pharmaceutical composition; and (iv) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the solid pharmaceutical composition; (b) combining the intragranular solid composition with extragranular components to form a blend, wherein the extragranular components consist essentially of: (i) microcrystalline cellulose in a concentration of 7.5 wt% of the solid pharmaceutical composition; and (ii) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.5 wt% of the solid pharmaceutical composition; (iii) silicified microcrystalline cellulose in a concentration of 11.75 wt% of the solid pharmaceutical composition; (iv) colloidal silicon dioxide in a concentration of 0.25 wt% of the solid pharmaceutical composition; and (iv) magnesium stearate in a concentration of 1.5 wt% of the solid pharmaceutical composition; and (c) tableting the blend to form of a solid pharmaceutical composition in the form of mini- tablets. In an embodiment, the tablet comprises 11.5 mg of erdafitinib. Diffusion-Based Drug Delivery Systems

[0148] Drug delivery systems particularly suitable for the effective release of drug formulations containing erdafitinib, such as those described in detail above or hereinafter, are described herein. These particular systems have been developed wherein, instead of an osmotic drug release mechanism, drug release is controlled by drug diffusion through a drug-permeable polymer component defining part of the system housing.

[0149] In certain embodiments, the system includes a drug-permeable polymer component or portion that forms a portion of the housing. For example, the drug-permeable component or portion of the system may be a portion of the housing formed of a material distinct from the remaining portion of housing (e.g., a strip or multiple strips of material extending along at least a portion of the length of the housing), such that the size, shape (e.g., arc angle), thickness, and material properties of the drug-permeable wall structure may be selected to achieve the desired drug release rate. In certain embodiments, the drug permeable portion, the drug impermeable portion, or both the drug permeable and impermeable portions are formed of thermoplastic polyurethane compositions, to provide (i) controlled diffusion of the drug from the system, (ii) desired mechanical properties (e.g., able to be straightened for insertion / removal, soft enough to be well-tolerated while indwelling, tubing remains intact with small compressions / extensions, elastic deformability in response to detrusor muscle contraction (compliancy)), (iii) a system that may be thermally shape set to have a desired retention shape, and / or (iv) a system which may be manufactured in a coextrusion process.

[0150] In some embodiments, the drug permeable portion is permeable to erdafitinib free base. In some embodiments, the drug permeable portion is permeable to erdafitinib free base and erdafitinib free base formulated with HP-"-CD. In some embodiments, the drug permeable portion is permeable to erdafitinib free base, erdafitinib HCl salt, and erdafitinib free base formulated with HP-"-CD. In some embodiments of any of the foregoing, the 34sf-5754313MoFo Docket No.: 76166-20030.40 material of the drug permeable portion is an aliphatic polyether-based TPU. In some embodiments of the foregoing, the material of the drug permeable portion is an aliphatic polyether-based TPU which is Lubrizol Tecophilic HP-60D-35 or HP-93A-100.

[0151] In some embodiments, the drug permeable portion is permeable to erdafitinib free base formulated with HP-"-CD. In some embodiments, the drug permeable portion is permeable to erdafitinib free base formulated with HP-"-CD, and is impermeable or practically impermeable to erdafitinib free base formulated without HP-"-CD. In some embodiments of any of the foregoing, the material of the drug permeable portion is an aliphatic polyether-based TPU. In some embodiments of the foregoing, the material of the drug-permeable portion is Lubrizol Tecoflex EG-80A.

[0152] Exemplary materials for the drug-permeable portion (e.g., the ^stripe^ material of the permeation system) include, but are not limited to, aliphatic polyether-based thermoplastic polyurethanes (TPUs) such as Lubrizol Tecophilic HP-60D-35, Tecophilic HP-93A-100, and Tecoflex EG-80A. In some embodiments, the material of the drug- permeable portion is Lubrizol Tecophilic HP-60D-35, Tecophilic HP-93A-100, or Tecoflex EG-80A. In some embodiments, the material of the drug-permeable portion is Lubrizol Tecoflex EG-80A. In some embodiments, the drug is erdafitinib free base, and the material of the drug-permeable portion is Lubrizol Tecophilic HP-60D-35 or Tecophilic HP-93A-100. In some embodiments, the drug is erdafitinib free base, the drug is formulated with HP-"-CD, and the material of the drug-permeable portion is Lubrizol Tecophilic HP-60D-35, Tecophilic HP-93A-100, or Tecoflex EG-80A. In some embodiments, the drug is erdafitinib free base, the drug is formulated with HP-"-CD, and the material of the drug- permeable portion is Lubrizol Tecoflex EG-80A. In some embodiments, the drug is erdafitinib HCl salt, and the material of the drug-permeable portion is Lubrizol Tecophilic HP-60D-35 or Tecophilic HP-93A-100.

[0153] Exemplary materials for the drug-impermeable portion (e.g., the ^base^ material of the permeation system) include, but are not limited to, silicone elastomer materials such as NuSil MED-4750; TPUs such as Lubrizol Carbothane Aliphatic PC-3575A, Tecothane Soft AR-62A, AR-75A-B20, AC-4075A-B20, Carbothane Aromatic AC-4075A, Tecothane TT-1074A, Tecoflex EG-80A; and ethylene vinyl acetate such as 3M CoTran 9712. In some embodiments, the material of the drug-impermeable portion is selected from MED-4750, PC-3575A, PC-3575A, AR-62A, AR-75A-B20, AC-4075A-B20, AC-4075A, TT-1074A, EG-80A, and CoTran 9712. In some embodiments, the material of the drug-impermeable portion is selected from MED-4750, PC-3575A, PC-3575A, AR-62A, AR-75A-B20, AC-4075A-B20, AC-4075A, TT-1074A, and CoTran 9712. In some embodiments, the material of the drug-impermeable portion is AR-75A-B20. In some embodiments, the material of the drug-impermeable portion is AC-4075A-B20. 35sf-5754313MoFo Docket No.: 76166-20030.40

[0154] In some embodiments, the material of the drug-permeable portion is EG-80A, and the material of the drug-impermeable portion is AR-75A-B20. In some embodiments, the material of the drug-permeable portion is EG-80A, and the material of the drug- impermeable portion is AC-4075A-B20.

[0155] It is to be understood that Lubrizol Tecophilic HP series materials are aliphatic polyether-based TPUs formulated to absorb equilibrium water contents of up to 100% of the weight of dry resin, designed for extrusion but also processable by injection molding. HP-60D-35 has a shore hardness of about 42D (ASTM D2240), specific gravity of about 1.12 (ASTM D792), flexural modulus (psi) of 4000 (ASTM D790), ultimate tensile (psi) of about 7,800 dry and 4900 wet (ASTM D412), ultimate elongation (%) of about 450 dry and 390 wet (D412); and water absorption (% by Lubrizol Method) of about 35. HP-93A-100 has a shore hardness of about 83A (ASTM D2240), specific gravity of about 1.13 (ASTM D792), flexural modulus (psi) of 2900 (ASTM D790), ultimate tensile (psi) of about 2200 dry and 1400 wet (ASTM D412), ultimate elongation (%) of about 1040 dry and 620 wet (D412); and water absorption (% by Lubrizol Method) of about 100.

[0156] It is to be understood that Lubrizol Tecoflex materials are aliphatic polyether- based TPUs processable by extrusion and injection molding. EG-80A has a shore hardness of about 72A (ASTM D2240), specific gravity of about 1.04 (ASTM D792), flexural modulus (psi) of 1,000 (ASTM D790), ultimate tensile (psi) of about 5,800 (ASTM D412), ultimate elongation (%) of about 660 (D412); tensile modulus (psi) of about 300 at 100% elongation, about 500 at 200% elongation, and about 800 at 300% elongation (ASTM D412); and mold shrinkage (in / in) of about 0.008-0.012 (ASTM D955).

[0157] It is to be understood that Lubrizol Aromatic Carbothane AC series materials are radiopaque (20% BaSO4filled) polycarbonate-based aromatic TPUs, processable by extrusion or injection molding. AC-4075A-B20 has a shore hardness of about 78A (ASTM D2240), specific gravity of about 1.38 (ASTM D792), ultimate tensile (psi) of about 8300 (ASTM D412), ultimate elongation (%) of about 400 (D412); tensile modulus (psi) of about 560 at 100% elongation, about 1300 at 200% elongation, and about 3400 at 300% elongation (ASTM D412); flexural modulus (psi) of about 1800, Vicat temperature (°C) of about 55, and mold shrinkage (in / in) (1^x0.25^x6^ bar) of about 0.011 (ASTM D955).

[0158] It is to be understood that Lubrizol Tecothane Soft materials are aromatic polyester hydrocarbon-based TPUs, processable by extrusion or injection molding. AR-75A has a shore hardness of about 79A (ASTM D785), a specific gravity of about 1.03 (ASTM D792), ultimate tensile (psi) of about 2000 (ASTM D412), ultimate elongation (%) of about 530 (ASTM D412), tensile modulus (psi) of about 730 at 100% elongation, about 1000 at 200% elongation, and about 1300 at 300% elongation (ASTM D412); flexural modulus (psi) of about 2500 (ASTM 790); Vicat softening point (°C) of about 75; and mold 36sf-5754313MoFo Docket No.: 76166-20030.40 shrinkage (in / in) (1^x0.25^x6^ bar) of about 0.08 (ASTM D955). AR-75A-B20 is 20% BaSO4 filled AR-75A, and can be manufactured, for example, by Compounding Solutions.

[0159] It is to be further understood that abovementioned test results for the Lubrizol Tecophilic HP. Tecoflex, Aromatic Carbothane AC, and Tecothane Soft materials are approximated based on small samples of TPU; therefore the properties of these materials may exhibit slight variation from the properties listed herein.

[0160] In one aspect, as shown in FIG. 1, a drug delivery system 100 is provided that includes a tubular housing having a drug reservoir lumen 106 bounded by a wall structure 104, wherein (i) at least a portion of the wall structure 104 is water permeable, and (ii) at least a portion of the wall structure is permeable to the drug (contained in drug unit 108) such that the drug is releasable in vivo by diffusion through the drug permeable portion of the wall structure 104. In certain embodiments, as discussed in further detail below, the wall structure includes first and second wall structures that together form the housing. As used herein, the phrase ^diffusion through the drug permeable portion^ (e.g., through the ^second wall structure^) refers to the drug being released by passing through the material forming the wall by molecular diffusion, and not by passing through an aperture or open structure extending through that wall.

[0161] In one aspect, as shown in FIG. 2, a drug delivery system 200 is provided that includes a housing with a first wall structure 206 formed from a first material and a second wall structure 205 formed from a second material, which are adjacent one another and together form a tube defining a drug reservoir lumen 208, wherein (i) the second wall structure 205, or both the first wall structure 206 and the second wall structure 205, are permeable to water, and (ii) the first wall structure 206 is impermeable to the drug and the second wall structure 205 is permeable to the drug, such that the drug is releasable in vivo by diffusion through the second wall structure 205. As used herein, the term ^impermeable to the drug^ refers to the wall being substantially impermeable to the solubilized drug, such that no substantial amount of the solubilized drug can diffuse therethrough over the therapeutic period in which the system is located in vivo.

[0162] In certain embodiments, the tube is cylindrical or another suitable shape or design. As used herein, the term ^cylindrical,^ when used in reference to the tubular housing, refers to the housing having a substantially cylindrical outer wall. In some embodiments, the system is ^closed^ and therefore does not include an aperture; drug release is only by diffusion through the second wall structure.

[0163] In some embodiments, as shown in FIGs. 2 and 3, the first wall structure 206 / 306 and the second wall structure 205 / 305 are adjacent one another and together form a cylindrical tube. For example, such systems may be formed in a coextrusion or 3D-printing process, such that the first and second wall structures are integrally formed. In one 37sf-5754313MoFo Docket No.: 76166-20030.40 embodiment, the coextruded first and second wall structures are thermoplastic polymers possessing the desired properties.

[0164] As shown in FIG. 3, the first wall structure 306 and second wall structure 305 together form a cylindrical tube having a lumen 308 in which a drug formulation is contained. The second wall structure 305 is in the form of a longitudinal strip extending along at least a portion of the length of the first wall structure 306 and is permeable to the drug, while the first wall structure 306 is not permeable to the drug. In certain embodiments, multiple drug permeable strips may be used in a single system. In certain embodiments, one permeable strip may be used in a single system. Thus, the size, shape, thickness, and material properties of the second wall structure may be selected to achieve a desired drug release rate.

[0165] In a preferred embodiment, as discussed in further detail below, the system is elastically deformable between a low-profile deployment shape (e.g., a relatively straightened shape) suited for insertion through the urethra of a patient and into the patient^s bladder and a relatively expanded retention shape (e.g., pretzel shape, bi-oval coil shape, S-shape, etc.) suited for retention within the bladder.

[0166] In some embodiments, as shown in FIGs. 7A-7C, the system further includes retention frame lumen 734. In certain embodiments, the retention frame lumen includes an elastic wire, such as a nitinol wire. In certain other embodiments, the retention frame lumen is filled with a shape set elastic polymer.

[0167] In other embodiments, as shown in FIGs. 1-3 and 8, the system does not include a retention frame lumen or a retention frame or wire. Instead, the material of the housing is configured to be elastically deformable between the straightened shape and the retention shape, in the absence of a retention frame or wire. In certain embodiments, the tubular housing is thermally shape set to have a coiled or other retention shape. Thus, in such embodiments, the design and manufacturing of the system is simplified, and the overall size of the system is minimized (or drug payload may be increased if the size of the system remains constant). In embodiments without a retention frame, the tubular housing material serves the functions of (i) forming the drug reservoir lumen, (ii) controlling drug release, and (iii) retaining the system in the bladder upon deployment.

[0168] In one embodiment, as shown in FIGs. 7A-7C, a drug delivery system 700 is provided that includes an elongated, elastic housing 702 having a drug reservoir lumen 704 extending between a first end 706 and a second end 708. The elastic housing 702 is formed of a tubular wall structure 710 that includes a first wall structure 716 and a second wall structure 724 that are adjacent one another and together form a tube defining the drug reservoir lumen 704, wherein (i) the second wall structure 724, or both the first wall structure 716 and the second wall structure 724, are permeable to water, and (ii) the first wall structure 716 is impermeable to the drug and the second wall structure 724 is 38sf-5754313MoFo Docket No.: 76166-20030.40 permeable to the drug, such that the drug is releasable in vivo by diffusion through the second wall structure 724.

[0169] In embodiments in which the first and second wall structures together form a cylindrical tube, any suitable end plugs or closures or thermally formed seals may be used to seal the ends of the tube after the drug is loaded. These end plugs / closures ensure that the drug permeable polymer portions forming a portion of the external tube are the only path for drug release.

[0170] In some embodiments, as shown in FIGs. 2 and 3, the wall 206, 205 / 306, 305 has a substantially constant thickness over its circumference. For example, the inner diameter 210 / 310 and outer diameter 212 / 312 of the first and second wall structures 206, 205 / 306, 305 (which together form the cylindrical tube) are the same. In other embodiments, the wall may have a varied thickness over the circumference of the wall.

[0171] Thus, for the systems described herein, drug release is controlled by diffusion of the drug through a drug-permeable component defining a portion of the system housing. The drug-permeable wall structure may be located, dimensioned, and have material properties to provide the desired rate of controlled drug diffusion from the system.

[0172] The particular material and arc angle of the drug permeable portion or wall structure can be selected to achieve a particular drug release profile, i.e., water and drug permeation rates. As used herein, the phrase ^arc angle^ refers to the angle dimension of an arc of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

[0173] For example, in certain embodiments, as shown in FIGs. 2 and 3, the second wall structure 205 / 305 comprises less than 90 percent of a cross sectional area of the tube, in a cross section normal to the longitudinal axis of the tube. In one embodiment, the second wall structure comprises less than 50 percent of a cross sectional area of the tube, in a cross section normal to the longitudinal axis of the tube. In one embodiment, the second wall structure comprises less than 25 percent of a cross sectional area of the tube, in a cross section normal to the longitudinal axis of the tube.

[0174] In certain embodiments, as shown at FIGs. 2, 3, 7A-C, and 8, the first and second wall structures that form the tube bounding the drug reservoir lumen are adjacent one another at two interface edges, such that the wall structures collectively form the tube defining the drug reservoir lumen. In these embodiments, the two interface edges are disposed at an arc angle of from about 15 degrees to about 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. As used herein, the phrase ^about^ with reference to the arc angles of the second wall structure refers to the arc angle plus or minus 3 degrees.

[0175] In one embodiment, as shown in FIG. 2, the second wall structure 205 has an arc angle 214 of about 60 degrees of a circumference of the cylindrical tube 200 in the 39sf-5754313MoFo Docket No.: 76166-20030.40 cross-section. In one embodiment, as shown in FIG. 3, the second wall structure 305 has an arc angle 314 of about 30 degrees of a circumference of the cylindrical tube 300 in the cross-section. In one embodiment, the second wall structure has an arc angle of about 15 degrees to about 270 degrees. As will be further described below, in certain embodiments, the second wall structure has an arc angle of about 45 degrees to about 90 degrees, of about 150 degrees to about 270 degrees, or of about 210 degrees to about 270 degrees, such as about 45 degrees, about 90 degrees, about 180 degrees, and about 240 degrees. In certain embodiments, the second wall structure has an arc angle of about 45 degrees, about 90 degrees, about 180 degrees, about 240 degrees, or about 270 degrees.

[0176] The second wall structure can be located on the inner curvature (0 degrees), the outer curvature (180 degrees), the top (90 degrees), or in-between, when the system is formed to have a retention shape as shown in FIG. 1. The top (90 degree) location may be preferable when the second wall structure is formed of a material that significantly swells once absorbing water.

[0177] Accordingly, tubular systems have been developed which are designed to reduce or control drug release rates without negatively altering the mechanical properties and suitable dimensions for system deployment and tolerability. In some embodiments, the designs reduce drug release rates by reducing the length of the drug permeable regions(s) such that the length runs along only a portion of the overall length of the system. Larger arc angles of the drug permeable region(s) can therefore be employed to tailor drug release rates from the system. Additionally, by decreasing the length of the drug permeable region, a lesser amount of drug permeable material, compared to conventional systems, may be used to effect a reduced drug release rate.

[0178] Once the drug is loaded into the drug reservoir lumen, any suitable end plugs or closures or thermally formed seals may be used to seal / close the first and second ends of the drug reservoir lumen. These end plugs / closures ensure that the second material forming a portion of the elastic housing is the sole path for drug release. In certain embodiments, the end plugs are formed of the first material (i.e., the material forming the first wall structure) that is impermeable to the drug.

[0179] In the foregoing embodiments, the first material or the first wall structure, the second material or the first wall structure, or both, is formed of a water permeable material. In a preferred embodiment, as described above with reference to the erdafitinib solid formulations, the drug is in a solid form (e.g., a tablet or plurality of tablets) and at least a portion of the tubular body is water permeable to permit in vivo solubilization of the drug while in the drug reservoir lumen. In embodiments, the first material or first wall structure may be the only water permeable portion. In other embodiments both the first and second materials / wall structures may be water permeable. 40sf-5754313MoFo Docket No.: 76166-20030.40

[0180] The material(s) for the wall structures of the present systems can be selected from a variety of suitable thermoplastic polyurethane (TPU)-based materials. In particular, the first material forming the first wall structure (i.e., the material that is impermeable to the drug contained in the drug reservoir) may be a polycarbonate-based aromatic thermoplastic polyurethane (e.g., a CARBOTHANETMTPU, such as AC-4075A, commercially available from Lubrizol) or an aromatic polyester hydrocarbon-based thermoplastic polyurethane (e.g., a TECOTHANETMTPU, such as AR-75A, commercially available from Lubrizol). For example, CARBOTHANE polyurethanes are cycloaliphatic polymers and are of the types produced from polycarbonate-based polyols. The general structure of the polyol segment is represented as O--[(CH2)6--CO3]n--(CH2)--O--. AC-4075A has a durometer Shore hardness of 77A, a specific gravity of 1.19, a flexural modulus of 1500 psi, and an ultimate elongation of 400%. AR-75A has a durometer Shore hardness of 79A, a specific gravity of 1.03, a flexural modulus of 2500 psi, and an ultimate elongation of 530%. In particular, the second material forming the second wall structure (i.e., the material that is permeable to the drug contained in the drug reservoir) may be an aliphatic polyether-based thermoplastic polyurethane (e.g., a TECOFLEXTMTPU, such as EG-80A, commercially available from Lubrizol). For example, TECOFLEX polyurethanes are cycloaliphatic polymers and are of the types produced from polyether-based polyols. The general structure of the polyol segment is represented as O--(CH2--CH2--CH2--CH2)x--O--. EG-80A has a durometer Shore hardness of 72A, a specific gravity of 1.04, a flexural modulus of 1000 psi, and an ultimate elongation of 660%. The TPUs may further include a radiopacity agent, such as barium sulfate, for example, AC-4075A-B20, which is a polycarbonate-based aromatic thermoplastic polyurethane having a 20% loading of barium sulfate.

[0181] In one embodiment, an inner diameter of the cylindrical tube may be from about 1.0 mm to about 2.5 mm. In one embodiment, an outer diameter of the cylindrical tube is from about 2.0 mm to about 4.1 mm. In one embodiment, a thickness of the first wall structure, the second wall structure, or both, is from about 0.2 mm to about 1.0 mm.

[0182] Thus, as compared to drug delivery systems utilizing a homogenous material (e.g., a blend of permeable and impermeable thermoplastic materials) to form a drug permeable tube, the mechanical properties of a tube utilizing the dual wall structure (e.g., the drug permeable strip embodiments) can be decoupled from the drug release (e.g., diffusion) properties of the tube. For example, in a single material tube, changing the material of tube inherently affects both the mechanical and diffusion properties of the system. Being able to control release rate with stripe angle may have the added benefit of not changing the system outer diameter; in contrast, control by changing wall thickness may become too large to fit through the urethra or too thin to provide the required mechanical strength of the system. Moreover, the drug release properties of a blended polymer may not be readily predictable. In addition, it is often challenging to achieve a truly homogeneous 41sf-5754313MoFo Docket No.: 76166-20030.40 blend when mixing two thermoplastics. Thus, it requires experimentation to modulate drug release rate with such a tubular drug delivery system. In contrast, the dual wall structure described herein may provide enhanced flexibility in tailoring a particular drug release rate from the delivery system.

[0183] For use in the bladder, it is important that the system be compliant (e.g., easily flexed, soft feeling) during detrusor muscle contraction in order to avoid or mitigate discomfort and irritation to the patient. Thus, it is noted the durometer of the first and second materials of construction are important, and the proportion of a high durometer material may be limited in constructing a system housing of a given size while keeping it suitably compliant in the bladder. For example, suitable first wall materials, such as TECOTHANE or CARBOTHANE, may have a Shore hardness greater than 70A, such as from 77A to 65D, while suitable second wall materials, such as TECOFLEX, may have a Shore hardness of less than 90A, or less than 80A, such as 72A. In some embodiments, the first material has a Shore hardness value from 70A to 80A while the second material has a Shore hardness value from 70A to 75A. Thus, in certain embodiments, the second wall material has a Shore hardness that is less than the Shore hardness of the first wall material, with both wall materials having a Shore hardness of less than 80A. Accordingly, it can be advantageous to utilize a combination of two different polymeric materials, rather than making the system housing entirely of the water-swelling hydrophilic, drug-permeable second material, to achieve desired mechanical properties of the tube.

[0184] In embodiments, the systems described herein are configured to release a therapeutically effective amount of the drug, where the rate of the release of the drug from the drug delivery system is zero order over at least 36 hours. In one embodiment, the rate of the release of the drug from the drug delivery system is essentially zero order over at least 7 days. In embodiments, the system is configured to release a therapeutically effective amount of the drug over a period from 2 days to 6 months, e.g., from 2 days to 90 days, from 7 days to 30 days, or from 7 days to 14 days. Desirably, the rate of the release of the drug from the drug delivery system is zero order over at least 7 days, e.g., from 7 to 14 days, or longer, such as up to 3 months or 90 days. In certain embodiments, the system is configured to begin release of the drug after a lag time. In certain embodiments, the lag time may be at least about 30 minutes, from about 12 hours to about 24 hours, or up to about 2 days. These systems may be effective to release a therapeutically effective amount of the drug for a period of up to 6 months, or up to 3 months (90 days).

[0185] As will be discussed in greater detail below, a drug formulation, such as those described throughout this disclosure, is disposed in the drug reservoir lumen defined by the first and second wall structures. In particular preferred embodiments, the drug is an erdafitinib-based pharmaceutical formulation, as described herein. In certain embodiments, the system is configured to release the erdafitinib at an average rate of 1 mg / day to 42sf-5754313MoFo Docket No.: 76166-20030.40 10 mg / day, depending on the desired treatment regimen. In some embodiments, the system is configured to release the erdafitinib at an average rate of 1 mg / day to 2 mg / day. In such embodiments, the two interface edges may be disposed at an arc angle of 45 degrees to 90 degrees. In some embodiments, the system is configured to release the erdafitinib at an average rate of 4 mg / day to 6 mg / day. In such embodiments, the two interface edges may be disposed at an arc angle of 150 degrees to 270 degrees.

[0186] In one embodiment, the system is configured to release the erdafitinib at an average rate of 1 mg / day and the two interface edges are disposed at an arc angle of about 45 degrees. In another embodiment, the system is configured to release the erdafitinib at an average rate of 2 mg / day and the two interface edges are disposed at an arc angle of about 90 degrees. In another embodiment, the system is configured to release the erdafitinib at an average rate of 4 mg / day and the two interface edges are disposed at an arc angle of about 180 degrees. In one embodiment, the system is configured to release the erdafitinib at an average rate of 6 mg / day and the two interface edges are disposed at an arc angle of 240 degrees. In certain embodiments, a release profile of the drug is substantially independent of pH over a pH range of 5 to 7. In certain embodiments, a release profile of the drug is substantially independent of pH over a pH range of 5.5 to 7. In certain embodiments, a release profile of the drug is substantially independent of pH over a pH range of 5.5 to 8. In certain embodiments, the release rates are retained over a period up to 6 months, in particular up to 3 months or 90 days.

[0187] In some embodiments, the system is configured to release the erdafitinib at a rate of about 2 mg / day to about 4 mg / day. In some embodiments, the system comprises two interface edges disposed at an angle of about 90 degrees to about 180 degrees. In some embodiments, the system is configured to release the erdafitinib at an average rate of 2 mg / day to about 4 mg / day and the two interface edges are disposed at an arc angle of about 90 degrees to about 180 degrees.

[0188] In one embodiment, a drug delivery system is provided, which has (i) a housing defining a drug reservoir lumen and a retention frame lumen, (ii) a plurality of tablets comprising erdafitinib disposed in the drug reservoir lumen, and (iii) a nitinol wire form (retention frame) disposed in the retention frame lumen. The drug reservoir lumen is defined / bounded by a first wall structure (base) formed of a first material, which is an aromatic polyester hydrocarbon-based thermoplastic polyurethane, particularly AC-4075A-B20, and a second wall structure (stripe) formed of a second material made of an aliphatic polyether-based thermoplastic polyurethane, particularly EG-80A, where the first and second wall structures are adjacent one another at two interface edges and together forming a tube defining the closed drug reservoir lumen. In an embodiment, the closed drug reservoir lumen contains a plurality of tablets, in particular a plurality of minitablets, in particular erdafitinib minitablets as described herein. In an embodiment, the amount of 43sf-5754313MoFo Docket No.: 76166-20030.40 erdafitinib in the drug reservoir lumen is about 500 mg. In an embodiment, the drug reservoir lumen comprises about 44 erdafitinib minitablets, in particular the erdafitinib tablets as described herein. In one embodiment, the plurality of tablets consists of 44 minitablets, having a total of about 500 mg erdafitinib. In an embodiment, the stripe angle is 90 degrees, and the average release rate of erdafitinib from the system is approximately 2 mg / day. In an embodiment, the stripe angle is 180 degrees, and the average release rate of erdafitinib from the system is approximately 4 mg / day. In an embodiment, the stripe angle is 210-270 degrees, and the average release rate of erdafitinib from the system is approximately 6 mg / day. In an embodiment, the stripe angle is 45 degrees, and the average release rate of erdafitinib from the system is approximately 1 mg / day. In an embodiment, the stripe angle is 90 degrees, and the average release rate of erdafitinib from the system is approximately 2 mg / day. In an embodiment, the stripe angle is 90 degrees, and the average release rate of erdafitinib from the system is approximately 2 mg / day at pH between about 5-and about 6.8, and approximately 1 mg / day at pH about 8. In an embodiment, the stripe angle is 180 degrees, and the average release rate of erdafitinib from the system is approximately 4 mg / day. In an embodiment, the stripe angle is 180 degrees, and the average release rate of erdafitinib from the system is approximately 4 mg / day at pH between about 5 and about 6.8, and approximately 2 mg / day at pH about 8. In an embodiment, the stripe angle is 210-270 degrees, in particular 270 degrees, and the average release rate of erdafitinib from the system is approximately 6 mg / day. In an embodiment, the stripe angle is 210-270 degrees, in particular 270 degrees, and the average release rate of erdafitinib from the system is approximately 6 mg / day at pH between about 5 and about 6.8, and approximately 3 mg / day at pH about 8. In an embodiment, the stripe angle is 45 degrees, and the average release rate of erdafitinib from the system is approximately 1 mg / day. In an embodiment, the stripe angle is 45 degrees, and the average release rate of erdafitinib from the system is approximately 1 mg / day at pH between about 5 and about 6.8, and approximately 0.5 mg / day at pH about 8. In an embodiment, the tablets have Formula 4D as described herein. In an embodiment, the tablets have Formula 4C as described herein. In an embodiment, the tablets have Formula 4B as described herein. In an embodiment, the tablets have Formula 4A as described herein. Other Aspects of the Drug Delivery Systems

[0189] In certain embodiments, the systems are configured for intravesical insertion and retention in a patient. For example, the systems can be elastically deformable between a relatively low profile (e.g., straightened) shape suited for insertion through a lumen into a body cavity of a patient, such as shown in FIGs. 7A-B, and a relatively expanded retention shape suited to retain the system within the body cavity, e.g., the bladder, such as shown in FIGs. 1, 4, 5, and 6A. The relatively expanded shape may include a pair of overlapping 44sf-5754313MoFo Docket No.: 76166-20030.40 coils, sometime referred to as a ^pretzel^ shape. In particular embodiments, the ends of the elongated system generally lie within the boundaries of a bi-oval-like shape.

[0190] When in the expanded retention shape after deployment in the bladder, for example, the systems may resist excretion in response to the forces of urination or other forces. After drug release, the systems can be removed, for example by cystoscope and forceps, or can be bioerodible, at least in part, to avoid a retrieval procedure.

[0191] The system may be loaded with at least one drug in the form of one or more drug units, such as the tablets described throughout this disclosure. Solid drug composition forms, such as tablets, can provide a relatively large drug payload volume to total system volume and potentially enhance stability of the drugs during shipping, storage, before use, or before drug release. Solid drugs, however, may need to be solubilizable in vivo in order to diffuse through the drug-permeable component and into the patient^s surrounding tissues or cavity in a therapeutically effective amount. The drug reservoir lumen may hold in an elongated form several of the disclosed drug tablets in an end-to-end serial arrangement. In some embodiments, the system holds from about 10 to 100 cylindrical drug tablets (e.g., 44 tablets), such as mini-tablets, which may be serially loaded in the drug reservoir lumen. In an aspect, the tablets are those as described herein. In an aspect, the tablets are those of Formula 4A. In an aspect, the tablets are those of Formula 4B. In an aspect, the tablets are those of Formula 4C. In an aspect, the tablets are those of Formula 4D.

[0192] The systems may be inserted into a patient using a cystoscope or catheter or any other suitable or customized inserter device. Typically, a cystoscope for an adult human has an outer diameter of about 5 mm and a working channel having an inner diameter of about 2.4 mm to about 2.6 mm. In embodiments, a cystoscope may have a working channel with a larger inner diameter, such as an inner diameter of 4 mm or more. Thus, the system may be relatively small in size. For example, when the system is elastically deformed to the relatively straightened shape, the system for an adult patient may have a total outer diameter that is less than about 2.6 mm, such as between about 2.0 mm and about 2.4 mm. In addition to permitting insertion, the relatively small size of the system may also reduce patient discomfort and trauma to the bladder. In one embodiment, the overall configuration of the system promotes in vivo tolerability for most patients. In a particular embodiment, the system is configured for tolerability based on bladder characteristics and design considerations described in U.S. Patent No. 11,065,426.

[0193] Within the three-dimensional space occupied by the system in the retention shape, the maximum dimension of the system in any direction preferably is less than 10 cm, the approximate diameter of the bladder when filled. In some embodiments, the maximum dimension of the system in any direction may be less than about 9 cm, such as about 8 cm, 7 cm, 6 cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 or smaller. In particular embodiments, the maximum dimension of the system in any direction is less than about 7 cm, such as 45sf-5754313MoFo Docket No.: 76166-20030.40 about 6 cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm or smaller. In preferred embodiments, the maximum dimension of the system in any direction is less than about 6 cm, such as about 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm or smaller. More particularly, the three-dimension space occupied by the system is defined by three perpendicular directions. Along one of these directions the system has its maximum dimension, and along the two other directions the system may have smaller dimensions. For example, the smaller dimensions in the two other directions may be less than about 4 cm, such as about 3.5 cm, 3 cm, 2.5 cm or less. In a preferred embodiment, the system has a dimension in at least one of these directions that is less than 3 cm.

[0194] In some embodiments, the system may have a different dimension in at least two of the three directions, and in some cases in each of the three directions, so that the system is non-uniform in shape. Due to the non-uniform shape, the system may be able to achieve an orientation of reduced compression in the empty bladder, which also is non-uniform in shape. In other words, a particular orientation of the system in the empty bladder may allow the system to exert less contact pressure against the bladder wall, making the system more tolerable for the patient.

[0195] The overall shape of the system may enable the system to reorient itself within the bladder to reduce its engagement or contact with the bladder wall. For example, the overall exterior shape of the system may be curved, and all or a majority of the exterior or exposed surfaces of the system may be substantially rounded. The system also may be substantially devoid of sharp edges, and its exterior surfaces may be formed from a material that experiences reduced frictional engagement with the bladder wall. Such a configuration may enable the system to reposition itself within the empty bladder so that the system applies lower contact pressures to the bladder wall. In other words, the system may slip or roll against the bladder wall into a lower energy position, meaning a position in which the system experiences less compression.

[0196] In one embodiment, the system is generally planar in shape even though the system occupies three-dimensional space. Such a system may define a minor axis, about which the system is substantially symmetrical, and a major axis that is substantially perpendicular to the minor axis. The system may have a maximum dimension in the direction of the major axis that does not exceed about 6 cm, and in particular embodiments is less than 5 cm, such as about 4.5 cm, about 4 cm, about 3.5 cm, about 3 cm, or smaller. The system may have a maximum dimension in the direction of the minor axis that does not exceed about 4.5 cm, and in particular embodiments is less than 4 cm, such as about 3.5 cm, about 3 cm, or smaller. The system is curved about substantially its entire exterior perimeter in both a major cross-sectional plane and a minor cross-sectional plane. In other words, the overall exterior shape of the system is curved and the cross-sectional shape of the system is rounded. Thus, the system is substantially devoid of edges, except for edges on 46sf-5754313MoFo Docket No.: 76166-20030.40 the two flat ends, which are completely protected within the interior of the system when the system lies in a plane. These characteristics enable the system to reorient itself into a position of reduced compression when in the empty bladder.

[0197] The system also may be small enough in the retention shape to permit intravesical mobility. In particular, the system when deployed may be small enough to move within the bladder, such as to move freely or unimpeded throughout the entire bladder under most conditions of bladder fullness, facilitating patient tolerance of the system. Free movement of the system also facilitates uniform drug delivery throughout the entire bladder.

[0198] The system also may be configured to facilitate buoyancy, such as with the use of low density materials of construction for the housing components and / or by incorporating gas or gas generating materials into the housing, as described for example in U.S. Patent No. 9,457,176. In general, the system in the dry and drug-loaded state may have a density in the range of about 0.5 g / mL to about 1.5 g / mL, such as between about 0.7 g / mL to about 1.3 g / mL. In some embodiments, the system in the dry and drug-loaded state has a density that is less than 1 g / mL.

[0199] In an embodiment, the intravesical drug delivery system is non-bioerodible. In another embodiment, the intravesical drug delivery system can be made to be completely or partially bioerodible so that no explantation, or retrieval, of the system is required following release of the drug formulation. In some embodiments, the system is partially bioerodible so that the system, upon partial erosion, breaks into non-erodible pieces small enough to be excreted from the bladder. For example, the systems described herein may be designed to conform with the characteristics of those described in U.S. Patent No. 8,690,840.

[0200] The drug delivery systems are sterilized before being inserted into a patient. In one embodiment, the system is sterilized using a suitable process such as gamma irradiation or ethylene oxide sterilization, although other sterilization processes may be used.

[0201] The systems described herein may include a radio-opaque portion or structure to facilitate detection or viewing (e.g., by X-ray imaging or fluoroscopy) of the system by a medical practitioner as part of the implantation or retrieval procedure. In one embodiment, the housing is constructed of a material that includes a radio-opaque filler material, such as barium sulfate or another radio-opaque material known in the art. Some housings may be made radio-opaque by blending radio-opaque fillers, such as barium sulfate or another suitable material, during the processing of the material from which the housing is formed. The radio-opaque material may be associated with the retention frame in those embodiments that include a retention frame. Ultrasound imaging or fluoroscopy may be used to image the system in vivo.

[0202] In some embodiments, the device constituent of the system comprises a drug- impermeable base material and a drug-permeable stripe material, and the base material is a 47sf-5754313MoFo Docket No.: 76166-20030.40 TPU having 20% BaSO4 filler, such as Lubrizol^s CarbothaneTMAC-4075A-B20 or TecothaneTMAR-75A-B20. (Lubrizol Life Science (Bethlehem, PA)).

[0203] The drug delivery system may further include a retrieval feature, such as a string, a loop, or other structure that facilitates removal of the system from the patient. In one case, the system may be removed from the bladder by engaging the string to pull the system through the urethra. The system may be configured to assume a relatively narrow or linear shape when pulling the system by the retrieval feature into the lumen of a catheter or cystoscope or into the urethra. Retention Of The System In A Body Cavity

[0204] The systems described herein are elastically deformable between a relatively low profile (e.g., straightened or uncoiled) shape suited for insertion through a lumen into the bladder (or other body cavity) of a patient and a relatively expanded retention shape suited to retain the system within the urinary bladder (or other body cavity). In certain embodiments, the drug delivery system may naturally assume the retention shape and may be deformed, either manually or with the aid of an external apparatus, into the relatively straightened shape for insertion into the body. Once deployed the system may spontaneously or naturally return to the initial, retention shape for retention in the body.

[0205] For the purposes of this disclosure, the terms ^retention shape,^ ^relatively expanded shape,^ and the like, generally denote any shape suited for retaining the system in the intended implantation location, including, but not limited to, a coiled or ^pretzel^ shape, such as shown in FIGs. 1 and 4, which is suited for retaining the system in the bladder. Similarly, the terms ^deployment shape,^ ^relatively low profile shape,^ ^relatively straightened shape,^ and the like, generally denote any shape suited for deploying the drug delivery system into the body, including, but not limited to, a linear or elongated shape, such as shown in FIG. 7A-B, which is suited for deploying the system through the working channel of a catheter, cystoscope, or other deployment instrument positioned in a lumen of the body, such as the urethra. For example, the housing or tube of the system may have two opposing free ends, which are directed away from one another when the system is in a low- profile deployment shape and which are directed toward one another when the system is in a relatively expanded retention shape.

[0206] In some embodiments, as shown in FIGs. 7A-7C, the system further includes retention frame lumen 734 and a retention frame (not shown) positioned in the retention frame lumen. For example, the retention frame lumen and retention frame may be as described in U.S. Application Publication No. 2010 / 0331770; U.S. Application Publication No. 2010 / 0060309; U.S. Application Publication No. 2011 / 0202036; and U.S. Application Publication No. 2011 / 0152839, which are incorporated herein by reference. For example, the retention frame lumen may be sealed with a suitable plug or adhesive material, such as a silicone adhesive material. 48sf-5754313MoFo Docket No.: 76166-20030.40

[0207] FIG. 4 illustrates a system 300 loaded with drug tablets 108 in the drug reservoir lumen of system housing 304. As can be seen in FIG. 5, prior to loading the tablets, the retention frame 305 urges the system housing 304 into a distinct expanded shape, as compared to the retention shape achieved when the system is loaded with drug tablets 108.

[0208] In certain embodiments, in which an increased payload is desired, additional length of the drug reservoir lumen / tube may be provided. In one embodiment, as shown in FIGs. 6A-6B, the retention frame has an outer periphery defined by two overlapping portions (coils) of nitinol wire. Each end portion of the wire is inwardly directed from the periphery and includes (i) a curved transition region having a smaller radius of curvature than the peripheral portions of the wire, and (ii) a straight portion that terminates with a rounded end cap. In contrast, in the system shown in FIG. 5, the retention frame has a periphery defined by a single coil. A system having the retention frame of FIGs. 6A-6B enables a comparatively longer drug reservoir (e.g., to accommodate more tablets) in a system having the same ^footprint^ (outer peripheral shape and dimension) as the system illustrated in FIG. 5.

[0209] In other embodiments, as shown in FIGs. 1-3, the system does not include a retention frame lumen or a retention frame or wire. Instead, the material of the housing is configured to be elastically deformable between the straightened shape and the retention shape, in the absence of a retention frame or wire. In such embodiments, the design and manufacturing of the system is simplified, and the overall size of the system is minimized (or drug payload may be increased where the size of the system remains constant). In embodiments without a retention frame, the tubular housing material serves the functions of (i) forming the drug reservoir lumen, (ii) controlling drug release, and (iii) retaining the system in the bladder upon deployment.

[0210] For example, the tubular housing may be thermally shape set to have the retention shape. Thus, the housing may comprise one or more thermoplastic materials that are suitable to be thermally formed into the retention shape. In certain embodiments, a drug delivery system includes a tubular housing having a closed drug reservoir lumen bounded by a wall structure comprising at least one thermoplastic material, wherein (i) at least a portion of the wall structure is water permeable and at least a portion of the wall structure is drug permeable, (ii) the tubular housing is elastically deformable from a retention shape suited to retain the system within the bladder to a relatively straightened shape suited for insertion through a lumen into the bladder, and (iii) the tubular wall is thermally shaped to have the retention shape.

[0211] In certain embodiments the first and second wall structures are each a thermoplastic polyurethane and the tubular housing is thermally shaped to have the retention shape. In one embodiment, the tubular wall has a spring constant effective to impede the system from assuming the relatively straightened shape once implanted in the 49sf-5754313MoFo Docket No.: 76166-20030.40 bladder. Thus, the properties of the tubular wall may cause the system to function as a spring, deforming in response to a compressive load but spontaneously returning to its initial shape once the load is removed.

[0212] In certain embodiments, the systems may naturally assume the retention shape, may be deformed into the relatively straightened shape, and may spontaneously return to the retention shape upon insertion into the body. The tubular wall structure in the retention shape may be shaped for retention in a body cavity, and in the relatively straightened shape may be shaped for insertion into the body through the working channel of a deployment instrument such as a catheter or cystoscope. To achieve such a result, the tubular wall structure may have an elastic limit, modulus, and / or spring constant selected to impede the system from assuming the relatively lower-profile shape once implanted. Such a configuration may limit or prevent accidental expulsion of the system from the body under expected forces. For example, the system may be retained in the bladder during urination or contraction of the detrusor muscle.

[0213] In a preferred embodiment, the system is elastically deformable between a relatively straightened shape suited for insertion through a catheter or cystoscope extending through a patient^s urethra of a patient and a curved or coiled shape suited to retain the system within the bladder (i.e., to prevent its expulsion from the bladder during urination) following release of the system from the end of the catheter or cystoscope.

[0214] As shown in FIG. 1, the retention shape may include a coiled or ^pretzel^ shape. The pretzel shape essentially comprises at least two sub-circles, each having its own smaller arch and sharing a common larger arch. When the pretzel shape is first compressed, the larger arch absorbs the majority of the compressive force and begins deforming, but with continued compression the smaller arches overlap, and subsequently, all three of the arches resist the compressive force. The resistance to compression of the system as a whole increases once the two sub-circles overlap, impeding collapse and voiding of the system as the bladder contracts during urination.

[0215] The wall structure in the retention shape may have a two-dimensional structure that is confined to a plane, a three-dimensional structure, such as a structure that occupies the interior of a spheroid, or some combination thereof. The retention shape may comprise one or more loops, curls, or sub-circles, connected either linearly or radially, turning in the same or in alternating directions, and overlapping or not overlapping. The retention shape may comprise one or more circles or ovals arranged in a two-dimensional or a three- dimensional configuration, the circles or ovals may be either closed or opened, having the same or different sizes, overlapping or not overlapping, and joined together at one or more connecting points. The retention shape also may be a three-dimensional structure that is shaped to occupy or wind about a spheroid-shaped space, such as a spherical space, a space having a prorate spheroid shape, or a space having an oblate spheroid shape. The wall 50sf-5754313MoFo Docket No.: 76166-20030.40 structure in the retention shape may be shaped to occupy or wind about a spherical space. The wall structure in the retention shape may generally take the shape of two intersecting circles lying in different planes, two intersecting circles lying in different planes with inwardly curled ends, three intersecting circles lying in different planes, or a spherical spiral. In each of these examples, the wall structure can be stretched to the linear shape for deployment through a deployment instrument. The wall structure may wind about or through the spherical space, or other spheroid-shaped space, in a variety of other manners.

[0216] Drug delivery systems utilizing thermally formed coextruded tubing with drug permeable and drug impermeable portions may integrate three functional components (drug reservoir / housing, drug permeation route, and retentive feature) into a single thermally shaped co-extruded tubing component, which may simplify the system design and the ability to control the drug release rate. As discussed herein, in such systems, the drug release rate can be relatively easily modified by controlling the angle and thickness of the drug permeable portion (e.g., strip) without changing whole tube housing material.

[0217] A thermally shaped coextruded tubular housing may be loaded with drug tablets and both ends may be sealed thermally or with adhesive (such as with the first wall material). If the local tube cross-section deformation or tube kinking occurs, the tablet loading will be difficult. Therefore, the tube dimensions should be chosen to prevent kinking when the tube is thermally shaped. The critical bending radius ofof elastic tubes under pure bending condition can be approximated using the following equation: &where v is Poisson^s ratio, r is the mean radius (i.e. (ID+OD) / 4), w is the tube wall thickness, ID is tube inner diameter, and OD is tube outer diameter. With a Poisson^s ratio v of 0.49 for polyurethanes, the estimated critical radius is 0.5 cm. Therefore, in some embodiments, when thermally shaping a polyurethane tube, the radius of curvature should preferably be above 0.5 cm all along the length of the tube to prevent kinking. Thus, in one embodiment, the retention shape comprises at least one loop having a radius of curvature of at least 0.5 cm. Drug Tablets

[0218] As discussed herein with reference to the erdafitinib pharmaceutical formulations, the drug may be provided in a solid form suitable for being loaded within the drug reservoir lumen of the system (e.g., solid mini-tablets). In a preferred embodiment, as shown in FIG. 1, a drug formulation is formed into drug units 108 that are loaded into the drug reservoir lumen of the system 100. Each of the drug units is a solid, discrete object that substantially retains a selectively imparted shape (at the temperature and pressure conditions to which the drug units (e.g., tablets) and the delivery system normally will be 51sf-5754313MoFo Docket No.: 76166-20030.40 exposed during assembly (e.g., loading into the system drug reservoir), storage, and handling before in vivo insertion).

[0219] The individual drug units may have essentially any selected shape and dimension that fits within the systems described herein. In one embodiment, the drug units are sized and shaped such that the drug reservoir lumens in the housings are substantially filled by a select number of drug units. Each drug unit may have a cross-sectional shape that substantially corresponds to a cross-sectional shape of the drug reservoir lumen of a particular housing. For example, the drug units may be substantially cylindrical in shape for positioning in a substantially cylindrical drug reservoir lumen. Once loaded, the drug units can, in some embodiments, substantially fill the drug reservoir lumen forming the drug housing portion.

[0220] In one embodiment, the drug units are shaped to align in a row when the system is in its deployment configuration. For example, each drug unit may have a cross-sectional shape that corresponds to the cross-sectional shape of the drug reservoir lumens in the housing, and each drug unit may have end face shapes that correspond to the end faces of adjacent drug units. The interstices or breaks between drug units can accommodate deformation or movement of the system, such as during deployment, while permitting the individual drug units to retain their solid form. Thus, the drug delivery system may be relatively flexible or deformable despite being loaded with a solid drug composition, such as a tablet, as each drug unit may be permitted to move with reference to adjacent drug units.

[0221] In embodiments in which the drug units are designed for insertion or implantation in a lumen or cavity in the body, such as the bladder, via a drug delivery system, the drug units may be ^mini-tablets^ that are suitably sized and shaped for insertion through a natural lumen of the body, such as the urethra. For the purpose of this disclosure, the term ^mini-tablet^ generally indicates a solid drug unit that is substantially cylindrical in shape, having end faces and a side face that is substantially cylindrical. The mini-tablet has a diameter, extending along the end face, in the range of about 1.0 to about 3.2 mm, such as between about 1.5 and about 3.1 mm. The mini-tablet has a length, extending along the side face, in the range of about 1.7 mm to about 4.8 mm, such as between about 2.0 mm and about 4.5 mm. The friability of the tablet may be less than about 2%. In an aspect, the tablets are those as described herein. In an aspect, the tablets are those of Formula 4A. In an aspect, the tablets are those of Formula 4B. In an aspect, the tablets are those of Formula 4C. In an aspect, the tablets are those of Formula 4D. Methods of Drug Delivery

[0222] The systems and methods or uses disclosed herein may be adapted for use in humans or for use in veterinary or livestock applications. Accordingly, the term ^patient^ 52sf-5754313MoFo Docket No.: 76166-20030.40 may refer to a human or other mammalian subject. In an embodiment, the patient is a human subject.

[0223] In certain embodiments, methods of treatment of urothelial cancers, such as bladder cancers, are provided herein. In certain embodiments, use of a drug delivery system as described herein for the manufacture of a medicament for the treatment of urothelial cancers, such as bladder cancers, are provided herein. In certain embodiments, a drug delivery system as described herein for use in the treatment of urothelial cancers, such as bladder cancers, are provided herein. In certain embodiments, erdafitinib for use in a drug delivery system as described herein for the treatment of urothelial cancers, such as bladder cancers, are provided herein. The methods or uses may include locally delivering or administering erdafitinib (such as in any of the formulations described herein) into the bladder of a patient in need of treatment, in particular a cancer patient, in an amount effective for the treatment of bladder cancer (e.g., from about 1-10 mg / day, as described herein). For example, the treatment may be effective at treating muscle invasive bladder cancer (MIBC), non-muscle invasive bladder cancer (NMIBC), and / or bacillus calmette- guérin (BCG)-naïve bladder cancer. In an aspect the patient, in particular a human, is a BCG-experienced bladder or NMIBC or MIBC cancer patient. In an aspect the patient, in particular a human, is a BCG- naïve bladder or NMIBC or MIBC cancer patient. In an aspect the patient, in particular a human, is a recurrent, bacillus Calmette-Guerin (BCG)- experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient, refusing or ineligible for radical cystectomy (RCy). In an aspect the patient, in particular a human, is a recurrent, BCG-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient, scheduled for RCy. In an aspect the patient, in particular a human, is a recurrent, intermediate-risk NMIBC (Ta and T1) cancer patient with a previous history of only low- grade disease. In an aspect the patient, in particular a human, is a MIBC cancer patient scheduled for RCy who has refused or is ineligible for cisplatin-based neoadjuvant chemotherapy.

[0224] In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment of bladder cancer, wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient with a urine based PCR or NGS assay. In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations comprising, consisting of, or consisting essential of: (a) evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations, in particular evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a urine 53sf-5754313MoFo Docket No.: 76166-20030.40 based PCR or NGS assay; and (b) delivering locally erdafitinib if the one or more FGFR genetic alterations, is present in the sample. In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment, 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, in particular 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 with a urine based PCR or NGS assay. In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment, wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient with a urine based PCR or NGS assay. In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is locally delivered into the bladder of the patient and wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient with a urine based PCR or NGS assay. In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient comprising, consisting of, or consisting essential of (a) evaluating a urine sample from a patient with bladder cancer for the presence of one or more FGFR genetic alterations, in particular evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a urine based PCR or NGS assay; and (b) delivering locally erdafitinib to the patient if the one or more FGFR genetic alterations, is present in the sample. In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and 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, in particular 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 with a urine based PCR or NGS assay. In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic 54sf-5754313MoFo Docket No.: 76166-20030.40 alterations in a urine sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient with a urine based PCR or NGS assay. In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient, wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient with a urine based PCR or NGS assay. In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient comprising, consisting of, or consisting essential of: (a) evaluating a urine sample from the patient with bladder cancer for the presence of the one or more FGFR genetic alterations, in particular evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a urine based PCR or NGS assay; and (b) delivering locally erdafitinib if the one or more FGFR genetic alterations, is present in the sample. In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and 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, in particular 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 with a urine based PCR or NGS assay. In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient with a urine based PCR or NGS assay. The methods or uses may include locally delivering or locally administering erdafitinib (such as in any of the formulations described herein) into the bladder of a patient in need of treatment, in particular a cancer patient, in an amount effective for the treatment of bladder cancer (e.g., from about 1-10 mg / day, as described herein). For example, the treatment may be effective at treating muscle invasive bladder cancer (MIBC), non-muscle invasive bladder cancer (NMIBC), and / or bacillus calmette-guérin (BCG)-naïve bladder cancer. In an aspect the patient, in particular a human, is a BCG-experienced bladder or NMIBC or MIBC cancer patient. In an aspect the patient, in particular a human, is a BCG- naïve bladder or NMIBC 55sf-5754313MoFo Docket No.: 76166-20030.40 or MIBC cancer patient. In an aspect the patient, in particular a human, is a recurrent, bacillus Calmette-Guerin (BCG)-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient, refusing or ineligible for radical cystectomy (RCy). In an aspect the patient, in particular a human, is a recurrent, BCG-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient, scheduled for RCy. In an aspect the patient, in particular a human, is a recurrent, intermediate-risk NMIBC (Ta and T1) cancer patient with a previous history of only low-grade disease. In an aspect the patient, in particular a human, is a MIBC cancer patient scheduled for RCy who has refused or is ineligible for cisplatin- based neoadjuvant chemotherapy.

[0225] In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment of bladder cancer, wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient with a tissue based PCR or NGS assay, or wherein the one or more FGFR genetic alterations are detected in a histopathological image of the tumor tissue via digital histopathology analysis. In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations comprising, consisting of, or consisting essential of: (a) evaluating a tumor tissue sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations, in particular evaluating a tumor tissue sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a tissue based PCR or NGS assay, or evaluating a histopathological image of a tumor tissue from a patient with bladder cancer for the presence of one or more FGFR genetic alterations via digital histopathology analysis; and (b) delivering locally erdafitinib if the one or more FGFR genetic alterations, is present in the sample. In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment, wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a histopathological image of the tumor tissue via digital histopathology analysis. In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment, wherein eligibility of the 56sf-5754313MoFo Docket No.: 76166-20030.40 patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a histopathological image of the tumor tissue via digital histopathology analysis. In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is locally delivered into the bladder of the patient and wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein the one or more FGFR alterations are detected in a histopathological image of the tumor tissue via digital histopathology analysis. In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient comprising, consisting of, or consisting essential of (a) evaluating a tumor tissue sample from a patient with bladder cancer for the presence of one or more FGFR genetic alterations, in particular evaluating a tumor tissue sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a tissue based PCR or NGS assay, or evaluating a histopathological image of a tumor tissue from a patient with bladder cancer for the presence of one or more FGFR genetic alterations via digital histopathology analysis; and (b) delivering locally erdafitinib to the patient if the one or more FGFR genetic alterations, is present in the sample. In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a histopathological image of the tumor tissue via digital histopathology analysis. In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a 57sf-5754313MoFo Docket No.: 76166-20030.40 tissue based PCR or NGS assay or wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a histopathological image of the tumor tissue via digital histopathology analysis. In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient, wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein the one or more FGFR alterations are detected in a histopathological image of the tumor tissue via digital histopathology analysis. In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient comprising, consisting of, or consisting essential of: (a) evaluating a tumor tissue sample from the patient with bladder cancer for the presence of the one or more FGFR genetic alterations, in particular evaluating a tumor tissue sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a tissue based PCR or NGS assay or evaluating a histopathological image of a tumor tissue from a patient with bladder cancer for the presence of one or more FGFR genetic alterations via digital histopathology analysis; and (b) delivering locally erdafitinib if the one or more FGFR genetic alterations, is present in the sample. In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a histopathological image of the tumor tissue via digital histopathology analysis. In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a 58sf-5754313MoFo Docket No.: 76166-20030.40 histopathological image of the tumor tissue via digital histopathology analysis. The methods or uses may include locally delivering or locally administering erdafitinib (such as in any of the formulations described herein) into the bladder of a patient in need of treatment, in particular a cancer patient, in an amount effective for the treatment of bladder cancer (e.g., from about 1-10 mg / day, as described herein). For example, the treatment may be effective at treating muscle invasive bladder cancer (MIBC), non-muscle invasive bladder cancer (NMIBC), and / or bacillus calmette-guérin (BCG)-naïve bladder cancer. In an aspect the patient, in particular a human, is a BCG-experienced bladder or NMIBC or MIBC cancer patient. In an aspect the patient, in particular a human, is a BCG- naïve bladder or NMIBC or MIBC cancer patient. In an aspect the patient, in particular a human, is a recurrent, bacillus Calmette-Guerin (BCG)-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient, refusing or ineligible for radical cystectomy (RCy). In an aspect the patient, in particular a human, is a recurrent, BCG-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient, scheduled for RCy. In an aspect the patient, in particular a human, is a recurrent, intermediate-risk NMIBC (Ta and T1) cancer patient with a previous history of only low-grade disease. In an aspect the patient, in particular a human, is a MIBC cancer patient scheduled for RCy who has refused or is ineligible for cisplatin-based neoadjuvant chemotherapy.

[0226] In certain embodiments, the urothelial cancers as described herein are susceptible to an FGFR2 genetic alteration and / or an FGFR3 genetic alteration.

[0227] As used herein, ^FGFR genetic alteration^ refers to an alteration in the wild type FGFR gene, including, but not limited to, FGFR fusion genes, FGFR mutations, FGFR amplifications, or any combination thereof, in particular FGFR fusion genes, FGFR mutations, or any combination thereof. In certain embodiments, the FGFR2 or FGFR3 genetic alteration is an FGFR gene fusion. ^FGFR fusion^ or ^FGFR gene fusion^ refers to a gene encoding a portion of FGFR (e.g., FGRF2 or FGFR3) and one of the herein disclosed fusion partners, or a portion thereof, created by a translocation between the two genes. The terms ^fusion^ and ^translocation^ are used interchangeable herein. The presence of one or more of the following FGFR fusion genes in a biological sample from a patient can be determined using the disclosed methods or uses or by methods known to those of ordinary skill in the art : FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof. In certain embodiments, FGFR3-TACC3 is FGFR3-TACC3 variant 1 (FGFR3-TACC3 V1) or FGFR3-TACC3 variant 3 (FGFR3- TACC3 V3). Table A provides the FGFR fusion genes and the FGFR and fusion partner exons that are fused. The sequences of the individual FGFR fusion genes are disclosed in Table A2. The underlined sequences correspond to either FGFR3 or FGFR2, the sequences represent the fusion partners. 59sf-5754313MoFo Docket No.: 76166-20030.40 Table ATable A2 C C C60 sf-5754313MoFo Docket No.: 76166-20030.40 C T T C61 sf-5754313MoFo Docket No.: 76166-20030.40 C C C A G C T G A T C62 sf-5754313MoFo Docket No.: 76166-20030.40 C C C63 sf-5754313MoFo Docket No.: 76166-20030.40 A C T A G T64 sf-5754313MoFo Docket No.: 76166-20030.40 T65 sf-5754313MoFo Docket No.: 76166-20030.40 G C G C A T66 sf-5754313MoFo Docket No.: 76166-20030.40 A C T A C67 sf-5754313MoFo Docket No.: 76166-20030.40 C68 sf-5754313MoFo Docket No.: 76166-20030.40 C

[0228] FGFR genetic alterations include FGFR single nucleotide polymorphism (SNP). ^FGFR single nucleotide polymorphism^ (SNP) refers to a FGFR2 or FGFR3 gene in which a single nucleotide differs among individuals. In certain embodiments, the FGFR2 or FGFR3 genetic alteration is an FGFR3 gene mutation. In particular, FGFR single nucleotide polymorphism^ (SNP) refers to a FGFR3 gene in which a single nucleotide differs among individuals. The presence of one or more of the following FGFR SNPs in a biological sample from a patient can be determined by methods known to those of ordinary skill in the art or methods disclosed in WO 2016 / 048833, FGFR3 R248C, FGFR3 S249C, 69 sf-5754313MoFo Docket No.: 76166-20030.40 FGFR3 G370C, FGFR3 Y373C, or any combination thereof. The sequences of the FGFR SNPs are provided in Table B. Table BSequences correspond to nucleotides 920-1510 of FGFR3 (Genebank ID # NM_000142.4). 70 sf-5754313MoFo Docket No.: 76166-20030.40 Nucleotides in bold underline represent the SNP. *Sometimes mistakenly referred to as Y375C in the literature.

[0229] In certain embodiments, the methods of or uses for treating an urothelial carcinoma as described herein comprise, consist of, or consist essentially of administering the drug delivery system as described herein to a patient that has been diagnosed with an urothelial carcinoma as described herein and harbors at least one FGFR2 genetic alteration and / or FGFR3 genetic alteration (i.e., one or more FGFR2 genetic alteration, one or more FGFR3 genetic alteration, or a combination thereof). In certain embodiments, the FGFR2 genetic alteration and / or FGFR3 genetic alteration is an FGFR3 gene mutation, FGFR2 gene fusion, or FGFR3 gene fusion. In some embodiments, the FGFR3 gene 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.

[0230] Also described herein are methods or uses of treating an urothelial carcinoma as described herein comprising, consisting of, or consisting essential of: (a) evaluating a biological sample from a patient with an urothelial carcinoma as described herein for the presence of one or more FGFR gene alterations, in particular one or more FGFR2 or FGFR3 gene alterations; and (b) administering a drug delivery system as described herein to the patient if one or more FGFR gene alterations, in particular one or more FGFR2 or FGFR3 gene alterations, is present in the sample.

[0231] The following methods for evaluating a biological sample for the presence of one or more FGFR genetic alterations apply equally to any of the above disclosed methods of treatment and uses.

[0232] Suitable methods for evaluating 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 Serial No. 16 / 723,975, which are incorporated herein in their entireties. For example, and without intent to be limiting, evaluating a biological sample for the presence of one or more FGFR genetic alterations can comprise any combination of the following steps: isolating RNA from the biological sample; synthesizing cDNA from the RNA; and amplifying the cDNA (preamplified or non-preamplified). In some embodiments, evaluating a biological sample for the presence of one or more FGFR genetic alterations can comprise: amplifying cDNA from the patient with a pair of primers that bind to and amplify one or more FGFR genetic alterations; and determining whether the one or more FGFR genetic alterations are present in the sample. In some aspects, the cDNA can be pre-amplified. In some aspects, the evaluating step can comprise isolating RNA from the sample, synthesizing cDNA from the isolated RNA, and pre-amplifying the cDNA.

[0233] Suitable primer pairs for performing an amplification step include, but are not limited to, those disclosed in WO 2016 / 048833, as exemplified below in Table C: 71sf-5754313MoFo Docket No.: 76166-20030.40 Table C

[0234] The presence of one or more FGFR genetic alterations can be evaluated at any suitable time point including upon diagnosis, following tumor resection, following first-line therapy, during clinical treatment, or any combination thereof. 72 sf-5754313MoFo Docket No.: 76166-20030.40

[0235] The methods and uses can further comprise evaluating the presence of one or more FGFR genetic alterations in the biological sample before the administering step.

[0236] The diagnostic tests and screens are typically conducted on a biological sample selected from blood, lymph fluid, bone marrow, a solid tumor sample, or any combination thereof. In certain embodiments, the biological sample is a solid tumor sample. In certain embodiments, the biological sample is a blood sample, or a urine sample.

[0237] Methods of identification and analysis of genetic alterations and up-regulation of proteins are known to a person skilled in the art. Screening methods could 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).

[0238] Identification of an individual carrying a genetic alteration in FGFR, in particular an FGFR genetic alteration as described herein, may mean that the patient would be particularly suitable for treatment with erdafitinib. Tumors may preferentially be screened for presence of a FGFR variant prior to treatment. The screening process will typically involve direct sequencing, oligonucleotide microarray analysis, or a mutant specific antibody. In addition, diagnosis of tumor with such genetic alteration could be performed using techniques known to a person skilled in the art and as described herein such as RT-PCR, FISH, next-generation sequencing (NGS).

[0239] In addition, genetic alterations of, for example FGFR, can be identified by direct sequencing of, for example, tumor biopsies using PCR and methods to sequence PCR products directly as hereinbefore described. The skilled artisan will recognize that all such well-known techniques for detection of the over expression, activation or mutations of the aforementioned proteins could be applicable in the present case.

[0240] In screening by RT-PCR, the level of mRNA in the tumor is assessed by creating a cDNA copy of the mRNA followed by amplification of the cDNA by PCR. Methods of PCR amplification, the selection of primers, and conditions for amplification, are known to a person skilled in the art. Nucleic acid manipulations and PCR are carried out by standard methods, as described for example in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc., or Innis, M.A. 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, a commercially available kit for RT-PCR (for example Roche Molecular Biochemicals) may be used, or methodology as set forth in United States patents 4,666,828; 4,683,202; 4,801,531; 5,192,659, 5,272,057, 5,882,864, and 6,218,529 and incorporated herein by reference. An example of an in-situ hybridization technique for assessing mRNA expression would be fluorescence in-situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152: 649). 73sf-5754313MoFo Docket No.: 76166-20030.40

[0241] Generally, in situ hybridization comprises the following major steps: (1) fixation of tissue to be analyzed; (2) prehybridization treatment of the sample to increase accessibility of target nucleic acid, and to reduce nonspecific binding; (3) hybridization of the mixture of nucleic acids to the nucleic acid in the biological structure or tissue; (4) post- hybridization washes to remove nucleic acid fragments not bound in the hybridization, and (5) detection of the hybridized nucleic acid fragments. The probes used in such applications are typically labelled, for example, with radioisotopes or fluorescent reporters. Preferred probes are sufficiently long, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to enable specific hybridization with the target nucleic acid(s) under stringent conditions. Standard methods for carrying out FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M. S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pps. 077-088; Series: Methods in Molecular Medicine.

[0242] 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) for priming first-strand cDNA synthesis, followed by second strand cDNA synthesis with random hexamer primers. The double-stranded cDNA is used as a template for in vitro transcription of cRNA using biotinylated ribonucleotides. cRNA is chemically fragmented according to protocols described by Affymetrix (Santa Clara, CA, USA), and then hybridized overnight on Human Genome Arrays.

[0243] Alternatively, the protein products expressed from the mRNAs may be assayed by immunohistochemistry of tumor samples, solid phase immunoassay with microtitre plates, Western blotting, 2-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and other methods known in the art for detection of specific proteins. Detection methods would include the use of site-specific antibodies. The skilled person will recognize that all such well-known techniques for detection of upregulation of FGFR or detection of FGFR variants or mutants could be applicable in the present case.

[0244] Abnormal levels of proteins such as FGFR can be measured using standard enzyme assays, for example, those assays described herein. Activation or overexpression could also be detected in a tissue sample, for example, a tumor tissue, by measuring the tyrosine kinase activity with an assay such as that from Chemicon International. The tyrosine kinase of interest would be immunoprecipitated from the sample lysate and its activity measured.

[0245] Alternative methods for the measurement of the over expression or activation of FGFR including the isoforms thereof, include the measurement of microvessel density. 74sf-5754313MoFo Docket No.: 76166-20030.40 This can for example be measured using methods described by Orre and Rogers (Int J Cancer (1999), 84(2) 101-8). Assay methods also include the use of markers.

[0246] Therefore, all of these techniques could also be used to identify tumors particularly suitable for treatment with the drug delivery systems of the invention.

[0247] According to certain embodiments, FGFR2 and / or FGFR3 genetic alterations can be identified using commercially available kits including, but not limiting to, a QIAGEN therascreen® FGFR RGQ RT-PCR kit.

[0248] According to certain embodiments, FGFR2 and / or FGFR3 genetic alterations can be identified in a liquid biological sample of the cancer patient, e.g. a urine sample.

[0249] According to certain embodiments, the analytes that can be used for FGFR(cfDNA), non-coding-RNA, exfoliated tumor cells, proteins.

[0250] According to certain embodiments, cfDNA can be analyzed in urine samples by ultracentrifugation or by molecular weight-based DNA separation techniques. For example DNA extraction from urine samples can be performed with the QIAamp DNA Blood Mini Kit (Qiagen, Valencia, CA, USA) according to the manufacturer^s instructions. The extracted cfDNA can be amplified and analyzed using the various procedures that include the polymerase chain reaction (PCR) and / or gene sequencing.

[0251] According to certain embodiments, urine-based molecular profiling can be performed using available kits including, but not limiting to, PCR and NGS assays. Non- limiting examples of available kits include: Urodiag® PCR Kit, which includes a mutation assay MASO (^Mutated Allele Specific Oligonucleotide)-PCR; AssureMDX which is a urine based test that studies e.g. mutations in FGFR3; PredicineCARETM, a urine cfDNA- based targeted NGS assay.

[0252] In some embodiments, the FGFR genetic alteration is detected using a NGS or PCR assay of a urine sample and a tumor tissue sample obtained from the patient. In some embodiments, there is high concordance between FGFR alterations detected with a urine sample assay and a tumor tissue sample assay. In some embodiments, a urine sample assay identifies bladder cancer patients that are not identified by a tumor tissue sample assay. In some embodiments, the patient is identified by a urine sample assay alone. In some embodiments, the patient is identified by a urine sample assay alone due to no available sample or insufficient tumor tissue. In some embodiments, a urine sample assay identifies at least about 5%, 10%, 15%, 20%, 25%, or 27% more bladder cancer patients than a tumor tissue sample assay. In some embodiments, a urine sample assay identifies between about 5% and 50%, 10% and 45%, 15% and 40%, 20% and 35%, or 25% and 30% more bladder cancer patients than a tumor tissue sample assay. In an embodiment, the urine sample assay is a NGS (next-generation sequencing) assay, in particular the PredicineCareTM(NGS) 75 sf-5754313MoFo Docket No.: 76166-20030.40 assay. In an embodiment, the tumor tissue sample assay is a PCR (polymerase chain reaction) assay, in particular the QIAGEN therascreen® FGFR RGQ RT-PCR kit.

[0253] In certain embodiments, a method of administering a drug to a patient includes inserting a drug delivery system as described herein into a patient and permitting the drug to be released from the system. For example, the system may include any features, or combinations of features, described herein. In one embodiment, the drug is released from the drug reservoir lumen via diffusion through the second material of the wall structure. In certain embodiments, a release profile of the drug is substantially independent of pH over a pH range of 5 to 7. In certain embodiments, a release profile of the drug is substantially independent of pH over a pH range of 5.5 to 7. In certain embodiments, a release profile of the drug is substantially independent of pH over a pH range of 5.5 to 8.

[0254] In certain embodiments, permitting the drug to be released from the system includes permitting water to be imbibed through the water permeable wall portions (e.g., through only the second wall structure / second material or through both the first and second wall structures / materials to solubilize the drug), and permitting the solubilized drug to be released from the system by diffusion through the second wall structure / material. That is, in certain embodiments, elution of drug from the system occurs following dissolution of the drug within the system. Bodily fluid enters the system, contacts the drug and solubilizes the drug, and thereafter the dissolved drug diffuses from the system. For example, the drug may be solubilized upon contact with urine in cases in which the system is inserted into the bladder. In one embodiment, releasing the drug from the system includes solubilizing the drug with water or an aqueous medium, such as for example urine, imbibed through the second wall structure / material, or both the first and second wall structures / materials.

[0255] In some embodiments, the device constituent of the system comprises a water- permeable and drug-impermeable base material and a water- and drug-permeable stripe material. For example, the base material may be a TPU such as Lubrizol^s CarbothaneTMAC-4075A or TecothaneTMAR-75A, and the stripe material may be a TPU such as a Lubrizol TECOFLEXTMTPU, such as EG-80A. (Lubrizol Life Science (Bethlehem, PA)).

[0256] In certain embodiments, the inserting comprises deploying the system through the patient^s urethra and into the patient^s urinary bladder. The system may release drug for several days, weeks, months, or more after the implantation procedure has ended. In one embodiment, deploying the drug delivery system in the patient includes inserting the system into a body cavity or lumen of the patient via a deployment instrument. For example, the system may be deployed through a deployment instrument, such as a catheter or cystoscope, positioned in a natural lumen of the body, such as the urethra, or into a body cavity, such as the bladder. The deployment instrument typically is removed from the body lumen while the drug delivery system remains in the bladder or other body cavity for a prescribed treatment period. 76sf-5754313MoFo Docket No.: 76166-20030.40

[0257] 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 body of the patient, e.g., in a body cavity such as the bladder. In embodiments, the system assumes a retention shape, such as an expanded or higher profile shape, once the system emerges from the deployment instrument into the cavity. The deployment instrument may be a commercially available system or a system specially adapted for the present drug delivery systems. In one embodiment, deploying the drug delivery system in the patient includes (i) elastically deforming the system into the relatively straightened shape; (ii) inserting the system through the patient^s urethra; and (iii) releasing the system into the patient^s bladder such that it assumes a coiled retention shape.

[0258] The drug delivery system may be passed through the deployment instrument, for example driven by a stylet, typically with aid of a lubricant, until the drug delivery system exits a lumen of the instrument and passes into the bladder.

[0259] In particular embodiments, the drug delivery systems described herein are deployed into a patient^s bladder transurethrally using a Urinary Placement Catheter, which comprises two components: a catheter-like shaft and a stylet that fits inside the shaft. The shaft may include a single lumen extrusion with an atraumatic distal tip that includes a Coudé bend, an exit port near the distal tip, and an internal lumen that extends from the exit port to an open proximal end. Depth markings on the shaft indicate insertion depth and orientation of the Coudé tip to assist with the intravesical drug delivery system insertion procedure. The stylet is a single lumen extrusion and is used to advance the drug delivery system through the clear shaft lumen and into the bladder.

[0260] Once deployed in vivo, the system subsequently releases the drug (e.g., erdafitinib) for the treatment of one or more conditions or diseases, locally to tissues at the deployment site. The release is controlled to release the drug in an effective amount over an extended period. Thereafter, the system may be removed, resorbed, excreted, or some combination thereof. In certain embodiments, the system resides in the bladder releasing the drug over a predetermined period, such as two weeks, three weeks, four weeks, a month, two months, three months or more.

[0261] The deployed system releases a desired quantity of drug over a desired, predetermined period. In embodiments, the system can deliver the desired dose of drug over an extended period, such as 12 hours, 24 hours, 2 days, 3 days, 5 days, 7 days, 10 days, 14 days, or 20, 25, 30, 45, 60, or 90 days, 6 months, or more. The rate of delivery and dosage of the drug can be selected depending upon the drug being delivered and the disease or condition being treated. In one embodiment, a rate of release of the drug from the drug delivery system is zero order over at least 36 hours. In one embodiment, a rate of the release of the drug from the drug delivery system is essentially zero order over at least 7 days, two weeks, three weeks, four weeks, a month, two months, three months or more. 77sf-5754313MoFo Docket No.: 76166-20030.40

[0262] Subsequently, the system may be retrieved from the body, such as in cases in which the system is non-bioerodible or otherwise needs to be removed. Retrieval systems for this purpose are known in the art or can be specially produced. The system also may be completely or partially bioerodible, resorbable, or biodegradable, such that retrieval is unnecessary, as either the entire system is resorbed or the system sufficiently degrades for expulsion, for example, from the bladder during urination. The system may not be retrieved or resorbed until some of the drug, or preferably most or all of the drug, has been released. If needed, a new drug-loaded system may subsequently be implanted, during the same procedure as the retrieval or at a later time. Methods of Making the Drug Delivery System

[0263] The systems described herein generally are formed by using a co-extrusion or 3D-printing process to form the elongated, elastic housing of the system; loading the drug reservoir lumen with a suitable quantity of the drug (e.g., with a suitable number of drug tablets); and closing off the ends of the tubular housing.

[0264] In some embodiments, the tubular wall structure may include a retention lumen extending through or along the structure. The retention lumen optionally may be loaded with an elastic retention frame, such as a nitinol wire or other superelastic wire, and then sealed to keep the frame inside the lumen and / or optionally may be filled with a gas (e.g., air) and then sealed at its ends prior or subsequent to drug loading of the system. In another embodiment, the retention lumen may be filled with high durometer silicone, prior to drug loading of the system, which is then cured into a solid, elastic form effective to bias the tubular wall structure in the coiled bladder retention shape.

[0265] In other embodiments, the method includes thermally shape setting the tubular structure to have a coiled retention shape which is elastically deformable into an uncoiled shape. In such embodiments, a retention lumen and frame may not be necessary.

[0266] Some steps or sub-steps of the method of making a drug delivery system may be performed in other orders or simultaneously.

[0267] The present disclosure may be further understood with reference to the following non-limiting examples. Embodiments 1. A solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N- [3-(l-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of at least 45 wt% of the solid pharmaceutical composition; and (b) at least one pharmaceutical excipient. 2. The solid pharmaceutical composition of embodiment 1, wherein the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent 78sf-5754313MoFo Docket No.: 76166-20030.40 (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, or any combination thereof. 3. The solid pharmaceutical composition of embodiment 1, wherein the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent (filler), a glidant, a lubricant, a formaldehyde scavenger, or any combination thereof. 4. A process for making a solid pharmaceutical composition comprising: (a) preparing an intragranular solid composition comprising or consisting essentially of: (i) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l- methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine); and (ii) 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) tableting the blend to form the solid pharmaceutical composition, wherein the erdafitinib free base is present in a concentration of at least 45 wt% of the solid pharmaceutical composition. 5. The process for making a solid pharmaceutical composition according to embodiment 4, wherein at least one intragranular pharmaceutical excipient and at least one extragranular pharmaceutical excipient comprise or are selected from at least one common (mutually occurring) pharmaceutical excipient. 6. The process for making a solid pharmaceutical composition according to embodiment 4, wherein the at least one intragranular excipient and the at least one extragranular pharmaceutical excipient do not comprise a common (mutually occurring) pharmaceutical excipient. 7. The process for making a solid pharmaceutical composition according to any of embodiments 4-6, wherein the intragranular solid composition is prepared by a roller compaction process. 8. The process for making a solid pharmaceutical composition according to any of embodiments 4-6, wherein the intragranular solid composition is prepared by a fluid bed granulation process. 79sf-5754313MoFo Docket No.: 76166-20030.40 9. The process for making a solid pharmaceutical composition according to any of embodiments 4-8, wherein the at least one extragranular pharmaceutical excipient comprises microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer, in particular in a weight ratio of 50:50. 10. The process for making a solid pharmaceutical composition according to any of embodiments 4-6, wherein: (a) the intragranular solid composition comprises a solubilizer, at least one binder, and a first quantity of a lubricant; (b) the extragranular pharmaceutical excipients comprise a diluent, a glidant, and a second quantity of a lubricant; and (c) the intragranular solid composition is prepared by a roller compaction process. 11. The process for making a solid pharmaceutical composition according to embodiment 10, wherein: the solubilizer is hydroxypropyl-beta-cyclodextrin; the binder is a combination of microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer; the lubricant is magnesium stearate; the diluent is anhydrous dibasic calcium phosphate; and the glidant is colloidal silicon dioxide. 12. The process for making a solid pharmaceutical composition according to any of embodiments 4-5, wherein: (a) the intragranular solid composition comprises a solubilizer, a diluent, and a disintegrant; (b) the extragranular pharmaceutical excipients comprise at least one binder and a lubricant; and (c) the intragranular solid composition is prepared by a fluid bed granulation process. 13. The process for making a solid pharmaceutical composition according to embodiment 12, wherein: the solubilizer comprises or is selected from hydroxypropyl-beta-cyclodextrin; the diluent comprises or is selected from microcrystalline cellulose; the disintegrant comprises or is selected from hydroxypropyl methylcellulose; 80sf-5754313MoFo Docket No.: 76166-20030.40 the at least one binder comprises or is selected from a combination of microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer; and the lubricant comprises or is selected from magnesium stearate. 14. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 1-13, wherein the erdafitinib free base is present in the solid pharmaceutical composition in a concentration of from 45 wt% to 55 wt%, from 47 wt% to 53 wt%, or about 50 wt%. 15. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 1-13, wherein the erdafitinib free base is present in the solid pharmaceutical composition in a concentration of from 45 wt% to 55 wt%, from 47 wt% to 53 wt%, or about 50 wt% and wherein the at least one extragranular excipient comprises microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer, in particular in a weight ratio of 50:50. 16. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 1-15, wherein the solid pharmaceutical composition further comprises a formaldehyde scavenger. 17. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 16, wherein the formaldehyde scavenger comprises or is selected from an amino acid, an amino sugar, an alpha-(a-)amine compound, conjugates thereof, or any combination thereof. 18. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 16, wherein the formaldehyde scavenger comprises or is selected from 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, pyrrolysine, asparagine, glutamine, tris(hydroxymethyl)aminomethane, conjugates thereof, pharmaceutically acceptable salts thereof, or any combination thereof. 19. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 16, wherein the formaldehyde scavenger is meglumine. 81sf-5754313MoFo Docket No.: 76166-20030.40 20. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 16-19, wherein the formaldehyde scavenger is present in the solid pharmaceutical composition in a concentration of from 0.01 wt% to 5 wt%, from 0.05 wt% to 3 wt%, from 0.1 wt% to 2 wt%, from 0.5 wt% to 1.5 wt%, or about 1 wt%. 21. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 1-20, wherein the solid pharmaceutical composition further comprises a compound having the formulaa salt thereof, a solvate thereof, or a combination thereof. 22. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 1-21, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises a solubilizer. 23. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 22, wherein the solubilizer comprises or is selected from (a) a cyclic oligosaccharide, (b) a cellulose which is functionalized with methoxy-, 2-hydroxypropoxy-, acetyl-, or succinoyl- moieties or a combination thereof, or (c) a salt thereof. 24. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 22, wherein the solubilizer comprises or is selected from hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrin sodium salt, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HPMC-E5), or any combination thereof. 25. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 22, wherein the at least one pharmaceutical excipient or the at least one intragranular pharmaceutical excipient comprises a solubilizer comprising hydroxypropyl-beta-cyclodextrin. 82 sf-5754313MoFo Docket No.: 76166-20030.40 26. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 22-25, wherein the total concentration of the solubilizer in the solid pharmaceutical composition is from 1 wt% to 20 wt%, from 5 wt% to 15 wt%, from 7 wt% to 12 wt%, or about 10 wt%. 27. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 1-26, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises at least one binder. 28. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 27, wherein the at least one binder comprises or is selected independently from a water soluble polymeric binder, a slightly water soluble polymeric binder, a water insoluble polymeric binder, or any combination thereof. 29. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 27, wherein the at least one binder comprises or is selected independently from polyvinylpyrrolidone (PVP), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO), polypropylene oxide (PPO), an ethylene glycol-propylene glycol copolymer, a poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, silicified microcrystalline cellulose, or combinations thereof. 30. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 27, wherein the at least one binder comprises or is selected from vinylpyrrolidone-vinyl acetate copolymer, silicified microcrystalline cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), or any combination thereof. 31. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 27, wherein the at least one binder comprises or is microcrystalline cellulose. 32. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 29-30, wherein the 83sf-5754313MoFo Docket No.: 76166-20030.40 vinylpyrrolidone-vinyl acetate copolymer has a molecular weight (Mw) range of from 45,000 g / mol to 70,000 g / mol. 33. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 27-32, wherein the total concentration of the at least one binder in the solid pharmaceutical composition is from 5 wt% to 30 wt%, from 10 wt% to 25 wt%, from 12 wt% to 22 wt%, or from 14 wt% to 19 wt%. 34. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 27-33, wherein the at least one binder comprises or further comprises a vinylpyrrolidone-vinyl acetate copolymer which is present in the solid pharmaceutical composition in a concentration of from 4 wt% to 12 wt%, from 6 wt% to 10 wt%, or from 7 wt% to 8 wt%. 35. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 27-34, wherein the at least one binder comprises or further comprises: (a) microcrystalline cellulose which is present in the solid pharmaceutical composition in a concentration of from 5 wt% to 20 wt%, from 6 wt% to 15 wt%, or from 7 wt% to 12 wt%; (b) silicified microcrystalline cellulose which is present in the solid pharmaceutical composition in a concentration of from 3 wt% to 18 wt%, from 4 wt% to 15 wt%, or from 5 wt% to 12 wt%; or (c) a combination of both (a) and (b). 36. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 1-35, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises a wetting agent. 37. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 36, wherein the wetting agent comprises or is an anionic surfactant. 38. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 36, wherein the wetting agent comprises or is selected independently from sodium lauryl sulfate, sodium stearyl fumarate, polysorbate 80, docusate sodium, or any combination thereof. 84sf-5754313MoFo Docket No.: 76166-20030.40 39. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 36-38, wherein the total concentration of the wetting agent in the solid pharmaceutical composition is from 0.01 wt% to 2.5 wt%, from 0.05 wt% to 1.0 wt%, or from 0.1 wt% to 0.5 wt%. 40. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 1-39, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises a disintegrant. 41. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 40, wherein the disintegrant comprises or is selected independently from a functionalized polysaccharide or a crosslinked polymer. 42. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 40, wherein the disintegrant comprises or is selected from (a) a cellulose which is functionalized with methoxy-, 2 hydroxypropoxy-, or carboxymethoxy- moieties, a salt thereof, or a combination thereof, (b) a carboxymethylated starch, or (c) a crosslinked polymer. 43. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 40, wherein the disintegrant comprises or is selected independently from hydroxypropyl methylcellulose, low- substituted hydroxypropylcellulose, crospovidone (crosslinked polyvinylpyrrolidone), croscarmellose sodium (cross-linked sodium carboxymethylcellulose), sodium starch glycolate, or any combination thereof. 44. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 40-43, wherein the total concentration of the disintegrant in the solid pharmaceutical composition is from 0.1 wt% to 3 wt%, from 0.5 wt% to 2.5 wt%, from 1 wt% to 2 wt%, or about 1.5 wt%. 45. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 1-44, wherein the at least one 85sf-5754313MoFo Docket No.: 76166-20030.40 pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises a diluent. 46. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 45, wherein the diluent comprises or is selected from a sugar, starch, microcrystalline cellulose, a sugar alcohol, a hydrogen phosphate salt, a dihydrogen phosphate salt, a carbonate salt, or combinations thereof. 47. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 45, wherein the diluent comprises or is selected from lactose (lactose monohydrate), dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, dibasic calcium phosphate, anhydrous dibasic calcium phosphate, calcium carbonate, sucrose, or any combination thereof. 48. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 45-47, wherein the total concentration of the diluent in the solid pharmaceutical composition is from 12 wt% to 30 wt%, from 15 wt% to 25 wt%, or from 18 wt% to 22 wt%. 49. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 47, wherein the diluent comprises or is selected from anhydrous dibasic calcium phosphate in a concentration of from 18 wt% to 20 wt%. 50. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 47, wherein the diluent comprises or is selected from microcrystalline cellulose in a concentration of from 20 wt% to 22 wt%. 51. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 1-50, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises a glidant. 52. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 51, wherein the glidant comprises or is selected from colloidal silicon dioxide, colloidal anhydrous silicon dioxide, talc, or any combination thereof. 86sf-5754313MoFo Docket No.: 76166-20030.40 53. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 51, wherein the glidant comprises or is colloidal silicon dioxide. 54. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 51-53, wherein the total concentration of the glidant in the solid pharmaceutical composition is from 0.01 wt% to 5 wt%, 0.05 wt% to 3 wt%, 0.1 wt% to 1 wt%, or about 0.5 wt%. 55. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 1-54, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises a lubricant. 56. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 55, wherein the lubricant comprises or is selected from a fatty acid, a fatty acid salt, a fatty acid ester, talc, a glyceride ester, a metal silicate, or any combination thereof. 57. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 55, wherein the lubricant comprises or is selected from magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactate, sodium stearoyl fumarate, titanium dioxide, or combinations thereof. 58. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 55, wherein the lubricant comprises or is magnesium stearate. 59. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 55-58, wherein the total concentration of the lubricant in the solid pharmaceutical composition is from 0.05 wt% to 5 wt%, 0.1 wt% to 3 wt%, 1 wt% to 2 wt%, or about 1.5 wt%. 60. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 1-59, wherein the solid pharmaceutical composition is a mini-tablet. 87sf-5754313MoFo Docket No.: 76166-20030.40 61. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 60, wherein the mini-tablet is in the form of a solid cylinder having a cylindrical axis, a cylindrical side face, circular end faces perpendicular to the cylindrical axis, a diameter across the circular end faces, and a length along the cylindrical side face. 62. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to embodiment 61, wherein length of the mini-tablet exceeds the diameter of the mini-tablet to provide the mini-tablet with an aspect ratio (length:diameter) of greater than 1:1. 63. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 61-62, wherein the mini- tablet has a diameter of from 1.0 mm to 3.2 mm, or from 1.5 mm to 3.1 mm. 64. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition according to any of embodiments 61-63, wherein the mini- tablet has a length of from 1.7 mm to 4.8 mm, or from 2.0 mm to 4.5 mm. 65. A solid pharmaceutical composition consisting essentially of: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N- [3-(l-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition; (c) meglumine in a concentration of 1 wt% of the solid pharmaceutical composition; (d) microcrystalline cellulose in a concentration of 10 wt% of the solid pharmaceutical composition; (e) anhydrous dibasic calcium phosphate in a concentration of 19 wt% of the solid pharmaceutical composition; 88sf-5754313MoFo Docket No.: 76166-20030.40 (f) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 8 wt% of the solid pharmaceutical composition; (g) colloidal silicon dioxide in a concentration of 0.5 wt% of the solid pharmaceutical composition; and (h) magnesium stearate in a concentration of 1.50 wt% of the solid pharmaceutical composition; or a solid pharmaceutical composition consisting essentially of: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N- [3-(l-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50-wt% of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin; (c) meglumine; (d) microcrystalline cellulose; (e) anhydrous dibasic calcium phosphate; (f) vinylpyrrolidone-vinyl acetate copolymer; (g) colloidal silicon dioxide; and (h) magnesium stearate. 66. A solid pharmaceutical composition consisting essentially of: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N- [3-(l-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition; (c) meglumine in a concentration of 1 wt% of the solid pharmaceutical composition; (d) microcrystalline cellulose in a concentration of 24.5 wt% of the solid pharmaceutical composition; (e) silicified microcrystalline cellulose in a concentration ofof the solid pharmaceutical composition; (f) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 6.0 wt% of the solid pharmaceutical composition; (g) colloidal silicon dioxide in a concentration of 0.5 wt% of the solid pharmaceutical composition; and (h) magnesium stearate in a concentration of 2.0 wt% of the solid pharmaceutical composition; or a solid pharmaceutical composition consisting essentially of: 89sf-5754313MoFo Docket No.: 76166-20030.40 (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N- [3-(l-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin; (c) meglumine; (d) microcrystalline cellulose; (e) silicified microcrystalline cellulose; (f) vinylpyrrolidone-vinyl acetate copolymer; (g) colloidal silicon dioxide; and (h) magnesium stearate. 67. A solid pharmaceutical composition consisting essentially of: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N- [3-(l-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition; (c) meglumine in a concentration of 1 wt% of the solid pharmaceutical composition; (d) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the solid pharmaceutical composition; (e) mannitol in a concentration of 21.0 wt% of the solid pharmaceutical composition; (f) sodium lauryl sulfate in a concentration of 0.25 wt% of the solid pharmaceutical composition; (g) microcrystalline cellulose in a concentration of 7.25 wt% of the solid pharmaceutical composition; (h) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.25 wt% of the solid pharmaceutical composition; (i) colloidal silicon dioxide in a concentration of 0.25 wt% of the solid pharmaceutical composition; and (j) magnesium stearate in a concentration of 1.50 wt% of the solid pharmaceutical composition; or a solid pharmaceutical composition consisting essentially of: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N- [3-(l-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin; (c) meglumine; 90sf-5754313MoFo Docket No.: 76166-20030.40 (d) hydroxypropyl methylcellulose; (e) mannitol; (f) sodium lauryl sulfate; (g) microcrystalline cellulose; (h) vinylpyrrolidone-vinyl acetate copolymer; (i) colloidal silicon dioxide; and (j) magnesium stearate. 68. A solid pharmaceutical composition consisting essentially of: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N- [3-(l-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition; (c) meglumine in a concentration of 1 wt% of the solid pharmaceutical composition; (d) microcrystalline cellulose in a concentration of 17.5 wt% of the solid pharmaceutical composition; (e) silicified microcrystalline cellulose in a concentration of 10.75 wt% of the solid pharmaceutical composition; (f) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.5 wt% of the solid pharmaceutical composition; (g) colloidal silicon dioxide in a concentration of 0.25 wt% of the solid pharmaceutical composition; (h) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the solid pharmaceutical composition; and (i) magnesium stearate in a concentration of 1.5 wt% of the solid pharmaceutical composition; or a solid pharmaceutical composition consisting essentially of: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N- [3-(l-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin; (c) meglumine; (d) microcrystalline cellulose; (e) silicified microcrystalline cellulose; (f) vinylpyrrolidone-vinyl acetate copolymer; (g) colloidal silicon dioxide; (h) hydroxypropyl methylcellulose; and 91sf-5754313MoFo Docket No.: 76166-20030.40 (i) magnesium stearate. 69. A process for making a solid pharmaceutical composition comprising: (a) preparing an intragranular solid composition by a roller compaction process, the intragranular solid composition consisting essentially of: (i) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N- [3-(l-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (ii) hydroxypropyl-beta-cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition; (iii) meglumine in a concentration ofof the solid pharmaceutical composition; (iv) microcrystalline cellulose in a concentration of 10 wt% of the solid pharmaceutical composition; (v) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 8 wt% of the solid pharmaceutical composition; and (vi) magnesium stearate in a concentration of 0.75 wt% of the solid pharmaceutical composition; (b) combining the intragranular solid composition with extragranular components to form a blend, wherein the extragranular components consist essentially of: (i) anhydrous dibasic calcium phosphate in a concentration of 19 wt% of the solid pharmaceutical composition; (ii) colloidal silicon dioxide in a concentration of 0.5 wt% of the solid pharmaceutical composition; and (iii) magnesium stearate in a concentration of 0.75 wt% of the solid pharmaceutical composition; and (c) tableting the blend to form of a solid pharmaceutical composition in the form of mini-tablets. 70. A process for making a solid pharmaceutical composition comprising: (a) preparing an intragranular solid composition by a roller compaction process, the intragranular solid composition consisting essentially of: (i) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N- [3-(l-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (ii) hydroxypropyl-beta-cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition; 92sf-5754313MoFo Docket No.: 76166-20030.40 (iii) meglumine in a concentration of 1 wt% of the solid pharmaceutical composition; (iv) microcrystalline cellulose in a concentration of 24.5 wt% of the solid pharmaceutical composition; (v) colloidal silicon dioxide in a concentration of 0.2 wt% of the solid pharmaceutical composition; and (vi) magnesium stearate in a concentration of 0.75 wt% of the solid pharmaceutical composition. (b) combining the intragranular solid composition with extragranular components to form a blend, wherein the extragranular components consist essentially of: (i) silicified microcrystalline cellulose in a concentration of 6.0 wt% of the solid pharmaceutical composition; (ii) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 6.0 wt% of the solid pharmaceutical composition; (iii) colloidal silicon dioxide in a concentration of 0.3 wt% of the solid pharmaceutical composition; and (iv) magnesium stearate in a concentration of 1.25 wt% of the solid pharmaceutical composition; and (c) tableting the blend to form of a solid pharmaceutical composition in the form of mini-tablets. 71. A process for making a solid pharmaceutical composition comprising: (a) preparing an intragranular solid composition by a fluid bed granulation process, the intragranular solid composition consisting essentially of: (i) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N- [3-(l-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (ii) hydroxypropyl-beta-cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition; (iii) meglumine in a concentration of 1 wt% of the solid pharmaceutical composition; (iv) mannitol in a concentration of 21 wt% of the solid pharmaceutical composition; (v) sodium lauryl sulfate in a concentration of 0.25 wt% of the solid pharmaceutical composition; and (vi) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the solid pharmaceutical composition; 93sf-5754313MoFo Docket No.: 76166-20030.40 (b) combining the intragranular solid composition with extragranular components to form a blend, wherein the extragranular components consist essentially of: (i) microcrystalline cellulose in a concentration of 7.25 wt% of the solid pharmaceutical composition; (ii) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.25 wt% of the solid pharmaceutical composition; (iii) colloidal silicon dioxide in a concentration of 0.25 wt% of the solid pharmaceutical composition; and (iv) magnesium stearate in a concentration of 1.50 wt% of the solid pharmaceutical composition; and (c) tableting the blend to form of a solid pharmaceutical composition in the form of mini-tablets. 72. A process for making a solid pharmaceutical composition comprising: (a) preparing an intragranular solid composition by a fluid bed granulation process, the intragranular solid composition consisting essentially of: (i) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N- [3-(l-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (ii) hydroxypropyl-beta-cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition; (iii) meglumine in a concentration of 1 wt% of the solid pharmaceutical composition; (iv) microcrystalline cellulose in a concentration of 10 wt% of the solid pharmaceutical composition; and (v) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the solid pharmaceutical composition; (b) combining the intragranular solid composition with extragranular components to form a blend, wherein the extragranular components consist essentially of: (i) microcrystalline cellulose in a concentration of 7.5 wt% of the solid pharmaceutical composition; and (ii) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.5 wt% of the solid pharmaceutical composition; (iii) silicified microcrystalline cellulose in a concentration of 10.75 wt% of the solid pharmaceutical composition; (iv) colloidal silicon dioxide in a concentration of 0.25 wt% of the solid pharmaceutical composition; and 94sf-5754313MoFo Docket No.: 76166-20030.40 (iv) magnesium stearate in a concentration of 1.5 wt% of the solid pharmaceutical composition; and (c) tableting the blend to form of a solid pharmaceutical composition in the form of mini-tablets. 73. A drug delivery system, comprising: a housing defining a closed drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being adjacent one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising a drug, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the drug and the second wall structure is permeable to the drug, such that the drug is releasable in vivo by diffusion through the second material forming the second wall structure. 74. A drug delivery system, comprising: a housing defining a closed drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being adjacent one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein the first material comprises an aromatic polyester hydrocarbon-based thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising a drug, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the drug and the second wall structure is permeable to the drug, such that the drug is releasable in vivo by diffusion through the second wall structure. 75. The drug delivery system of either one of embodiments 73 and 74, wherein the second wall structure forms a longitudinal strip extending along the length of the tube. 95sf-5754313MoFo Docket No.: 76166-20030.40 76. The system of any one of embodiments 73-75, wherein the system is configured to release a therapeutically effective amount of the drug at a substantially zero order release rate over at least 36 hours. 77. The system of any one of embodiments 73-76, wherein the system is configured to release the drug over a period of 2 days to 6 months. 78. The system of any one of embodiments 73-77, wherein the two interface edges are disposed at an arc angle of from 15 degrees to 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. 79. The system of any one of embodiments 73-78, wherein the drug comprises erdafitinib, in particular is erdafitinib. 80. The system of embodiment 79, wherein the system is configured to release the erdafitinib at an average rate of 1 mg / day to 10 mg / day. 81. The system of embodiment 79, wherein the system is configured to release the erdafitinib at an average rate of 1 mg / day to 2 mg / day. 82. The system of embodiment 81, wherein the two interface edges are disposed at an arc angle of 45 degrees to 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. 83. The system of embodiment 79, wherein the system is configured to release the erdafitinib at an average rate of 4 mg / day to 6 mg / day. 84. The system of embodiment 83, wherein the two interface edges are disposed at an arc angle of 150 degrees to 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. 85. The system of embodiment 79, wherein the system is configured to release the erdafitinib at an average rate of 1 mg / day. 86. The system of embodiment 85, wherein the two interface edges are disposed at an arc angle of about 45 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. 96sf-5754313MoFo Docket No.: 76166-20030.40 87. The system of embodiment 79, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day. 88. The system of embodiment 87, wherein the two interface edges are disposed at an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. 89. The system of embodiment 79, wherein the system is configured to release the erdafitinib at an average rate of 4 mg / day. 90. The system of embodiment 89, wherein the two interface edges are disposed at an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. 91. The system of embodiment 79, wherein the system is configured to release the erdafitinib at an average rate of 6 mg / day. 92. The system of embodiment 91, wherein the two interface edges are disposed at an arc angle of 210 degrees to 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. 93. The system of any one of embodiments 79-92, wherein the system comprises 500 mg of the erdafitinib. 94. The system of any one of embodiments 73-93, wherein a release profile of the drug is substantially independent of pH over a pH range of 5 to 7. 95. The system of any one of embodiments 73-94, wherein the second wall structure comprises less than 50 percent of a cross sectional area of the tube, in a cross section normal to the longitudinal axis of the tube. 96. The system of any one of embodiments 73-94, wherein the second wall structure comprises less than 25 percent of a cross sectional area of the tube, in a cross section normal to the longitudinal axis of the tube. 97. The system of any one of embodiments 73-96, wherein the tube has a substantially constant thickness over its circumference. 97sf-5754313MoFo Docket No.: 76166-20030.40 98. The system of any one of embodiments 73-97, further comprising a pair of end plugs and / or an adhesive material that seal the ends of the tube. 99. The system of any one of embodiments 73-98, wherein the first and second wall structures are integrally formed. 100. The system of embodiment 99, wherein the tube is formed in an extrusion process. 101. The system of any one of embodiments 73-100, wherein the system is elastically deformable between a relatively straightened deployment shape suited for insertion through the urethra of a patient and into the patient^s bladder and a retention shape suited to retain the system within the bladder. 102. The system of any one of embodiments 73-101, wherein the system is elastically deformable and comprises overlapping curls formed by the tube, and the tube has two opposing free ends, which are directed away from one another when the system is in a low-profile deployment shape and which are directed toward one another when the system is in a relatively expanded retention shape. 103. The system of any one of embodiments 73-102, wherein the system is elastically deformable and has a bi-oval retention shape, and the tube has two opposing free ends which lie within an outer boundary of the bi-oval retention shape. 104. The system of any one of embodiments 73-103, further comprising a retention frame lumen. 105. The system of embodiment 104, further comprising a nitinol wire disposed in the retention frame lumen. 106. The system of any one of embodiments 73-105, wherein the first material has a Shore durometer value from 70A to 80A. 107. The system of any one of embodiments 73-106, wherein the second material has a Shore durometer value from 70A to 75A. 98sf-5754313MoFo Docket No.: 76166-20030.40 108. The system of any one of embodiments 73-107, wherein the drug formulation comprises the solid pharmaceutical composition of any one of embodiments 1, 2, 3, and 14-68. 109. The system of any one of embodiments 73-108, wherein the drug formulation is in the form of a plurality of mini-tablets serially arranged in the drug lumen. 110. The system of embodiment 109, wherein the plurality of mini-tablets comprise the mini-tablets of any one of embodiments 60-64. 111. A drug delivery system, comprising: a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure. 112. The system of embodiment 111, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, and (i) the system is configured to release the erdafitinib at an average rate of 2 mg / day and the two interface edges are disposed at an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, (ii) the system is configured to release the erdafitinib at an average rate of 4 mg / day and the two interface edges are disposed at an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, or (iii) the system is configured to release the erdafitinib at an average rate of 6 mg / day and the two interface edges are disposed at an arc angle of 240 degrees. 113. A drug delivery system, comprising: a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic polyester hydrocarbon-based thermoplastic polyurethane 99sf-5754313MoFo Docket No.: 76166-20030.40 and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second wall structure. 114. The system of embodiment 113, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, and (i) the system is configured to release the erdafitinib at an average rate of 2 mg / day and the two interface edges are disposed at an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, or (ii) the system is configured to release the erdafitinib at an average rate of 4 mg / day and the two interface edges are disposed at an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. 115. The system of any one of embodiments 111-114, wherein the system is elastically deformable and comprises overlapping curls formed by the tube, and the tube has two opposing free ends, which are directed away from one another when the system is in a low-profile deployment shape and which are directed toward one another when the system is in a relatively expanded retention shape. 116. The systems of any one of embodiments 111-115, wherein a release profile of the erdafitinib is substantially independent of pH over a pH range of 5 to 7. 117. A drug delivery system, comprising: a housing defining a closed drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being adjacent one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, with the second wall structure forming a longitudinal strip extending along the length of the tube, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising the solid pharmaceutical composition of any one of embodiments 1, 2, 3 and 14-68, 100sf-5754313MoFo Docket No.: 76166-20030.40 wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the system is configured to release a therapeutically effective amount of the erdafitinib at a substantially zero order release rate over at least 3 days, and wherein (i) the system is configured to release the erdafitinib at an average rate of 2 mg / day and the two interface edges are disposed at an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, (ii) the system is configured to release the erdafitinib at an average rate of 4 mg / day and the two interface edges are disposed at an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, or (iii) the system is configured to release the erdafitinib at an average rate of 6 mg / day and the two interface edges are disposed at an arc angle of 240 degrees. 118. A drug delivery system, comprising: a housing defining a closed drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being adjacent one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, with the second wall structure forming a longitudinal strip extending along the length of the tube, wherein the first material comprises an aromatic polyester hydrocarbon-based thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising the solid pharmaceutical composition of any one of embodiments 1, 2, 3, and 14-68, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second wall structure, wherein the system is configured to release a therapeutically effective amount of the erdafitinib at a substantially zero order release rate over at least 3 days, and wherein (i) the system is configured to release the erdafitinib at an average rate of 2 mg / day and the two interface edges are disposed at an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, or (ii) the system is configured to release the erdafitinib at an average rate of 4 mg / day and the two 101sf-5754313MoFo Docket No.: 76166-20030.40 interface edges are disposed at an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. 119. A method of treatment of bladder cancer, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment of bladder cancer. 120. The method of embodiment 119, wherein the bladder cancer is muscle invasive bladder cancer. 121. The method of embodiment 119, wherein the bladder cancer is non-muscle invasive bladder cancer. 122. The method of embodiment 119, wherein the bladder cancer is bacillus calmette-guérin (BCG)-naïve. 123. The method of any one of embodiments 119-122, wherein the erdafitinib is in the form of the solid pharmaceutical composition of any one of embodiments 1, 2, 3 and 14-68. 124. A method of intravesical administration of erdafitinib, comprising: deploying an intravesical system into the bladder of a patient, the system comprising the solid pharmaceutical composition of any one of embodiments 1, 2, 3, and 14-68; and releasing the erdafitinib from the system. 125. The method of embodiment 124, wherein the intravesical system is the drug delivery system of any one of embodiments 73-118, and releasing the erdafitinib from the system comprises releasing the erdafitinib from the drug reservoir lumen via diffusion through the second wall structure. 126. The method of either of embodiments 124 or 125, wherein the system is elastically deformed into a low-profile deployment shape and inserted through the urethra and into the patient^s bladder, and then assumes a relatively expanded retention shape within the bladder. 127. A drug delivery system comprising: a device configured for intravesical deployment; and a drug formulation disposed within the device and comprising erdafitinib, 102sf-5754313MoFo Docket No.: 76166-20030.40 wherein the system is configured to release the erdafitinib from the device following intravesical deployment of the drug delivery system. 128. The drug delivery system of embodiment 127, wherein the drug formulation comprises a plurality of tablets which comprise the erdafitinib. 129. The drug delivery system of embodiment 128, wherein the tablets comprise the solid pharmaceutical composition of any one of embodiments 1, 2, 3 and 14-68. 130. The drug delivery system of any one of embodiments 127 to 129, wherein the system is configured to release the erdafitinib by diffusion through a drug permeable portion of the device. 131. The drug delivery system of any one of embodiments 127 to 130, wherein the system is configured to release the erdafitinib at a release rate from about 1 mg / day to about 6 mg / day, such as 2 to 4 mg / day. 132. A method of treating non-muscle invasive bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC) in a cancer patient, comprising: locally delivering a therapeutically effective amount of erdafitinib into the bladder of the patient. 133. The method of embodiment 132, wherein the locally delivering erdafitinib comprises releasing the erdafitinib from an intravesical system at a release rate from about 1 mg / day to about 6 mg / day, such as 2 to 4 mg / day. 134. The method of embodiment 133, wherein the intravesical system is maintained in the patient^s bladder for up to 90 days, and then, optionally, replaced with another erdafitinib-releasing intravesical system. 135. 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) muscle-invasive urothelial carcinoma of the bladder staged cT2-T3a in a cancer patient, comprising: locally delivering a therapeutically effective amount of erdafitinib into the bladder of the patient. 103sf-5754313MoFo Docket No.: 76166-20030.40 136. The method embodiment 131, wherein the patient undergoes transurethral resection of bladder tumor (TURBT) to reduce the total tumor(s) size to less than or equal to 3 cm, prior to the locally delivering of the erdafitinib into the bladder. 137. The method of embodiment 135 or 136, wherein the locally delivering erdafitinib comprises releasing the erdafitinib from an intravesical system at a release rate from about 1 mg / day to about 6 mg / day, such as 2 to 4 mg / day. 138. The method of embodiment 137, wherein the intravesical system is maintained in the patient^s bladder for up to 90 days, and then, optionally, replaced with another erdafitinib-releasing intravesical system. 139. A method of treating a Bacillus Calmette^Guérin (BCG) experienced patient having recurrent high-grade Ta / T1 urothelial carcinoma of the bladder within 18 months of completion of prior BCG therapy, comprising: locally delivering a therapeutically effective amount of erdafitinib into the bladder of the patient. 140. The method of embodiment 139, wherein the locally delivering erdafitinib comprises releasing the erdafitinib from an intravesical system at a release rate from about 1 mg / day to about 6 mg / day, such as 2 to 4 mg / day. 141. The method of embodiment 140, wherein the intravesical system is maintained in the patient^s bladder for up to 90 days, and then, optionally, replaced with another erdafitinib-releasing intravesical system. 142. The method of any one of embodiments 132 to 141, wherein the erdafitinib is locally delivered into the bladder from a drug delivery system according to any one of embodiments 127 to 131. 143. The method of any one of embodiments 132 to 142, wherein the patient harbors at least one FGFR2 genetic alteration and / or FGFR3 genetic alteration. Additional Embodiments 1. A method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment of bladder cancer, wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient, in particular wherein the 104sf-5754313MoFo Docket No.: 76166-20030.40 one or more FGFR genetic alterations are detected in a urine sample from the patient with a urine based PCR or NGS assay. 2. A method of treating bladder cancer harboring one or more FGFR genetic alterations comprising, consisting of, or consisting essential of: (a) evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations, in particular evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a urine based PCR or NGS assay; and (b) delivering locally erdafitinib if the one or more FGFR genetic alterations, is present in the sample. 3. A method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment, 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, in particular 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 with a urine based PCR or NGS assay. 4. A method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment, wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient with a urine based PCR or NGS assay. 5. Erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is locally delivered into the bladder of the patient and wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient with a urine based PCR or NGS assay. 6. Erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient comprising, consisting of, or consisting essential of (a) evaluating a urine sample from a patient with bladder cancer for the presence of one or more FGFR genetic alterations, in particular evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a urine 105sf-5754313MoFo Docket No.: 76166-20030.40 based PCR or NGS assay; and (b) delivering locally erdafitinib to the patient if the one or more FGFR genetic alterations, is present in the sample. 7. Erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and 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, in particular 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 with a urine based PCR or NGS assay. 8. Erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient with a urine based PCR or NGS assay. 9. Use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient, wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient with a urine based PCR or NGS assay. 10. Use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient comprising, consisting of, or consisting essential of: (a) evaluating a urine sample from the patient with bladder cancer for the presence of the one or more FGFR genetic alterations, in particular evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a urine based PCR or NGS assay; and (b) delivering locally erdafitinib if the one or more FGFR genetic alterations, is present in the sample. 11. Use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a urine 106sf-5754313MoFo Docket No.: 76166-20030.40 sample from the patient, in particular 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 with a urine based PCR or NGS assay. 12. Use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient with a urine based PCR or NGS assay. 13. The method, erdafitinib for use, or use according to any one of the preceding embodiments, wherein the one or more FGFR genetic alterations comprise one or more FGFR2 or FGFR3 genetic alterations. 14. The method, erdafitinib for use, or use according to any one of the preceding embodiments, wherein the one or more FGFR genetic alterations comprise one or more FGFR2 or FGFR3 point mutations or fusions. 15. The method, erdafitinib for use, or use according to any one of the preceding embodiments, wherein the one or more FGFR genetic alterations are detected in a urine sample of the patient before locally delivering erdafitinib. 16. The method, erdafitinib for use, or use according to any one of the preceding embodiments wherein erdafitinib is locally delivered in the form of a solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l- methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of at least 45 wt% of the solid pharmaceutical composition; and (b) at least one pharmaceutical excipient. 17. The method, erdafitinib for use, or use according to embodiment 16, wherein the at least one pharmaceutical excipient comprises a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, or any combination thereof. 107sf-5754313MoFo Docket No.: 76166-20030.40 18. The method, erdafitinib for use, or use according to embodiment 16 or 17, wherein the erdafitinib free base is present in the solid pharmaceutical composition in a concentration of from 45 wt% to 55 wt%, from 47 wt% to 53 wt%, or about 50 wt% and / or wherein the solid pharmaceutical composition comprises an intragranular solid composition comprising at least one intragranular pharmaceutical excipient and an extragranular solid composition comprising at least one extragranular pharmaceutical excipient and wherein the at least one extragranular pharmaceutical excipient comprises microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer, in particular in a weight ratio of 50:50. 19. The method, erdafitinib for use, or use according to any one of embodiments 16 to 18, wherein the solid pharmaceutical composition further comprises a formaldehyde scavenger selected from the group consisting of 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, pyrrolysine, asparagine, glutamine, tris(hydroxymethyl)aminomethane, conjugates thereof, pharmaceutically acceptable salts thereof, or any combination thereof. 20. The method, erdafitinib for use, or use according to embodiment 19, wherein the formaldehyde scavenger is meglumine. 21. The method, erdafitinib for use, or use according to embodiment 19 or 20 , wherein the formaldehyde scavenger is present in the solid pharmaceutical composition in a concentration of from 0.01 wt% to 5 wt%, from 0.05 wt% to 3 wt%, from 0.1 wt% to 2 wt%, from 0.5 wt% to 1.5 wt%, or about 1 wt%. 22. The method, erdafitinib for use, or use according to any one of embodiments 16 to 21, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises a solubilizer selected from the group consisting of hydroxypropyl-beta- cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrin sodium salt, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HPMC-E5), or any combination thereof. 23. The method, erdafitinib for use, or use according to embodiment 22, wherein the solubilizer is hydroxypropyl-beta-cyclodextrin. 108sf-5754313MoFo Docket No.: 76166-20030.40 24. The method, erdafitinib for use, or use according to embodiment 22 or 23, wherein the total concentration of the solubilizer in the solid pharmaceutical composition is from 1 wt% to 20 wt%, from 5 wt% to 15 wt%, from 7 wt% to 12 wt%, or about 10 wt%. 25. The method, erdafitinib for use, or use according to any one of embodiments 16 to 24, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises at least one binder selected from the group consisting of polyvinylpyrrolidone (PVP), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO), polypropylene oxide (PPO), an ethylene glycol- propylene glycol copolymer, a poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, silicified microcrystalline cellulose, and combinations thereof. 26. The method, erdafitinib for use, or use according to embodiment 25, wherein the total concentration of the at least one binder in the solid pharmaceutical composition is from 5 wt% to 30 wt%, from 10 wt% to 25 wt%, from 12 wt% to 22 wt%, or from 14 wt% to 19 wt%. 27. The method, erdafitinib for use, or use according to any one of embodiments 16 to 26, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises a wetting agent. 28. The method, erdafitinib for use, or use according to embodiment 27, wherein the wetting agent comprises sodium lauryl sulfate, sodium stearyl fumarate, polysorbate 80, docusate sodium, or any combination thereof. 29. The method, erdafitinib for use, or use according to embodiment 27 or 28, wherein the total concentration of the wetting agent in the solid pharmaceutical composition is from 0.01 wt% to 2.5 wt%, from 0.05 wt% to 1.0 wt%, or from 0.1 wt% to 0.5 wt%. 30. The method, erdafitinib for use, or use according to any one of embodiments 1 to 29, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises a disintegrant. 109sf-5754313MoFo Docket No.: 76166-20030.40 31. The method, erdafitinib for use, or use according to embodiment 30, wherein the disintegrant comprises hydroxypropyl methylcellulose, low-substituted hydroxypropylcellulose, crospovidone (crosslinked polyvinylpyrrolidone), croscarmellose sodium (cross-linked sodium carboxymethylcellulose), sodium starch glycolate, or any combination thereof. 32. The method, erdafitinib for use, or use according to embodiment 30 or 31, wherein the total concentration of the disintegrant in the solid pharmaceutical composition is from 0.1 wt% to 3 wt%, from 0.5 wt% to 2.5 wt%, from 1 wt% to 2 wt%, or about 1.5 wt%. 33. The method, erdafitinib for use, or use according to any one of embodiments 16 to 32, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises a diluent. 34. The method, erdafitinib for use, or use according to embodiment 33, wherein the diluent comprises lactose (lactose monohydrate), dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, dibasic calcium phosphate, anhydrous dibasic calcium phosphate, calcium carbonate, sucrose, or any combination thereof. 35. The method, erdafitinib for use, or use according to embodiment 33 or 34, wherein the total concentration of the diluent in the solid pharmaceutical composition is from 12 wt% to 30 wt%, from 15 wt% to 25 wt%, or from 18 wt% to 22 wt%. 36. The method, erdafitinib for use, or use according to any one of embodiments 16 to 35 , wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises a glidant. 37. The method, erdafitinib for use, or use according to embodiment 36, wherein the glidant comprises colloidal silicon dioxide, colloidal anhydrous silicon dioxide, talc, or any combination thereof. 38. The method, erdafitinib for use, or use according to embodiment 36 or 37, wherein the total concentration of the glidant in the solid pharmaceutical composition is from 0.01 wt% to 5 wt%, 0.05 wt% to 3 wt%, 0.1 wt% to 1 wt%, or about 0.5 wt%. 110sf-5754313MoFo Docket No.: 76166-20030.40 39. The method, erdafitinib for use, or use according to any one of embodiments 16 to 38, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises a lubricant. 40. The method, erdafitinib for use, or use according to embodiment 39, wherein the lubricant comprises magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactate, sodium stearoyl fumarate, titanium dioxide, or combinations thereof. 41. The method, erdafitinib for use, or use according to embodiment 39 or 40, wherein the total concentration of the lubricant in the solid pharmaceutical composition is from 0.05 wt% to 5 wt%, 0.1 wt% to 3 wt%, 1 wt% to 2 wt%, or about 1.5 wt%. 42. The method, erdafitinib for use, or use according to any one of embodiments 16 to 41, wherein the solid pharmaceutical composition is a mini-tablet. 43. The method, erdafitinib for use, or use according to embodiment 42, wherein the mini- tablet is in the form of a solid cylinder having a cylindrical axis, a cylindrical side face, circular end faces perpendicular to the cylindrical axis, a diameter across the circular end faces, and a length along the cylindrical side face. 44. The method, erdafitinib for use, or use according to embodiment 43, wherein length of the mini-tablet exceeds the diameter of the mini-tablet to provide the mini-tablet with an aspect ratio (length:diameter) of greater than 1:1. 45. The method, erdafitinib for use, or use according to embodiment 43 or 44, wherein the mini-tablet has a diameter of from 1.0 mm to 3.2 mm, or from 1.5 mm to 3.1 mm. 46. The method, erdafitinib for use, or use according to any one of embodiments 16, 42 to 45 wherein the solid pharmaceutical composition consists essentially of: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l- methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition; (c) meglumine in a concentration of 1 wt% of the solid pharmaceutical composition; 111sf-5754313MoFo Docket No.: 76166-20030.40 (d) microcrystalline cellulose in a concentration of 17.5 wt% of the solid pharmaceutical composition; (e) silicified microcrystalline cellulose in a concentration of 10.75 wt% of the solid pharmaceutical composition; (f) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.5 wt% of the solid pharmaceutical composition; (g) colloidal silicon dioxide in a concentration of 0.25 wt% of the solid pharmaceutical composition; (h) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the solid pharmaceutical composition; and (i) magnesium stearate in a concentration of 1.5 wt% of the solid pharmaceutical composition; or wherein the solid pharmaceutical composition comprises: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l- methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin; (c) meglumine; (d) microcrystalline cellulose; (e) silicified microcrystalline cellulose; (f) vinylpyrrolidone-vinyl acetate copolymer; (g) colloidal silicon dioxide; (h) hydroxypropyl methylcellulose; and (i) magnesium stearate. 47. The method, erdafitinib for use, or use according to any one of embodiments 16, 42 to 45, wherein the solid pharmaceutical composition comprises: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l- methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition; (c) microcrystalline cellulose in a concentration of 17.5 wt% of the solid pharmaceutical composition; (d) silicified microcrystalline cellulose in a concentration of 11.75 wt% of the solid pharmaceutical composition; (e) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.5 wt% of the solid pharmaceutical composition; 112sf-5754313MoFo Docket No.: 76166-20030.40 (f) colloidal silicon dioxide in a concentration of 0.25 wt% of the solid pharmaceutical composition; (g) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the solid pharmaceutical composition; and (h) magnesium stearate in a concentration of 1.5 wt% of the solid pharmaceutical composition; or wherein the solid pharmaceutical composition comprises: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l- methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin; (c) microcrystalline cellulose; (d) silicified microcrystalline cellulose; (e) vinylpyrrolidone-vinyl acetate copolymer; (f) colloidal silicon dioxide; (g) hydroxypropyl methylcellulose; and (h) magnesium stearate. 48. The method, erdafitinib for use, or use according to any one of embodiments 1 to 15, wherein erdafitinib is locally delivered in the form of a drug delivery system, comprising: a housing defining a closed drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being adjacent one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, such that erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure. 113sf-5754313MoFo Docket No.: 76166-20030.40 49. The method, erdafitinib for use, or use according to any one of embodiments 1 to 15, wherein erdafitinib is locally delivered in the form of a drug delivery system, comprising: a housing defining a closed drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being adjacent one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein the first material comprises an aromatic polyester hydrocarbon-based thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, such that erdafitinib is releasable in vivo by diffusion through the second wall structure. 50. The method, erdafitinib for use, or use according to embodiment 48 or 49, wherein the second wall structure forms a longitudinal strip extending along the length of the tube. 51. The method, erdafitinib for use, or use according to any one of embodiments 48 to 50, wherein the drug delivery system is configured to release erdafitinib over a period of 2 days to 6 months. 52. The method, erdafitinib for use, or use according to any one of embodiments 48 to 51, wherein the two interface edges are disposed at an arc angle of from 15 degrees to 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. 53. The method, erdafitinib for use, or use according to any one of embodiments 48 to 52, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 1 mg / day to 10 mg / day. 54. The method, erdafitinib for use, or use according to embodiment 53, wherein the two interface edges are disposed at an arc angle of 45 degrees to 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. 55. The method, erdafitinib for use, or use according to embodiment 53, wherein the two interface edges are disposed at an arc angle of 150 degrees to 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. 114sf-5754313MoFo Docket No.: 76166-20030.40 56. The method, erdafitinib for use, or use according to any one of embodiments 48 to 52, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day. 57. The method, erdafitinib for use, or use according to embodiment 56, wherein the two interface edges are disposed at an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. 58. The method, erdafitinib for use, or use according to any one of embodiments 48 to 52, wherein the system is configured to release the erdafitinib at an average rate of 4 mg / day. 59. The method, erdafitinib for use, or use according to embodiment 58, wherein the two interface edges are disposed at an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. 60. The method, erdafitinib for use, or use according to any one of embodiments 48 to 59, wherein the system comprises 500 mg of erdafitinib. 61. The method, erdafitinib for use, or use according to any one of embodiments 48 to 60, wherein a release profile of erdafitinib is substantially independent of pH over a pH range of 5 to 7. 62. The method, erdafitinib for use, or use according to any one of embodiments 48 to 61, wherein the second wall structure comprises less than 50 percent of a cross sectional area of the tube, in a cross section normal to the longitudinal axis of the tube. 63. The method, erdafitinib for use, or use according to any one of embodiments 48 to 62, wherein the second wall structure comprises less than 25 percent of a cross sectional area of the tube, in a cross section normal to the longitudinal axis of the tube. 64. The method, erdafitinib for use, or use according to any one of embodiments 48 to 63, wherein the tube has a substantially constant thickness over its circumference. 65. The method, erdafitinib for use, or use according to any one of embodiments 48 to 64, further comprising a pair of end plugs and / or an adhesive material that seal the ends of the tube. 115sf-5754313MoFo Docket No.: 76166-20030.40 66. The method, erdafitinib for use, or use according to any one of embodiments 48 to 65, wherein the first and second wall structures are integrally formed. 67. The method, erdafitinib for use, or use according to any one of embodiments 48 to 66, wherein the system is elastically deformable between a relatively straightened deployment shape suited for insertion through the urethra of a patient and into the patient^s bladder and a retention shape suited to retain the system within the bladder. 68. The method, erdafitinib for use, or use according to any one of embodiments 48 to 67, wherein the system is elastically deformable and comprises overlapping curls formed by the tube, and the tube has two opposing free ends, which are directed away from one another when the system is in a low-profile deployment shape and which are directed toward one another when the system is in a relatively expanded retention shape. 69. The method, erdafitinib for use, or use according to any one of embodiments 48 to 68, wherein the system is elastically deformable and has a bi-oval retention shape, and the tube has two opposing free ends which lie within an outer boundary of the bi-oval retention shape. 70. The method, erdafitinib for use, or use according to any one of embodiments 48 to 69, further comprising a retention frame lumen. 71. The method, erdafitinib for use, or use according to any one of embodiments 48 to 70, wherein the first material has a Shore durometer value from 70A to 80A. 72. The method, erdafitinib for use, or use according to any one of embodiments 48 to 71, wherein the drug formulation comprises the solid pharmaceutical composition as defined in any one of embodiments 16 to 47. 73. The method, erdafitinib for use, or use according to any one of embodiments 48 to 72, wherein the drug formulation is in the form of a plurality of mini-tablets serially arranged in the drug lumen. 74. The method, erdafitinib for use, or use according to embodiment 73, wherein the plurality of mini-tablets comprise the mini-tablets as defined in any one of embodiments 43 to 45. 116sf-5754313MoFo Docket No.: 76166-20030.40 75. The method, erdafitinib for use, or use according to any one of embodiments 1 to 15, wherein erdafitinib is locally delivered in the form of a drug delivery system, comprising: a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure. 76. The method, erdafitinib for use, or use according to embodiment 75, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, and (i) the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg / day and the two interface edges are disposed at an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, (ii) the drug delivery system is configured to release the erdafitinib at an average rate of 4 mg / day and the two interface edges are disposed at an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, or (iii) the drug delivery system is configured to release the erdafitinib at an average rate of 6 mg / day and the two interface edges are disposed at an arc angle of 240 degrees. 77. The method, erdafitinib for use, or use according to embodiment 75 or 76, wherein the system is elastically deformable and comprises overlapping curls formed by the tube, and the tube has two opposing free ends, which are directed away from one another when the system is in a low-profile deployment shape and which are directed toward one another when the system is in a relatively expanded retention shape. 78. The method, erdafitinib for use, or use according to any one of embodiments 1 to 15, wherein erdafitinib is locally delivered in the form of a drug delivery system, comprising: a housing defining a closed drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being adjacent one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, with the second wall structure forming a longitudinal strip extending along the length of the tube, wherein the first 117sf-5754313MoFo Docket No.: 76166-20030.40 material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising the solid pharmaceutical composition of any one of embodiments 16 to 47, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the drug delivery system is configured to release a therapeutically effective amount of the erdafitinib at a substantially zero order release rate over at least 3 days, and wherein (i) the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg / day and the two interface edges are disposed at an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, (ii) the drug delivery system is configured to release the erdafitinib at an average rate of 4 mg / day and the two interface edges are disposed at an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, or (iii) the drug delivery system is configured to release the erdafitinib at an average rate of 6 mg / day and the two interface edges are disposed at an arc angle of 240 degrees. 79. The method, erdafitinib for use, or use according to any one of embodiments 1 to 15, wherein erdafitinib is locally delivered in the form of a drug delivery system, comprising: a housing defining a closed drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, the first and s...

Claims

MoFo Docket No.: 76166-20030.40 CLAIMS We claim:

1. Erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is locally delivered into the bladder of the patient and wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient.

2. Erdafitinib for use of claim 1, wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient with a urine based PCR or NGS assay.

3. Erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient comprising, consisting of, or consisting essential of (a) evaluating a urine sample from a patient with bladder cancer for the presence of one or more FGFR genetic alterations; and (b) delivering locally erdafitinib to the patient if the one or more FGFR genetic alterations, is present in the sample.

4. Erdafitinib for use of claim 3, wherein the use comprises evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a urine based PCR or NGS assay.

5. Erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and 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.

6. Erdafitinib for use of claim 5, 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 with a urine based PCR or NGS assay 7. Erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient.

8. Erdafitinib for use of claim 7, wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient with a urine based PCR or NGS assay 156sf-5754313MoFo Docket No.: 76166-20030.40 9. Erdafitinib for use according to any one of claims 1-8, wherein the one or more FGFR genetic alterations comprise one or more FGFR2 or FGFR3 genetic alterations.

10. Erdafitinib for use according to any one of claims 1-9, wherein the one or more FGFR genetic alterations comprise one or more FGFR2 or FGFR3 point mutations or fusions.

11. Erdafitinib for use according to any one claims 1-10, wherein the one or more FGFR genetic alterations are detected in a urine sample of the patient before locally delivering erdafitinib.

12. Erdafitinib for use according to any one of claims 1-11, wherein the one or more FGFR genetic alterations is selected from FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, wherein FGFR3-TACC3 is FGFR3-TACC3 variant 1 (FGFR3-TACC3 V1) or FGFR3-TACC3 variant 3 (FGFR3-TACC3 V3), FGFR3- BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

13. Erdafitinib for use according to claim 12, wherein the FGFR2 genetic alteration and / or the FGFR3 genetic alteration is selected from FGFR3-TACC3 variant 1 (FGFR3-TACC3 V1) , FGFR3 G370C, FGFR3 S249C, FGFR3 Y373C, and FGFR3 R248C.

14. Erdafitinib for use according to any one of claims 1-13, wherein erdafitinib is locally delivered in the form of a solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l- methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of at least 45 wt% of the solid pharmaceutical composition; and (b) at least one pharmaceutical excipient.

15. Erdafitinib for use according to claim 14, wherein the at least one pharmaceutical excipient comprises a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, or any combination thereof.

16. Erdafitinib for use according to claim 14 or 15, wherein the erdafitinib free base is present in the solid pharmaceutical composition in a concentration of from 45 wt% to 55 wt%, from 47 wt% to 53 wt%, orand / or wherein the solid pharmaceutical composition comprises an intragranular solid composition comprising at least one intragranular pharmaceutical excipient and an extragranular solid composition comprising at least one extragranular pharmaceutical excipient and wherein the at least one 157sf-5754313MoFo Docket No.: 76166-20030.40 extragranular pharmaceutical excipient comprises microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer.

17. Erdafitinib for use according to any one of claims 14 to 16, wherein the at least one extragranular pharmaceutical excipient comprises microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer in a weight ratio of 50:

50.

18. Erdafitinib for use according to any one of claims 14 to 17, wherein the solid pharmaceutical composition further comprises a formaldehyde scavenger selected from the group consisting of 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, pyrrolysine, asparagine, glutamine, tris(hydroxymethyl)aminomethane, conjugates thereof, pharmaceutically acceptable salts thereof, or any combination thereof.

19. Erdafitinib for use according to claim 18, wherein the formaldehyde scavenger is meglumine.

20. Erdafitinib for use according to claim 18 or 19, wherein the formaldehyde scavenger is present in the solid pharmaceutical composition in a concentration of from 0.01 wt% to 5 wt%, from 0.05 wt% to 3 wt%, from 0.1 wt% to 2 wt%, from 0.5 wt% to 1.5 wt%, or about 1 wt%.

21. Erdafitinib for use according to any one of claims 14 to 20, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises a solubilizer selected from the group consisting of hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrin sodium salt, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HPMC-E5), or any combination thereof.

22. Erdafitinib for use according to claim 21, wherein the solubilizer is hydroxypropyl-beta- cyclodextrin.

23. Erdafitinib for use according to claim 21 or 22, wherein the total concentration of the solubilizer in the solid pharmaceutical composition is from 1 wt% to 20 wt%, from 5 wt% to 15 wt%, from 7 wt% to 12 wt%, or about 10 wt%. 158sf-5754313MoFo Docket No.: 76166-20030.40 24. Erdafitinib for use according to any one of claims 14 to 23, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises at least one binder selected from the group consisting of polyvinylpyrrolidone (PVP), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO), polypropylene oxide (PPO), an ethylene glycol-propylene glycol copolymer, a poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, silicified microcrystalline cellulose, and combinations thereof.

25. Erdafitinib for use according to claim 24, wherein the total concentration of the at least one binder in the solid pharmaceutical composition is from 5 wt% to 30 wt%, from 10 wt% to 25 wt%, from 12 wt% to 22 wt%, or from 14 wt% to 19 wt%.

26. Erdafitinib for use according to any one of claims 14 to 25, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises a wetting agent.

27. Erdafitinib for use according to claim 26, wherein the wetting agent comprises sodium lauryl sulfate, sodium stearyl fumarate, polysorbate 80, docusate sodium, or any combination thereof.

28. Erdafitinib for use according to claim 26 or 27, wherein the total concentration of the wetting agent in the solid pharmaceutical composition is from 0.01 wt% to 2.5 wt%, from 0.05 wt% to 1.0 wt%, or from 0.1 wt% to 0.5 wt%.

29. Erdafitinib for use according to any one of claims 14 to 28, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises a disintegrant.

30. Erdafitinib for use according to claim 29, wherein the disintegrant comprises hydroxypropyl methylcellulose, low-substituted hydroxypropylcellulose, crospovidone (crosslinked polyvinylpyrrolidone), croscarmellose sodium (cross-linked sodium carboxymethylcellulose), sodium starch glycolate, or any combination thereof. 159sf-5754313MoFo Docket No.: 76166-20030.40 31. Erdafitinib for use according to claim 29 or 30, wherein the total concentration of the disintegrant in the solid pharmaceutical composition is from 0.1 wt% to 3 wt%, from 0.5 wt% to 2.5 wt%, from 1 wt% to 2 wt%, or about 1.5 wt%.

32. Erdafitinib for use according to any one of claims 14 to 31, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises a diluent.

33. Erdafitinib for use according to claim 32, wherein the diluent comprises lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, dibasic calcium phosphate, anhydrous dibasic calcium phosphate, calcium carbonate, sucrose, or any combination thereof.

34. Erdafitinib for use according to claim 32 or 33, wherein the total concentration of the diluent in the solid pharmaceutical composition is from 12 wt% to 30 wt%, from 15 wt% to 25 wt%, or from 18 wt% to 22 wt%.

35. Erdafitinib for use according to any one of claims 14 to 34, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises a glidant.

36. Erdafitinib for use according to claim 35, wherein the glidant comprises colloidal silicon dioxide, colloidal anhydrous silicon dioxide, talc, or any combination thereof.

37. Erdafitinib for use according to claim 35 or 36, wherein the total concentration of the glidant in the solid pharmaceutical composition is from 0.01 wt% to 5 wt%, 0.05 wt% to 3 wt%, 0.1 wt% to 1 wt%, or about 0.5 wt%.

38. Erdafitinib for use according to any one of claims 14 to 37, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient or the at least one extragranular pharmaceutical excipient comprises or further comprises a lubricant.

39. Erdafitinib for use according to claim 38, wherein the lubricant comprises magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactate, sodium stearoyl fumarate, titanium dioxide, or combinations thereof. 160sf-5754313MoFo Docket No.: 76166-20030.40 40. Erdafitinib for use according to claim 38 or 39, wherein the total concentration of the lubricant in the solid pharmaceutical composition is from 0.05 wt% to 5 wt%, 0.1 wt% to 3 wt%, 1 wt% to 2 wt%, or about 1.5 wt%.

41. Erdafitinib for use according to any one of claims 14 to 40, wherein the solid pharmaceutical composition is a mini-tablet.

42. Erdafitinib for use according to claim 41, wherein the mini-tablet is in the form of a solid cylinder having a cylindrical axis, a cylindrical side face, circular end faces perpendicular to the cylindrical axis, a diameter across the circular end faces, and a length along the cylindrical side face.

43. The erdafitinib for use according to claim 42, wherein length of the mini-tablet exceeds the diameter of the mini-tablet to provide the mini-tablet with an aspect ratio (length:diameter) of greater than 1:

1.

44. Erdafitinib for use according to claim 42 or 43, wherein the mini-tablet has a diameter of from 1.0 mm to 3.2 mm, or from 1.5 mm to 3.1 mm.

45. Erdafitinib for use according to any one of claims 14, or 41 to 44 wherein the solid pharmaceutical composition comprises: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l- methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin; (c) meglumine; (d) microcrystalline cellulose; (e) silicified microcrystalline cellulose; (f) vinylpyrrolidone-vinyl acetate copolymer; (g) colloidal silicon dioxide; (h) hydroxypropyl methylcellulose; and (i) magnesium stearate.

46. Erdafitinib for use according to any one of claims 14, 41 to 44, wherein the solid pharmaceutical composition consists essentially of: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l- methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; 161sf-5754313MoFo Docket No.: 76166-20030.40 (b) hydroxypropyl-beta-cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition; (c) meglumine in a concentration of 1 wt% of the solid pharmaceutical composition; (d) microcrystalline cellulose in a concentration of 17.5 wt% of the solid pharmaceutical composition; (e) silicified microcrystalline cellulose in a concentration of 10.75 wt% of the solid pharmaceutical composition; (f) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.5 wt% of the solid pharmaceutical composition; (g) colloidal silicon dioxide in a concentration of 0.25 wt% of the solid pharmaceutical composition; (h) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the solid pharmaceutical composition; and (i) magnesium stearate in a concentration of 1.5 wt% of the solid pharmaceutical composition.

47. Erdafitinib for use according to any one of claims 14, 41 to 44, wherein the solid pharmaceutical composition comprises: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l- methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin; (c) microcrystalline cellulose; (d) silicified microcrystalline cellulose; (e) vinylpyrrolidone-vinyl acetate copolymer; (f) colloidal silicon dioxide; (g) hydroxypropyl methylcellulose; and (h) magnesium stearate.

48. Erdafitinib for use according to any one of claims 14, 41 to 44, wherein the solid pharmaceutical composition comprises: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l- methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition; (c) microcrystalline cellulose in a concentration of 17.5 wt% of the solid pharmaceutical composition; 162sf-5754313MoFo Docket No.: 76166-20030.40 (d) silicified microcrystalline cellulose in a concentration of 11.75 wt% of the solid pharmaceutical composition; (e) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.5 wt% of the solid pharmaceutical composition; (f) colloidal silicon dioxide in a concentration of 0.25 wt% of the solid pharmaceutical composition; (g) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the solid pharmaceutical composition; and (h) magnesium stearate in a concentration of 1.5 wt% of the solid pharmaceutical composition.

49. Erdafitinib for use according to any one of claims 1 to 13, wherein erdafitinib is locally delivered in the form of a drug delivery system, comprising: a housing defining a closed drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being adjacent one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, such that erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure.

50. Erdafitinib for use according to any one of claims 1 to 13, wherein erdafitinib is locally delivered in the form of a drug delivery system, comprising: a housing defining a closed drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being adjacent one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein the first material comprises an aromatic polyester hydrocarbon-based thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising erdafitinib, 163sf-5754313MoFo Docket No.: 76166-20030.40 wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, such that erdafitinib is releasable in vivo by diffusion through the second wall structure.

51. Erdafitinib for use according to claim 49 or 50, wherein the second wall structure forms a longitudinal strip extending along the length of the tube.

52. Erdafitinib for use according to any one of claims 49 to 51, wherein the drug delivery system is configured to release erdafitinib over a period of 2 days to 6 months.

53. Erdafitinib for use according to any one of claims 49 to 52, wherein the two interface edges are disposed at an arc angle of from 15 degrees to 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

54. Erdafitinib for use according to any one of claims 49 to 53, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 1 mg / day to 10 mg / day.

55. Erdafitinib for use according to claim 54, wherein the two interface edges are disposed at an arc angle of 45 degrees to 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

56. Erdafitinib for use according to claim 54, wherein the two interface edges are disposed at an arc angle of 150 degrees to 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

57. Erdafitinib for use according to claim 54, wherein the two interface edges are disposed at an arc angle of 90 degrees to 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

58. Erdafitinib for use according to any one of claims 49 to 53 or 57, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day to 4 mg / day.

59. Erdafitinib for use according to any one of claims 49 to 53 , wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day. 164sf-5754313MoFo Docket No.: 76166-20030.40 60. Erdafitinib for use according to claim 59, wherein the two interface edges are disposed at an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

61. Erdafitinib for use according to any one of claims 49 to 53, wherein the system is configured to release the erdafitinib at an average rate of 4 mg / day.

62. Erdafitinib for use according to claim 61, wherein the two interface edges are disposed at an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

63. Erdafitinib for use according to any one of claims 49 to 62, wherein the system comprises 500 mg of erdafitinib.

64. Erdafitinib for use according to any one of claims 49 to 63, wherein a release profile of erdafitinib is substantially independent of pH over a pH range of 5 to 7.

65. Erdafitinib for use according to any one of claims 49 to 64, wherein the second wall structure comprises less than 50 percent of a cross sectional area of the tube, in a cross section normal to the longitudinal axis of the tube; or wherein the second wall structure comprises less than 25 percent of a cross sectional area of the tube, in a cross section normal to the longitudinal axis of the tube.

66. Erdafitinib for use according to any one of claims 49 to 65, wherein the tube has a substantially constant thickness over its circumference; or wherein the tube further comprises a pair of end plugs and / or an adhesive material that seal the ends of the tube; or wherein the first and second wall structures are integrally formed.

67. Erdafitinib for use according to any one of claims 49 to 66, wherein the system is elastically deformable between a relatively straightened deployment shape suited for insertion through the urethra of a patient and into the patient^s bladder and a retention shape suited to retain the system within the bladder.

68. Erdafitinib for use according to any one of claims 49 to 67, wherein the system is elastically deformable and comprises overlapping curls formed by the tube, and the tube has two opposing free ends, which are directed away from one another when the system is in a low-profile deployment shape and which are directed toward one another when the system is in a relatively expanded retention shape. 165sf-5754313MoFo Docket No.: 76166-20030.40 69. Erdafitinib for use according to any one of claims 49 to 68, wherein the system is elastically deformable and has a bi-oval retention shape, and the tube has two opposing free ends which lie within an outer boundary of the bi-oval retention shape.

70. Erdafitinib for use according to any one of claims 49 to 69, further comprising a retention frame lumen.

71. Erdafitinib for use according to any one of claims 49 to 70, wherein the first material has a Shore durometer value from 70A to 80A.

72. Erdafitinib for use according to any one of claims 49 to 71, wherein the drug formulation comprises the solid pharmaceutical composition as defined in any one of claims 14 to 48.

73. Erdafitinib for use according to any one of claims 49 to 72, wherein the drug formulation is in the form of a plurality of mini-tablets serially arranged in the drug lumen.

74. Erdafitinib for use according to claim 73, wherein the plurality of mini-tablets comprise the mini-tablets as defined in any one of claims 42 to 44.

75. Erdafitinib for use according to any one of claims 1 to 13, wherein erdafitinib is locally delivered in the form of a drug delivery system, comprising: a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure.

76. Erdafitinib for use according to claim 75, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, and (i) the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg / day and 166sf-5754313MoFo Docket No.: 76166-20030.40 the two interface edges are disposed at an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, (ii) the drug delivery system is configured to release the erdafitinib at an average rate of 4 mg / day and the two interface edges are disposed at an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, or (iii) the drug delivery system is configured to release the erdafitinib at an average rate of 6 mg / day and the two interface edges are disposed at an arc angle of 240 degrees.

77. Erdafitinib for use according to claim 75 or 76, wherein the system is elastically deformable and comprises overlapping curls formed by the tube, and the tube has two opposing free ends, which are directed away from one another when the system is in a low- profile deployment shape and which are directed toward one another when the system is in a relatively expanded retention shape.

78. Erdafitinib for use according to any one of claims 1 to 13, wherein erdafitinib is locally delivered in the form of a drug delivery system, comprising: a housing defining a closed drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being adjacent one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, with the second wall structure forming a longitudinal strip extending along the length of the tube, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising the solid pharmaceutical composition of any one of claims 14 to 48, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the drug delivery system is configured to release a therapeutically effective amount of the erdafitinib at a substantially zero order release rate over at least 3 days, and wherein (i) the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg / day and the two interface edges are disposed at an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, (ii) the drug delivery system is configured to release the erdafitinib at an average rate of 4 mg / day and the two interface edges are disposed at an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the 167sf-5754313MoFo Docket No.: 76166-20030.40 tube, or (iii) the drug delivery system is configured to release the erdafitinib at an average rate of 6 mg / day and the two interface edges are disposed at an arc angle of 240 degrees.

79. Erdafitinib for use according to any one of claims 1 to 13, wherein erdafitinib is locally delivered in the form of a drug delivery system, comprising: a housing defining a closed drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being adjacent one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, with the second wall structure forming a longitudinal strip extending along the length of the tube, wherein the first material comprises an aromatic polyester hydrocarbon-based thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising the solid pharmaceutical composition of any one of claims 14 to 48, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second wall structure, wherein the drug delivery system is configured to release a therapeutically effective amount of the erdafitinib at a substantially zero order release rate over at least 3 days, and wherein (i) the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg / day and the two interface edges are disposed at an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, or (ii) the drug delivery system is configured to release the erdafitinib at an average rate of 4 mg / day and the two interface edges are disposed at an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

80. Erdafitinib for use according to any one of claims 73 to 79, wherein the drug delivery system comprises 44-46 of erdafitinib minitablets.

81. Erdafitinib for use according to any one of claims 73 to 80, wherein the drug formulation comprises the solid pharmaceutical formulation of any one of claims 45-46.

82. Erdafitinib for use according to any one of claims 73 to 80, wherein the drug formulation comprises the solid pharmaceutical formulation of any one of claims 47-48. 168sf-5754313MoFo Docket No.: 76166-20030.40 83. Erdafitinib for use according to any one of claims 49 to 82, wherein the first material comprises AC-4075A-B20 or AR-75A and the second material comprises EG-80A.

84. Erdafitinib for use according to any one of claims 49 to 83, wherein the first material has a shore hardness of about 78A; specific gravity of about 1.38; ultimate tensile (psi) of about 8300; ultimate elongation (%) of about 400 (D412); tensile modulus (psi) of about 560 at 100% elongation, about 1300 at 200% elongation, and about 3400 at 300% elongation (ASTM D412); flexural modulus (psi) of about 1800; Vicat temperature (°C) of about 55; and / or mold shrinkage (in / in) (1^x0.25^x6^ bar) of about 0.011 (ASTM D955).

85. Erdafitinib for use according to any one of claims 49 to 84, wherein the second material has a shore hardness of about 72A; specific gravity of about 1.04; flexural modulus (psi) of 1,000; ultimate tensile (psi) of about 5,800; ultimate elongation (%) of about 660 (D412); tensile modulus (psi) of about 300 at 100% elongation, about 500 at 200% elongation, and about 800 at 300% elongation (ASTM D412); and mold shrinkage (in / in) of about 0.008- 0.0012.

86. Erdafitinib for use according to any one of claims 49 to 83, wherein the first material has a shore hardness of about 79A; a specific gravity of about 1.03; ultimate tensile (psi) of about 2000; ultimate elongation (%) of about 530; tensile modulus (psi) of about 730 at 100% elongation, about 1000 at 200% elongation, and about 1300 at 300% elongation; flexural modulus (psi) of about 2500 (ASTM 790); Vicat softening point (°C) of about 75; and mold shrinkage (in / in) (1^x0.25^x6^ bar) of about 0.

08. 169sf-5754313

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