Methods of treating bladder cancer using intravesical administration of erdafitinib

Abstract

Provided herein are methods of treatment comprising administering erdafitinib and drug delivery systems comprising erdafitinib for use in the treatment of bladder cancer.

Description

METHODS OF TREATING BLADDER CANCER USING INTRAVESICAL ADMINISTRATION OF ERDAFITINIBCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application Nos. 63 / 582,833, filed September 14, 2023; 63 / 582,835, filed September 14, 2023;63 / 583,820, filed September 19, 2023; 63 / 590,367, filed October 13, 2023; 63 / 590,368, filed October 13, 2023; 63 / 590,370, filed October 13, 2023; 63 / 590,376, filed October 13, 2023; 63 / 623,192, filed January 19, 2024; 63 / 561,725, filed March 5, 2024; 63 / 566,181, filed March 15, 2024; 63 / 640,816, filed April 30, 2024; and 63 / 691,878, filed September 6, 2024, the contents of each of which are incorporated herein in their entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (761662002540seqlist.xml; Size: 53,246 bytes; and Date of Creation: August 28, 2024) is herein incorporated by reference in its entirety.FIELD OF THE INVENTION

[0003] The present disclosure is generally in the field of methods of treatment for bladder cancer.BACKGROUND

[0004] The present disclosure is generally in the field of pharmaceutical formulations and drug-device combination products, and more particularly relates to erdafitinib based formulations and systems for intravesical administration of such formulations.

[0005] Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl-lH- pyrazol-4-yl)quinoxalin-6-yl]ethane-l,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.

[0006] Currently, Erdafitinib (BAL VERSA®) 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.

[0007] Individuals with high-risk NMIBC are often initially treated with BCG, however up to 50% of patients experience recurrence. A subset of patients may receive a radical cystectomy, however the utility of radical cystectomy is limited due to high morbidity and decreased quality of life.BRIEF SUMMARY

[0008] Provided herein are methods of treating recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) comprising administering erdafitinib locally to the bladder of a patient. Also provided herein are methods of treating recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising administering erdafitinib locally to the bladder of a patient.

[0009] In some aspects, a drug delivery system is provided herein, 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, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 2.5 mg / day to about 3.5 mg / day, and wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure.

[0010] In some aspects, a drug delivery system is provided herein, 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, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 3 mg / day and wherein the two interface edges are disposed at an arc angle of about 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] 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.

[0012] 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.

[0013] FIG. 2 is a transverse cross-sectional view of one embodiment of a drug delivery system, in accordance with the present disclosure.

[0014] FIG. 3 is a transverse cross-sectional view of one embodiment of a drug delivery system, in accordance with the present disclosure.

[0015] FIG. 4 is a photograph of one embodiment of a drug delivery system loaded with erdafitinib drug tablets, in accordance with the present disclosure.

[0016] 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.

[0017] 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.

[0018] FIG. 6B is a partial magnified view of one end of the retention frame of FIG. 6A.

[0019] 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.

[0020] FIG. 7B is a longitudinal cross-sectional view of the drug delivery system shown in FIG. 7A, taken along line 7B-7B.

[0021] FIG. 7C is a transverse cross-sectional view of the drug delivery system shown in FIG. 7A, taken along line 7C-7C.

[0022] 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.

[0023] FIG. 9A shows the two doses for erdafitinib treatment (TAR-210-B, about 2mg / day; TAR-210-D, about 4 mg / day) and the two cohorts of participants treated in the clinical study described herein in Example 1.

[0024] FIG. 9B depicts a clinical protocol for administration of erdafitinib. TURBT, transurethral resection of the bladder tumor as described herein in Example 1.

[0025] FIG. 10 shows a summary of demographics for the 43 patients in Cohorts 1 and 3 treated in the clinical study (16 patients from Cohort 1 and 27 patients from Cohort 3) described herein in Example 1, Part A.

[0026] FIGS. 11A-11B shows a summary of baseline disease characteristics for the 43 patients treated in the clinical study described herein in Example 1, Part A.

[0027] FIG. 12A is a swim lane plot for treatment duration and response of patients in Cohort 1 of the clinical study described herein in Example 1, Part A, treated with TAR-210-B (about 2 mg / day erdafitinib; diagonally striped) or TAR-210-D (about 4 mg / day erdafitinib; dotted). A key describing patient treatment status and milestones is included. Non-CR, noncomplete response; non-PD, non-progressive disease.

[0028] FIG. 12B is a swim lane plot for treatment duration and response of patients in Cohort 3 of the clinical study described herein in Example 1, Part A, treated with TAR-210-B (about 2 mg / day erdafitinib; diagonally striped) or TAR-210-D (about 4 mg / day erdafitinib; dotted). A key describing patient treatment status and milestones is included. Non-CR, noncomplete response; non-PD, non-progressive disease.

[0029] FIG. 13 shows a summary of recurrence-free survival for the 16 patients treated in Cohort 1 of the clinical study of Example 1, Part A.

[0030] FIG. 14 shows a summary of complete response for the 15 patients treated and showing treatment efficacy in Cohort 3 of the clinical study of Example 1, Part A.

[0031] FIG. 15 shows a summary of the duration of response for the 13 patients achieving complete response in Cohort 3 of the clinical study of Example 1, Part A.

[0032] FIG. 16 shows a summary of treatment disposition for the 43 patients treated in Cohorts 1 and 3 of the described clinical study of Example 1, Part A, including ongoing study treatment, completed study treatment, and discontinued study treatment.

[0033] FIG. 17 shows a summary of treatment-emergent adverse effects for 43 patients treated in Cohorts 1 and 3 of the described clinical study in Example 1, Part A.

[0034] FIG. 18 shows the quantified urine concentration of erdafitinib (left) and the quantified plasma concentration of erdafitinib (right) from patient samples after TAR-210-B (dashed line) or TAR-210-D (solid line) administration in Example 1, Part A.

[0035] FIG. 19A is a schematic overview of a clinical study related to the safety and efficacy of an intravesical drug delivery system (TAR-210) in the treatment of patients with intermediate risk (IR) non-muscle invasive bladder cancer (NMIBC), described in Example 2. SOC, standard of care; LG, low-grade; MMC, mitomycin C; Gem, gemcitabine.

[0036] FIG. 19B is a schematic overview of the treatment phase of the clinical study described in Example 2. Patients are randomized 1 : 1 and treated as described in Group A with either the intravesical drug delivery system (TAR-210) or Group B with gemcitabine or MMC for up to 1 year. TURBT, transurethral resection of bladder tumor; CT, computed tomography; IV, intravenous; MRI, magnetic resonance imaging; EOT, end of treatment.

[0037] FIG. 20 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.

[0038] FIG. 21 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).

[0039] FIG. 22A 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.

[0040] FIG. 22B 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.

[0041] FIG. 23 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 1.

[0042] FIG. 24A 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; circle pattern) or TAR-210-D (about 4 mg / day erdafitinib; dash pattern). Patients are from the first in human study as described in Example 1. 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).

[0043] FIG. 24B 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; circle pattern) or TAR-210-D (about 4 mg / day erdafitinib; dash pattern). Patients are from the first in human study as described in Example 1. 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).

[0044] FIG. 25 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.

[0045] FIGS. 26A-26D show an updated protocol for the Phase I clinical trial of intravesical administration of erdafitinib of Example 1.

[0046] FIG. 27A is a top, schematic view of an embodiment of a drug delivery system according to the present disclosure, shown in a coiled retention shape. In FIG. 27A, the portion of the housing bounding the drug reservoir lumen is shown as being translucent, revealing the erdafitinib minitablets contained therein.

[0047] FIG. 27B is a bottom, schematic view of the drug delivery system of FIG. 27A, shown in a coiled retention shape. In FIG. 27B, the portion of the housing bounding the drug reservoir lumen is shown as being translucent, revealing the erdafitinib minitablets contained therein.

[0048] FIG. 28 is a transverse cross-sectional view of the drug delivery system of FIG. 27A, taken along lines A-A of FIG. 27A.

[0049] FIG. 29A is a side, schematic view of the drug delivery system of FIG. 27A, shown in a relatively straightened insertion shape. In FIG. 29A, the portion of the housing bounding the drug reservoir lumen is shown as being translucent, revealing the erdafitinib minitablets contained therein.

[0050] FIG. 29B is a side cross-sectional view of a portion of the drug delivery system of FIG. 27A, shown in a relatively straightened insertion shape. In FIG. 29B, the housing is shown in cross section to reveal the erdafitinib minitablets located in the drug reservoir lumen and the retention frame located in the retention frame lumen; the ends of the drug delivery system are truncated.

[0051] FIG. 30A shows a summary of demographics for the 64 patients in Cohorts 1 and 3 treated in the clinical study (21 patients from Cohort 1 and 43 patients from Cohort 3) described herein in Example 1, Part C.

[0052] FIG. 30B shows a summary of baseline disease characteristics for the 64 patients treated in the clinical study (21 patients from Cohort 1 and 43 patients from Cohort 3) described herein in Example 1, Part C.

[0053] FIG. 31A is a swim lane plot for treatment duration and response of patients in Cohort 1 of the clinical study described herein in Example 1, Part C, treated with TAR-210-B (about 2 mg / day erdafitinib; circle pattern) or TAR-210-D (about 4 mg / day erdafitinib; dash pattern). A key describing patient treatment status and milestones is included. RFS, recurrence-free survival.

[0054] FIG. 31B is a swim lane plot for treatment duration and response of patients in Cohort 3 of the clinical study described herein in Example 1, Part C, treated with TAR-210-B (about 2 mg / day erdafitinib; circle pattern) or TAR-210-D (about 4 mg / day erdafitinib; dotted pattern). A key describing patient treatment status and milestones is included. DOR, duration of response; CR, complete response; Non-CR, non-complete response; non-PD, nonprogressive disease.

[0055] FIG. 32A shows the urine concentration of erdafitinib from patient samples after TAR-210-B or TAR-210-D administration in Example 1, Part C.

[0056] FIG. 32B shows the plasma concentration of erdafitinib from patient samples after TAR-210-B or TAR-210-D administration in Example 1, Part C.

[0057] FIG. 33 shows pie charts demonstrating the proportion of efficacy evaluable patients enrolled by urine and tissue sample for Cohort 1 (HR-NMIBC) and Cohort 3 (IR- NMIBC) patients in Example 4, Part B.

[0058] FIG. 34A shows a diagram illustrating the proportion of Cohort 1 patients with HR-NMIBC who were recurrence-free by enrolled sample type in Example 4, Part B.

[0059] FIG. 34B shows a diagram illustrating the proportion of Cohort 3 patients with IR-NMIBC with a complete response at 3 -month evaluation by enrolled sample type in Example 4, Part B.

[0060] FIG. 35 shows a summary of demographics and baseline disease characteristics for the 21 HR-NMIBC (Cohort 1) patients and 49 IR-NMIBC (Cohort 3) patients treated in the clinical study described herein in Example 1, Part D.

[0061] FIG. 36A is a swim lane plot for treatment duration and response of HR-NMIBC (Cohort 1) patients of the clinical study described herein in Example 1, Part D, treated with TAR-210-B (about 2 mg / day erdafitinib; diagonally striped) or TAR-210-D (about 4 mg / day erdafitinib; dotted). A key describing patient treatment status and milestones is included.

[0062] FIG. 36B is a swim lane plot for treatment duration and response of IR-NMIBC (Cohort 3) patients of the clinical study described herein in Example 1, Part D, treated with TAR-210-B (about 2 mg / day erdafitinib; diagonally striped) or TAR-210-D (about 4 mg / day erdafitinib; dotted). A key describing patient treatment status and milestones is included.

[0063] FIG. 37A shows the quantified urine concentration of erdafitinib from patient samples after TAR-210-B (dashed line) or TAR-210-D (solid line) administration in Example 1, Part D.

[0064] FIG. 37B shows the quantified plasma concentration of erdafitinib from patient samples after TAR-210-B (dashed line) or TAR-210-D (solid line) administration in Example 1, Part D.DETAILED DESCRIPTION

[0065] With limited available therapies and poor outcomes, provided herein are methods of treating non-muscle invasive bladder cancer (NMIBC), in particular high risk (HR) NMIBC such as for example recurrent HR-NMIBC, and intermediate risk (IR) NMIBC such as for example recurrent IR-NMIBC in multiple cohorts of patients. Intravesical delivery of erdafitinib provides for localized bladder cancer treatment while avoiding systemic toxicities,providing a much-needed therapeutic option for NMIBC. As demonstrated herein, methods of treating HR-NMIBC, in particular recurrent bacillus Calmette-Guerin (BCG)-experienced high risk NMIBC comprising administering about 2 mg / day erdafitinib to about 4 mg / day erdafitinib for about 90 days locally to the bladder of the patient result in a recurrence-free (RF) rate of at least 85% in a population of patients receiving 2 mg / day erdafitinib and a RF rate of at least 80% in a population of patients receiving 4 mg / day erdafitinib. Further, methods of treating IR-NMIBC, in particular recurrent intermediate-risk NMIBC are presented, comprising administering about 2 mg / day to about 4 mg / day erdafitinib for about 90 days locally to the bladder of the patient results in a complete response (CR) rate of at least 75% in a population of patients receiving 2 mg / day erdafitinib and a CR rate of at least 90% in a population of patients receiving 4 mg / day erdafitinib. Methods of the instant application demonstrate excellent RF and CR rates for each cohort of treated patients, respectively. Further, the methods provided herein showed limited treatment-emergent adverse effects (TEAEs) and very few serious TEAEs, suggesting a safe and well-tolerated treatment.

[0066] In further aspects, local and continuous administration of erdafitinib to the bladder according to the methods presented herein demonstrated improved rates of event free survival and duration of response (DOR). Patients who received such treatment and achieved efficacious response were likely to experience 6 months of event free survival or DOR.

[0067] The unexpected improvement in RF and CR rates of the methods disclosed herein provides the added benefit of delaying invasive alternative treatments such as surgical removal of the bladder (radical cystectomy), which results in significant impacts to an individual’s quality of life. Such quality-of-life impacts include incontinence, sexual disfunction, infertility, and bowel function complications. Moreover, local administration of erdafitinib to the bladder according to the methods presented herein results in reduced side effects as compared to systemic chemotherapy. Together, these clinical improvements yield a safe and effective treatment method for individuals with NMIBC such as recurrent high- and intermediate-risk NMIBC.

[0068] Also described herein are erdafitinib formulations and release systems that are tailored for intravesical drug delivery, to take advantage of this route of administration, for treating NMIBC in a patient. Further provided are systems capable of delivering erdafitinib at effective release rates for the local treatment of bladder cancer.

[0069] 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.Certain Terminology

[0070] Disease-free survival (DFS) is defined as the time from randomization to the date of the first documented recurrence of non-muscle invasive bladder cancer (NMIBC) of any grade, disease progression, or death due to any cause, whichever occurs first (i.e., up to 5 years).

[0071] Recurrence is defined as reappearance of NMIBC independent of grade based on pathological assessment.

[0072] 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.

[0073] Recurrence-free survival (RFS) rate is defined as the proportion of patients having RFS, from initiation of the study treatment to detection of high-grade Ta or T1 bladder cancer or positive urine cytology, wherein the proportion is assessed initially at about 3 months or about 90 days of the erdafitinib treatment, then again every 3 months while on study (year 1) and during follow-up (every 3 months to end of year 2, and every 6 months in year 3).

[0074] Recurrence-free rate is defined as the proportion of patients with at least one disease assessment who are free of recurrence, wherein the proportion is assessed initially at about 3 months or about 90 days of the erdafitinib treatment, then again every 3 months while on study (year 1) and during follow-up (every 3 months to end of year 2, and every 6 months in year 3).

[0075] High-grade recurrence rate is defined as the proportion of patients having a detection of high-grade Ta or T1 bladder cancer or positive urine cytology for HG urothelial carcinoma (HGUC or repeat sample showing suspicious for HGUC), wherein the proportion is assessed initially at about 3 months or about 90 days of the erdafitinib treatment, then again every 3 months while on study (year 1) and during follow-up (every 3 months to end of year 2, and every 6 months in year 3).

[0076] Low-grade recurrence rate is defined as the proportion of patients having a detection of low-grade Ta or T1 bladder cancer or positive urine cytology for LG urothelial carcinoma, wherein the proportion is assessed initially at about 3 months or about 90 days of the erdafitinib treatment, then again every 3 months while on study (year 1) and during follow-up (every 3 months to end of year 2, and every 6 months in year 3).

[0077] Progressive disease rate is defined as the proportion of patients that progress to muscle invasive bladder cancer (MIBC) (stage T2 or higher), wherein the proportion is assessed initially at about 3 months or about 90 days of the erdafitinib treatment, then again every 3 months while on study (year 1) and during follow-up (every 3 months to end of year 2, and every 6 months in year 3).

[0078] Non-complete response (non-CR) or non-progressive disease (non-PD) is defined as no new tumors or larger tumors identified on cystoscopy.

[0079] Disease progression is defined as having post-baseline assessments of > T2 disease or positive lymph nodes or metastases.

[0080] Complete Response (CR) is defined as the absence of urothelial carcinoma by cystoscopy, confirmed pathologically at first assessment, and negative urine cytology.

[0081] Complete response (CR) rate is defined as the proportion of patients with an absence of urothelial carcinoma by cystoscopy, confirmed pathologically at first assessment, and negative urine cytology.

[0082] 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.

[0083] Pathological Complete Response (pCR) Rate is defined as percentage of participants with no pathologic evidence of intravesical disease (pTO) and no pathologic evidence of nodal involvement (pNO).

[0084] No Pathologic Evidence of Intravesical Disease (pTO) rate is defined as percentage of participants with no Pathologic Evidence of Intravesical Disease.

[0085] BCG-experienced describes an individual that experiences recurrent high-grade Ta / Tl disease within 18 months of completion of prior BCG Therapy. The minimum treatment requirements for a prior BCG therapy is at least 5 of 6 full doses of an initial induction course of BCG (with or without maintenance therapy). Full dose BCG is defined as 1 full vial containing a minimum of 1 X 108colony forming units.

[0086] Rate of downstaging to less than (<) pT2 is defined as percentage of participants with pT stage <2.

[0087] 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.

[0088] The present application contemplates all combinations of any of the embodiments disclosed herein.

[0089] Embodiments described herein for methods of treatment are also applicable for use in treating, or for use in a method for treating or for the manufacture of a medicament forthe treatment of. For example, disclosure of a method of treating recurrent bacillus Calmette- Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient by administering erdafitinib as described herein can also be worded as erdafitinib for use in treating recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient as described herein, or erdafitinib for use in a method for treating recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient as described herein, or erdafitinib for the manufacture of a medicament for treating recurrent bacillus Calmette- Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient as described herein, or use of erdafitinib for the manufacture of a medicament for the treatment of recurrent bacillus Calmette Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient as described herein.

[0090] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.Erdafitinib Formulation & Tablets

[0091] 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’-(l- methylethyl)-N-[3-(l-methyl-U / -pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) are provided. As another example, drug tablets comprising erdafitinib HC1 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.

[0092] 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 orexcipient 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.

[0093] 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.

[0094] 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 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 bindersolution 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.

[0095] 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 HC1 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 HC1 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.

[0096] 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 -P- cyclodextrin (HP-P-CD). In some embodiments of the foregoing, the drug tablets can include about 10% by weight of hydroxypropyl-P-cyclodextrin (HP-P-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-P-cyclodextrin (HP-P-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-P-cyclodextrin (HP-P-CD) based on the total weight of the tablet.

[0097] In embodiments, the erdafitinib drug tablets includes erdafitinib in its HC1 salt form. In one aspect, erdafitinib drug tablets can include greater than or equal to 40 wt% erdafitinib HC1 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 HC1 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 HC1 salt form, or from 45 wt% to 55 wt% of erdafitinib in its HC1 salt form. In embodiments, the drug tablets can include 50% by weight of erdafitinib in its HC1 salt form, based on the total weight of the tablet.

[0098] 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.

[0099] 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. As disclosed herein, “minitablets” and “tablets” are used interchangeably, to mean a tablet which may permit inserting the system-housed drug tablets through a lumen such as the urethra into a cavity such as the bladder.

[0100] 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 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.

[0101] The API used in the solid tablet formulations can be erdafitinib, which is N-(3,5- dimethoxyphenyl)-N’-(l-methylethyl)-N-[3-(l-methyl-17 / -pyrazol-4-yl)quinoxalin-6-yl]ethane-l,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 HC1 salt, particularly erdafitinib HC1 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.

[0102] 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 least one diluent, at least one glidant, at least one lubricant, and the like, or any combinationthereof. 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.

[0103] 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

[0104] 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)-l -[3-(l -methyl- 17 / -pyrazol-4-yl)quinoxalin-6-yl]-2, 3,4, 5 -tetrahydro- 1JT- 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.

[0105] 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, orpostpone the formation of degradation products when erdafitinib contacts formaldehyde. Therefore, the erdafitinib pharmaceutical formulation stability such as its 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.

[0106] 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.

[0107] 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.

[0108] 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 theformation of degradation products such as the following compound, which can form from erdafitinib in the presence of formaldehyde: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.

[0109] 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.

[0110] In some embodiments, the pharmaceutical compositions as described herein, in particular the erdafitinib drug tablets, do not contain a stabilizer or formaldehyde scavenger.Solubilizers[OHl] 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 cellulosewhich 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.

[0112] 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.

[0113] 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% to 18 wt%, alternatively 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.

[0114] In an aspect, a solubilizer for the erdafitinib tablet formulation disclosed herein can comprise or can be hydroxypropyl-beta-cyclodextrin (HP-P-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-P-cyclodextrin (HP-P-CD), and 1% by weight of meglumine based on the total weight of the tablet. In embodiments, thedrug tablets can include at least about 45% by weight of erdafitinib in its free base form, 10% by weight of hydroxypropyl -P-cyclodextrin (HP-P-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-P-cyclodextrin (HP-P-CD), and 0% by weight of meglumine based on the total weight of the tablet.Binders

[0115] 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 insoluble polymeric binders, or any combination thereof. Polymeric binders can include non-ionic polymers.

[0116] 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.

[0117] In an aspect, suitable binders can include or can be selected from polyvinylpyrrolidone (PVP, also termed polyvidone, povidone, or poly(l -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 polypropylene 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(l -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 polypropylene 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.

[0118] In further aspects, suitable binders can include or can be selected from polymers of or copolymers of vinylpyrrolidone (VP, also l-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).

[0119] 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 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%.

[0120] 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.

[0121] 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 vinylpyrrolidone-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 vinylpyrrolidone-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 vinylpyrrolidone-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.

[0122] 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 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.

[0123] 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%.

[0124] 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

[0125] 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.

[0126] In an embodiment, the erdafitinib solid pharmaceutical composition does not include one or more wetting agents.Disintegrants

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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%.

[0131] In an embodiment, the erdafitinib solid pharmaceutical composition does not include one or more disintegrants.Diluents or Fillers

[0132] 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.

[0133] 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.

[0134] 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 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 aconcentration 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.

[0135] 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

[0136] 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 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.

[0137] 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

[0138] 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.

[0139] 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 dioxide, orcombinations 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

[0140] 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.

[0141] Erdafitinib formulations with a range of excipient combinations, both intragranular and extragranular, are provided in Table 1 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 2 which set forth formulations 3.2, 3.3, 3.4, and 4.1.Table 1. Exemplary erdafitinib minitablet formulationsparticular 11,5 mg, of erdafitinib. In an embodiment, the above erdafitinib minitablet formulations are about 23 mg tablets, in particular 23 mg tablets.In an embodiment, the above erdafitinib minitablet formulations contain about 11.5 mg, in particular 11,5 mg, of erdafitinib, and are about 23 mg tablets, in particular 23 mg tablets.Table 2. Examples of erdafitinib formulationsIn an embodiment, the above erdafitinib minitablet formulations contain about 11.5 mg, in particular 11,5 mg, of erdafitinib. In an embodiment, the above erdafitinib minitablet formulations are about 23 mg tablets, in particular 23 mg tablets.In an embodiment, the above erdafitinib minitablet formulations contain about 11.5 mg, in particular 11,5 mg, of erdafitinib, and are about 23 mg tablets, in particular 23 mg tablets.

[0142] 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 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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% vinylpyrrolidonevinyl 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% 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) vinylpyrrolidonevinyl 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. In an embodiment, the tablet is a 23 mg tablet.

[0151] 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. In an embodiment, the tablet is a 23 mg tablet.

[0152] 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% magnesiumstearate, 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 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. In an embodiment, the tablet is a 23 mg tablet.

[0153] 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. In an embodiment, the tablet is a 23 mg tablet.

[0154] 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 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. In an embodiment, the tablet is a 23 mg tablet.

[0155] Accordingly, Formulation 3.4 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) 1 wt% meglumine; (d) 17.5 wt% microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidonevinyl 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.

[0156] 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) 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. In an embodiment, the tablet is a 23 mg tablet.Diffusion-Based Drug Delivery Systems

[0157] 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.

[0158] 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.

[0159] 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-P-CD. In some embodiments, the drug permeable portion is permeable to erdafitinib free base, erdafitinib HC1 salt, and erdafitinib free base formulated with HP-P-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 an aliphatic poly ether-based TPU which is Lubrizol Tecophilic HP-60D-35 or HP-93A-100.

[0160] In some embodiments, the drug permeable portion is permeable to erdafitinib free base formulated with HP-P-CD. In some embodiments, the drug permeable portion is permeable to erdafitinib free base formulated with HP-P-CD, and is impermeable or practically impermeable to erdafitinib free base formulated without HP-P-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 TecoflexEG-80A.

[0161] 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- 93 A- 100, and Tecoflex EG-80A. In some embodiments, the material of the drug-permeable portion is Lubrizol Tecophilic HP-60D-35, Tecophilic HP-93 A-100, or Tecoflex EG-80A. In some embodiments, the material of the drug-permeable portion is Lubrizol Tecoflex EG-80 A. 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-P-CD, and the material of the drug-permeable portion is Lubrizol Tecophilic HP-60D-35, Tecophilic HP- 93 A-100, or Tecoflex EG-80 A. In some embodiments, the drug is erdafitinib free base, the drug is formulated with HP-P-CD, and the material of the drug-permeable portion is Lubrizol Tecoflex EG-80A. In some embodiments, the drug is erdafitinib HC1 salt, and the material of the drug-permeable portion is Lubrizol Tecophilic HP-60D-35 or Tecophilic HP-93A-100.

[0162] 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 someembodiments, the material of the drug-impermeable portion is selected from MED-4750, PC- 3575 A, PC-3575 A, AR-62A, AR-75A-B20, AC-4075 A-B20, AC-4075 A, TT-1074A, EG- 80A, and CoTran 9712. In some embodiments, the material of the drug-impermeable portion is selected from MED-4750, PC-3575 A, PC-3575 A, AR-62A, AR-75A-B20, AC-4075 A- 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.

[0163] 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.

[0164] It is to be understood that Lubrizol Tecophilic HP series materials are aliphatic poly ether-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 83 A (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.

[0165] 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).

[0166] It is to be understood that Lubrizol Aromatic Carbothane AC series materials are radiopaque (20% BaSCh filled) 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 about560 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).

[0167] 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 shrinkage (in / in) (1”X0.25”X6” bar) of about 0.08 (ASTM D955). AR-75A-B20 is 20% BaSO4filled AR-75A, and can be manufactured, for example, by Compounding Solutions.

[0168] 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.

[0169] 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.

[0170] 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 bydiffusion 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.

[0171] 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.

[0172] 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 embodiment, the coextruded first and second wall structures are thermoplastic polymers possessing the desired properties.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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 isconfigured 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.

[0177] 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 permeable to the drug, such that the drug is releasable in vivo by diffusion through the second wall structure 724.

[0178] 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.

[0179] 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.

[0180] 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.

[0181] 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 drugpermeation 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.

[0182] 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.

[0183] 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.

[0184] 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 crosssection. 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 crosssection. 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 120 degrees to about 150 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 135 degrees, about 180 degrees, and about 240 degrees. In certain embodiments, the second wall structure has an arc angle of about 125 degrees to about 145 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.

[0185] 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 preferablewhen the second wall structure is formed of a material that significantly swells once absorbing water.

[0186] In some embodiments, the intravesical drug delivery system comprises base AC- 4075A-B20 and stripe EG-80-A as described herein, wherein the stripe angle (see, e.g., FIG.8) is between 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the stripe angle is between 45 degrees and 90 degrees, in particular 90 degrees. In some embodiments, the intravesical drug delivery system with a stripe angle of 90 degrees releases about 2 mg / day erdafitinib. In some embodiments, the stripe angle is between 125 degrees and 145 degrees. In some embodiments, the stripe angle is 135 degrees + / - 10 degrees. In some embodiments, the intravesical drug delivery system with a stripe angle between 125 degrees and 145 degrees releases about 2.5 mg / day to about 3.5 mg / day erdafitinib. In some embodiments, the intravesical drug delivery system with a stripe angle of 135 degrees + / - 10 degrees releases about 2.5 mg / day to about 3.5 mg / day erdafitinib. In some embodiments, the stripe angle is between 150 degrees and 270 degrees, in particular 180 degrees. In some embodiments, the intravesical drug delivery system with a stripe angle of 180 degrees releases about 4 mg / day erdafitinib. In some embodiments, the stripe angle is about 135 degrees. In some embodiments, the intravesical drug delivery system with a stripe angle of 135 degrees releases about 3 mg / day erdafitinib. In some embodiments, the intravesical drug delivery system is closed at the ends. In some embodiments, the intravesical drug delivery system is sealed at the ends of the drug lumen, (e.g., FIG. 7 ref. 704) and therefore does not include an aperture for drug release. In some embodiments, the intravesical drug delivery system drug release is only by diffusion through the stripe (FIG. 7, second wall structure, ref. 724).

[0187] 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.

[0188] 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 thedrug 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.

[0189] 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 some 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.

[0190] 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 CARBOTHANE™ TPU, such as AC-4075 A, commercially available from Lubrizol) or an aromatic polyester hydrocarbon-based thermoplastic polyurethane (e.g., a TECOTHANE™ TPU, 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) e — CO3]n— (CH2) — O-. AC-4075 A 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 ultim — e elo — ation — f 530%. In particular, the second material forming the second wall structure (i.e. — the m — erial that is permeable to the drug contained in the drug reservoir) may be an aliphatic polyether-based thermoplastic polyurethane (e.g., a TECOFLEX™ TPU, 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 bariumsulfate, for example, AC-4075A-B20, which is a polycarbonate-based aromatic thermoplastic polyurethane having a 20% loading of barium sulfate.

[0191] 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. In some embodiments, a thickness of the second wall structure is from about 0.16 mm to about 0.24 mm. In one embodiment, a thickness of the second wall structure is from about 0.16 mm to about 0.24 mm, wherein the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib.

[0192] 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 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.

[0193] 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 aShore 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.

[0194] 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).

[0195] 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 about 2 mg / day to about 4 mg / day, for example about 2.5 mg / day to about 3.5 mg / day, depending on the desired treatment regimen. In some embodiments, the system is configured to release the erdafitinib at an average rate of about 2 mg / day to about 4 mg / day. In such embodiments, the two interface edges may be disposed at an arc angle of 45 degrees to 270 degrees, for example at an arc angle of 90 degrees to 180 degrees, more in particular at an arc angle of 125 degrees to 145 degrees.

[0196] In one 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 anaverage rate of 4 mg / day and the two interface edges are disposed at an arc angle of about 180 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.

[0197] 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 ni tinol 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 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 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. 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 tablets have Formula 4D as described herein. In an embodiment, the tablets have Formula 4C asdescribed herein. In an embodiment, the tablets have Formula 4B as described herein. In an embodiment, the tablets have Formula 4A as described herein. In an embodiment, the tablets have Formula 4.1 as described herein. In an embodiment, the tablets have Formula 3.4 as described herein. In an embodiment, the tablets have Formula 3.3 as described herein. In an embodiment, the tablets have Formula 3.2 as described herein.Other Aspects of the Drug Delivery Systems

[0198] 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 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.

[0199] 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.

[0200] 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, from about 30 to 60 cylindrical drug tablets, from about 40 to 50 cylindrical drug tablets, from about 42 to 46 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 4 A. 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. In an aspect, the tablets are those of 4.1. In an aspect, the tablets are those ofFormula 3.4. In an aspect, the tablets are those of Formula 3.3. In an aspect, the tablets are those of Formula 3.2.

[0201] 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.

[0202] 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 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.

[0203] 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.

[0204] 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.

[0205] 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 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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 TPU having 20% BaSCU filler, such as Lubrizol’s Carbothane™ AC-4075A-B20 or Tecothane™ AR-75A-B20. (Lubrizol Life Science (Bethlehem, PA)).

[0212] 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 systemthrough 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

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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 303 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.

[0217] 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.

[0218] 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.

[0219] 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. A photograph showing the cross-section of the drug reservoir lumen of adrug delivery system without drug disposed therein is shown in FIG. 8. In FIG. 8, the second wall structure has an arc angle 802 of about 30 degrees of a circumference of the cylindrical tube in the cross-section.

[0220] 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 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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 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.

[0225] 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.

[0226] 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 of curvature (R*) of 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+0D) / 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 Delivery System

[0227] In some embodiments, provided herein is 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, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 2 mg / day to about 4 mg / day, optionally wherein the system is configured to release the erdafitinib at an average rate of about 2.5 mg / day to about 3.5 mg / day, and wherein the two interface edges are disposed at an arc angle of about 90 degrees to about 180 degrees, preferably about 125 degrees to about 145 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the drug delivery system comprises about 40 to about 50, about 42 to about 48, or about 44 to about 46 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 42 to 46 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the drug delivery system is configured to release the erdafitinib at an average rate of 3 mg / day and the two interface edges are disposed at an arc angle of 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the drug delivery system comprises AC-4075A-B20 and EG-80-A. In some embodiments, the drug formulation comprises (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 some embodiments, the drug formulation comprises (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 some embodiments, the drug formulation comprises (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.

[0228] In some embodiments, provided herein is 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, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 3 mg / day and wherein the two interface edges are disposed at an arc angle of about 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the drug delivery system comprises about 40 to about 50, about 42 to about 48, or about 44 to about 46 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 42 to 46 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the drug delivery system is configured torelease the erdafitinib at an average rate of 3 mg / day and the two interface edges are disposed at an arc angle of 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the drug delivery system comprises AC- 4075A-B20 and EG-80-A. In some embodiments, the drug formulation comprises (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 some embodiments, the drug formulation comprises (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 some embodiments, the drug formulation comprises (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.

[0229] FIGS. 27A to 29 depict an embodiment of a drug delivery system in accordance with the present disclosure. The drug delivery system 2700 of FIGS. 27A to 29 is referred to herein as “TAR-210-C” and is designed to release approximately 3 mg of erdafitinib per day. FIG. 27A is a top, schematic view of the drug delivery system 2700 shown in a coiled retention shape. FIG. 27B is a bottom, schematic view of the drug delivery system 2700 shown in a coiled retention shape. FIG. 28 is a transverse cross-sectional view of the drug delivery system 2700, taken along lines A-A of FIG. 27A. FIG. 29A is a side, schematic view of the drug delivery system 2700 shown in a relatively straightened insertion shape. FIG. 29B is a side cross-sectional view of a portion of the drug delivery system 2700 shown in a relatively straightened insertion shape.

[0230] Referring to FIGS. 27A and 27B, in some embodiments, the drug delivery system 2700 includes a housing 2704. The housing 2704 defines a drug reservoir lumen 2732 and a retention frame lumen 2734 (visible in FIG. 27B only). In FIGS. 27A and 27B, the portionof the housing 2704 bounding the drug reservoir lumen 2732 is shown as being translucent, revealing erdafitinib minitablets 2708 contained therein.

[0231] As with other embodiments disclosed herein, the drug reservoir lumen 2732 and retention frame lumen 2734 can be monolithic with one another, e.g., co-molded in an extrusion process. As mentioned above, the drug reservoir lumen 2732 contains a plurality of erdafitinib minitablets 2708 to be described in more detail below. The retention frame lumen 2734 houses a retention frame 2903 (visible in FIGS. 28 and 29B), such as an elastic or superelastic nitinol wire. As described with other embodiments of the drug delivery systems disclosed herein, the drug delivery system 2700 is elastically deformable between a low- profile deployment shape (e.g., a relatively straightened shape; see FIGS. 29A, 29B) suited for insertion through the urethra of a patient and into the patient’s bladder, and a relatively expanded retention shape (e.g., bi-oval coil shape; FIGS. 27A and 27B) suited for retention of the drug delivery system 2700 within the bladder. According to embodiments, when in the deployment shape, the drug delivery system 2700 can be inserted through the urethra of a patient using a urinary placement catheter. Due to the elastic nature of the retention frame 2903, the drug delivery system 2700 naturally returns to the retention shape when free of external constraints, e.g., upon exiting a urinary placement catheter.

[0232] Referring to FIG. 27A, in some embodiments, when in the coiled retention shape, the drug delivery system 2700 has a maximum dimension (e.g., L in FIG. 27A) in any direction (X, Y) that is equal to or less than about 6 cm. In some embodiments, when in the coiled retention shape, the drug delivery system 2700 has a maximum dimension (e.g., L in FIG. 27A) in any direction (X, Y) that is equal to or less than about 5.5 cm. In some embodiments, when in the coiled retention shape, the drug delivery system 2700 fits within an envelope (X, Y) of 5.5 cm by 4.5 cm.

[0233] Referring to the transverse cross-sectional view of FIG. 28, the drug reservoir lumen 2732 and retention frame lumen 2734 of the housing 2704 are shown. According to embodiments, the drug reservoir lumen 2732 is bounded by a first wall structure formed of a first material 2906 and a second wall structure formed of a second material 2905. According to embodiments, the second material 2905 of the second wall structure, or both the first material 2906 of the first wall structure and the second material 2905 of the second wall structure, are permeable to water. According to some embodiments, both the first material 2906 of the first wall structure and the second material 2905 of the second wall structure are permeable to water. According to some embodiments, the first material 2906 of the first wall structure is impermeable to the erdafitinib and the second material 2905 of the second wallstructure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material 2905 forming the second wall structure. According to embodiments, the first material 2906 comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material 2905 comprises an aliphatic polyether- based thermoplastic polyurethane. In some embodiments, the first material 2906 is AC- 4075A and the second material 2905 is EG-80-A. In some embodiments, the first material 2906 is AC-4075A-B20 and the second material 2905 is EG-80-A.

[0234] Still referring to FIG. 28, in some embodiments, the first and second wall structures are adjacent one another at two interface edges 2905A, 2905B and together form a tube. For example, the first and second wall structures can be bonded together or co-extruded at the interface edges 2905A, 2905B. The two interface edges 2905A, 2905B can be disposed at an arc angle 2914 of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis Z of the tube. In some embodiments, as shown in FIG. 28, the arc angle 2914 is about 135 degrees. In some embodiments, the arc angle 2914 is about 135 degrees and contains the second material 2905 forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle 2914. According to embodiments, the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material 2905 forming the second wall structure.

[0235] As recited 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. For example, in some embodiments, the arc angle 2914 is about 135 degrees such that the second wall structure occupies about 135 degrees of the circumference of the drug reservoir lumen 2704 and the first wall structure occupies about 225 degrees of the circumference of the drug reservoir lumen 2704. Unless indicated otherwise, the terms “arc angle” and “stripe angle” are used interchangeably throughout this disclosure.

[0236] Still referring to FIG. 28, in some embodiments, the second material 2905 of the drug delivery system 2700 defines a wall thickness T extending along the diameter of the drug reservoir lumen 2732 that is 0.2 ± 0.04 mm. In some embodiments, the drug reservoir lumen 2732 defines an inner diameter D that is 2.64 ± 0.05 mm.

[0237] As discussed above, in some embodiments, the housing 2704 of the drug delivery system 2700 comprises a retention frame lumen 2734. According to embodiments, the wireform 2903 is disposed within the retention frame lumen 2734 and defines a diameter d that is about 0.305 mm.

[0238] Referring to FIGS. 29A-29B, the drug delivery system 2700 is shown in a relatively straightened, insertion shape. In FIG. 29A, the portion of the housing bounding the drug reservoir lumen 2732 is shown as being translucent, revealing the erdafitinib minitablets 2708 contained therein. In FIG. 29B, the housing is shown in cross-section to reveal the erdafitinib minitablets 2708 located in the drug reservoir lumen 2732 and the retention frame 2903 located in the retention frame lumen 2734. In FIG. 29B, the ends 2808, 2810 of the drug delivery system 2700 are truncated.

[0239] As shown in FIG. 29A, and as mentioned above, some embodiments of the drug delivery system 2700 include first and second opposed ends, 2808, 2810, e.g., defined by the housing 2704. Still referring to FIG 29A, according to some embodiments, the drug delivery system 2700 defines a length 2812 between the first and second opposed ends 2808, 2810 that is about 17 cm. According to some embodiments, the drug reservoir lumen 2732 is sealed at the first and second opposed ends, 2808, 2810, e.g., with plugs 2820 (see FIG. 29B), thermoplastic, and / or sealant. Being sealed at the opposed ends 2808, 2810 ensures that the drug-permeable second wall structure of the drug reservoir lumen 2732 is the only path for drug release.

[0240] In some embodiments, the drug formulation comprises (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 drug formulation.

[0241] Referring to FIGS. 29A and 29B, in some embodiments the drug formulation comprises minitablets 2708. n some embodiments the drug formulation consists of minitablets 2708. In some embodiments, the drug delivery system 2700 comprises about 42 to 44 erdafitinib minitablets 2708. In some embodiments, the drug delivery system 2700 comprises 43 erdafitinib minitablets 2708. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg erdafitinib. In some embodiments, the drug formulation comprises about 500 mg erdafitinib.

[0242] In some embodiments, each minitablet 2708 has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet 2708 has a weight that is about 23 mg.

[0243] Referring to FIG. 29A, in some embodiments, each minitablet 2708 defines a thickness 2802 that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet 2708 defines a thickness 2802 that is about 3.2 mm.

[0244] Still referring to FIG. 29A, in some embodiments, each minitablet 2708 defines a diameter 2806 is that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet 2708 defines a diameter 2806 that is about 2.63 mm.

[0245] Referring to FIG. 29B, in some embodiments, the plurality of the minitablets 2708 are arranged in series and define a drug core 2822. For example, the drug core 2822 may comprise 43 erdafitinib minitablets 2708. The drug core 2822 may define a drug core length 2824 between an outside face of a first minitablet 2708a in the drug core 2822 and an opposite-facing outside face of a last minitablet 2708b in the drug core 2822. According to embodiments, the drug core length 2824 can be about 15 cm.

[0246] In some embodiments, provided herein is 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, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the drug formulation comprises (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 drug formulation.

[0247] In some embodiments, provided herein is 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) 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 first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the drug formulation comprises (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; I 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 drug formulation.

[0248] In some embodiments, provided herein is 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 impermeableto 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 first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (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 drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib.

[0249] In some embodiments, provided herein is 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, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at anarc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (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 drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A.

[0250] In some embodiments, provided herein is 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, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of acircumference of the tube in a cross section normal to a longitudinal axis of the tube, whereinthe arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (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 drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg.

[0251] In some embodiments, provided herein is 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, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of acircumference of the tube in a cross section normal to a longitudinal axis of the tube, whereinthe arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (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 drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm.

[0252] In some embodiments, provided herein is 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 impermeableto 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 first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, whereinthe arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (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 drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets,wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter that is about 2.63 mm.

[0253] In some embodiments, provided herein is 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, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, whereinthe arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (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 drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. Insome embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter that is about 2.63 mm. In some embodiments, the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposed ends, for example, with plugs, thermoplastic, and / or sealant.

[0254] In some embodiments, provided herein is 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, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, whereinthe arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In someembodiments, the drug formulation comprises (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 drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter that is about 2.63 mm. In some embodiments, the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposed ends, for example, with plugs, thermoplastic, and / or sealant. In some embodiments, the housing of the drug delivery system comprises a retention frame lumen and a wireform disposed in the retention frame lumen. In some embodiments, the wireform has a diameter that is about 0.305 mm and a length that is about 156 mm. In some embodiments, the wireform is a nitinol wire.

[0255] In some embodiments, provided herein is 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 materialcomprises 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, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, whereinthe arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (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 drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has athickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter that is about 2.63 mm. In some embodiments, the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposed ends, for example, with plugs, thermoplastic, and / or sealant. In some embodiments, the housing of the drug delivery system comprises a retention frame lumen and a wireform disposed in the retention frame lumen. In some embodiments, the wireform has a diameter that is about 0.305 mm and a length that is about 156 mm. In some embodiments, the wireform is a nitinol wire. In some embodiments, the plurality of the minitablets are arranged in series and define a drug core length between a first face of a first minitablet and an opposed second face of a last minitablet in the drug core, wherein the drug core length is about 15 cm.

[0256] In some embodiments, provided herein is 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, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments,both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (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 drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter that is about 2.63 mm. In some embodiments, the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposed ends, for example, with plugs, thermoplastic, and / or sealant. In some embodiments, the housing of the drug delivery system comprises a retention frame lumen and a wireform disposed in the retention frame lumen. In some embodiments, the wireform has a diameter that is about 0.305 mm and a length that is about 156 mm. In some embodiments, the wireform is a nitinol wire. In some embodiments, the plurality of the minitablets are arranged in series and define a drug core length between a first face of a first minitablet and an opposed second face of a last minitablet in the drug core,wherein the drug core length is about 15 cm. In some embodiments, the second material of the drug delivery system, defines a wall thickness extending along the diameter of the drug reservoir lumen that is 0.2 ± 0.04 mm.

[0257] In some embodiments, provided herein is 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, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, whereinthe arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (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 drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mgand about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter that is about 2.63 mm. In some embodiments, the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposed ends, for example, with plugs, thermoplastic, and / or sealant. In some embodiments, the housing of the drug delivery system comprises a retention frame lumen and a wireform disposed in the retention frame lumen. In some embodiments, the wireform has a diameter that is about 0.305 mm and a length that is about 156 mm. In some embodiments, the wireform is a nitinol wire. In some embodiments, the plurality of the minitablets are arranged in series and define a drug core length between a first face of a first minitablet and an opposed second face of a last minitablet in the drug core, wherein the drug core length is about 15 cm. In some embodiments, the second material of the drug delivery system, defines a wall thickness extending along the diameter of the drug reservoir lumen that is 0.2 ± 0.04 mm. In some embodiments, the drug reservoir lumen defines an inner diameter that is 2.64 ± 0.05 mm.

[0258] In some embodiments, provided herein is 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 theerdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, whereinthe arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (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 drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter that is about 2.63 mm. In someembodiments, the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposed ends, for example, with plugs, thermoplastic, and / or sealant. In some embodiments, the housing of the drug delivery system comprises a retention frame lumen and a wireform disposed in the retention frame lumen. In some embodiments, the wireform has a diameter that is about 0.305 mm and a length that is about 156 mm. In some embodiments, the wireform is a nitinol wire. In some embodiments, the plurality of the minitablets are arranged in series and define a drug core length between a first face of a first minitablet and an opposed second face of a last minitablet in the drug core, wherein the drug core length is about 15 cm. In some embodiments, the second material of the drug delivery system, defines a wall thickness extending along the diameter of the drug reservoir lumen that is 0.2 ± 0.04 mm. In some embodiments, the drug reservoir lumen defines an inner diameter that is 2.64 ± 0.05 mm. In some embodiments, the drug delivery system is elastically deformable between a coiled retention shape and a relatively straightened insertion shape. In some embodiments, the coiled retention shape comprises a bioval shape.

[0259] In some embodiments, provided herein is 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, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments,both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (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 drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter that is about 2.63 mm. In some embodiments, the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposed ends, for example, with plugs, thermoplastic, and / or sealant. In some embodiments, the housing of the drug delivery system comprises a retention frame lumen and a wireform disposed in the retention frame lumen. In some embodiments, the wireform has a diameter that is about 0.305 mm and a length that is about 156 mm. In some embodiments, the wireform is a nitinol wire. In some embodiments, the plurality of the minitablets are arranged in series and define a drug core length between a first face of a first minitablet and an opposed second face of a last minitablet in the drug core,wherein the drug core length is about 15 cm. In some embodiments, the second material of the drug delivery system, defines a wall thickness extending along the diameter of the drug reservoir lumen that is 0.2 ± 0.04 mm. In some embodiments, the drug reservoir lumen defines an inner diameter that is 2.64 ± 0.05 mm. In some embodiments, the drug delivery system is elastically deformable between a coiled retention shape and a relatively straightened insertion shape. In some embodiments, the coiled retention shape comprises a bioval shape. In some embodiments, when in the coiled retention shape, the drug delivery system has a maximum dimension in any direction that is equal to or less than about 6 cm. In some embodiments, when in the coiled retention shape, the drug delivery system has a maximum dimension in any direction that is equal to or less than about 5.5 cm. In some embodiments, when in the coiled retention shape, the drug delivery system fits within an envelope of 5.5 cm by 4.5 cm.

[0260] In some embodiments, the first wall structure and the second wall structure are permeable to water. In some embodiments, the first wall structure is impermeable to the erdafitinib, and the second wall structure is permeable to the erdafitinib. In some embodiments, the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube.

[0261] In some embodiments, provided herein is 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 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 first and second wall structures are adjacent one another at two interface edges and together form a tube.

[0262] In some embodiments, the drug delivery system described herein is configured to release the erdafitinib at an average rate of about 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, wherein a thickness of the first wall structure, asecond wall structure, or both, is from about 0.2 mm to about 1.0 mm, wherein the thickness of the second wall structure is from about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib.

[0263] In some embodiments, the drug delivery system described herein is configured to release the erdafitinib at an average rate of about 2.5 mg / day to about 3.5 mg / day and the two interface edges are disposed at an arc angle of about 125 degrees to about 145 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein a thickness of the first wall structure, a second wall structure, or both, is from about 0.2 mm to about 1.0 mm, wherein the thickness of the second wall structure is from about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib.

[0264] In some embodiments, the drug delivery system described herein is configured to release the erdafitinib at an average rate of about 3 mg / day and the two interface edges are disposed at an arc angle of about 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein a thickness of the first wall structure, a second wall structure, or both, is from about 0.2 mm to about 1.0 mm, wherein the thickness of the second wall structure is from about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib.

[0265] In some embodiments, the drug delivery system described herein is configured to release the erdafitinib at an average rate of about 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, wherein a thickness of the first wall structure, a second wall structure, or both, is from about 0.2 mm to about 1.0 mm, wherein the thickness of the second wall structure is from about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib.Drug Tablets

[0266] 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 substantiallyretains 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 exposed during assembly (e.g., loading into the system drug reservoir), storage, and handling before in vivo insertion).

[0267] 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.

[0268] 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.

[0269] 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 “minitablet” 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 4 A. 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 Treatment

[0270] In some aspects, provided herein is a method of treating HR-NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising administering about 2 mg / day to about 4 mg / day of erdafitinib, for example, about 2.5 mg / day to about 3.5 mg / day of erdafitinib, for at least about 90 days locally to the bladder of the patient, in particular wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein.

[0271] In other aspects, provided herein is a method of treating HR-NMIBC, e.g., recurrent, BCG-experienced HR-NMIBC in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of 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 joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later. In some embodiments, the method of treating results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent, BCG-experienced HR-NMIBC. In some embodiments, the second wall structure, or both the first wall structure and the second wall structure, are permeable to water. In some embodiments, 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. In some embodiments, the arc angle is 45 degrees to 90 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the arc angle is 150 degrees to 270 degrees of a circumference of the tube incross-section normal to the longitudinal axis of the tube. In some embodiments, the arc angle is 125 degrees to 145 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube.

[0272] In some embodiments, the method comprises administering about 2 mg / day to about 4 mg / day of erdafitinib for at least about 90 days locally to the bladder of a patient with HR-NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high risk nonmuscle invasive bladder cancer (HR-NMIBC). In some embodiments, the method comprises administering about 2 mg / day of erdafitinib to the patient with recurrent bacillus Calmette- Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC). In some embodiments, the method comprises administering about 4 mg / day of erdafitinib to the patient with recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC).

[0273] In some embodiments, the method of treatment results in a recurrence-free rate of at least 50% in the population of patients receiving treatment, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent BCG-experienced HR-NMIBC. In some embodiments, the recurrence-free rate in the population of patients is at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%. In some embodiments, the recurrence-free rate in the population of patients is at least 50%. In some embodiments, the recurrence-free rate in the population of patients is at least 55%. In some embodiments, the recurrence-free rate in the population of patients is at least 60%. In some embodiments, the recurrence-free rate in the population of patients is at least 65%. In some embodiments, the recurrence-free rate in the population of patients is at least 70%. In some embodiments, the recurrence-free rate in the population of patients is at least 75%. In some embodiments, the recurrence-free rate in the population of patients is at least 80%. In some embodiments, the recurrence-free rate in the population of patients is at least 85%. In some embodiments, the recurrence-free rate in the population of patients is about 80% for patients treated with about 2 mg / day of erdafitinib. In some embodiments, the recurrence-free rate in the population of patients is about 80% for patients treated with about 2 mg / day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the recurrence-free rate in the population of patients is at least 88.9% for patients treated with about 2 mg / day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the recurrence-free rate in the population of patients is about 83%, such as about 83.3%, for patients treated with about 4 mg / day oferdafitinib. In some embodiments, the recurrence-free rate in the population of patients is about 83%, such as about 83.3%, for patients treated with about 4 mg / day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the recurrence-free rate in the population of patients is at least 85.7% for patients treated with about 4 mg / day, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the recurrence-free rate in the population of patients is about 82%, such as about 81.8%, for patients treated with about 2 mg / day to about 4 mg / day of erdafitinib. In some embodiments, the recurrence-free rate in the population of patients is about 82%, such as about 81.8%, for patients treated with about 2 mg / day to about 4 mg / day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments the recurrence- free rate is assessed at 3 months or 90 days of the erdafitinib treatment.

[0274] In some embodiments, the method further comprises performing a transurethral resection of bladder tumor (TURBT) prior to administering the erdafitinib.

[0275] In some embodiments, the method comprises administering about 2 mg / day to about 4 mg / day of erdafitinib for at least about 90 days locally to the bladder of the patient, where the patient has high-grade Ta or T1 bladder cancer. In some embodiments, the population of patients have high-grade Ta or T1 bladder cancer. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent BCG-experienced HR-NMIBC. In some embodiments, the patient has a histologically confirmed high-grade Ta or T1 lesion. In some embodiments, the population of patients have a histologically confirmed high-grade Ta or T1 lesion. In some embodiments, the patient does not have carcinoma in situ (CIS). In some embodiments, the population of patients do not have carcinoma in situ (CIS). In some embodiments, the patient has recurrent high-grade Ta or T1 bladder cancer within 18 months of completion of prior BCG therapy. In some embodiments, the population of patients have recurrent high-grade Ta or T1 bladder cancer within 18 months of completion of prior BCG therapy. In some embodiments, the patient has previously received at least 5 of 6 full doses of an induction course of BCG. In some embodiments, the population of patients have previously received at least 5 of 6 full doses of an induction course of BCG. In some embodiments, the patient has high-risk papillary-only NMIBC. In some embodiments, the population of patients have high-risk papillary-only NMIBC. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein.

[0276] In other aspects, provided herein is a method of treating IR-NMIBC, e.g., recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising administering about 2 mg / day to about 4 mg / day of erdafitinib, for example, about 2.5 mg / day to about 3.5 mg / day of erdafitinib, for at least about 90 days locally to the bladder of the patient, in particular wherein such treatment results in an at least 50% complete response rate in a population of patients receiving such treatment. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR-NMIBC.

[0277] In other aspects, provided herein is a method of treating IR-NMIBC, e.g., recurrent, IR-NMIBC in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of 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 joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later. In some embodiments, the method of treating results in a complete response rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR- NMIBC. In some embodiments, the second wall structure, or both the first wall structure and the second wall structure, are permeable to water. In some embodiments, 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. In some embodiments, the two interface edges are disposed at an arc angle of 45 degrees to 90 degrees of a circumference of the tube in crosssection normal to the longitudinal axis of the tube, in particular at an arc angle of 90 degrees. In some embodiments, the two interface edges are disposed at an arc angle of 150 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis ofthe tube, in particular at an arc angle of 180 degrees. In some embodiments, the two interface edges are disposed at an arc angle of 125 degrees to 145 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, in particular at an arc angle of 135 degrees.

[0278] In some embodiments, the method comprises administering about 2 mg / day to about 4 mg / day of erdafitinib for at least about 90 days locally to the bladder of a patient with IR-NMIBC, e.g., recurrent IR-NMIBC. In some embodiments, the method comprises administering about 2 mg / day of erdafitinib to a patient with recurrent IR-NMIBC. In some embodiments, the method comprises administering about 4 mg / day of erdafitinib to a patient with recurrent IR-NMIBC.

[0279] In some embodiments, the method of treatment results in a complete response rate of at least 50% in the population of patients with recurrent IR-NMIBC receiving treatment. In some embodiments, the complete response rate in the population of patients is at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%. In some embodiments, the complete response rate in the population of patients is at least 50%. In some embodiments, the complete response rate in the population of patients is at least 55%. In some embodiments, the complete response rate in the population of patients is at least 60%. In some embodiments, the complete response rate in the population of patients is at least 65%. In some embodiments, the complete response rate in the population of patients is at least 70%. In some embodiments, the complete response rate in the population of patients is at least 75%. In some embodiments, the complete response rate in the population of patients is at least 80%. In some embodiments, the complete response rate in the population of patients is at least 85%. In some embodiments, the complete response rate in the population of patients is about 75% for patients treated with about 2 mg / day erdafitinib. In some embodiments, the complete response rate in the population of patients is 75% for patients treated with about 2 mg / day, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein. In some embodiments, the complete response rate in the population of patients is about 100% for patients treated with about 4 mg / day erdafitinib. In some embodiments, the complete response rate in the population of patients is 100% for patients treated with about 4 mg / day, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein. In some embodiments, the complete response rate in the population of patients is about 87%, such as about 86.7%, for patients treated with about 2 mg / day to about 4 mg / day of erdafitinib. In some embodiments, the complete response rate in the population of patients is about 87%, such as about 86.7%,for patients treated with about 2 mg / day to about 4 mg / day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein. In some embodiments the complete response rate is assessed at 3 months or 90 days of the erdafitinib treatment.

[0280] In some embodiments, the method comprises administering about 2 mg / day to about 4 mg / day of erdafitinib for at least about 90 days locally to the bladder of the patient, where the patient has a history of only low-grade disease. In some embodiments, the population of patients have a history of only low-grade disease. In some embodiments, the patient has recurrent intermediate risk papillary disease. In some embodiments, the population of patients have recurrent intermediate risk papillary disease. In some embodiments, the patient has not previously had carcinoma in situ. In some embodiments, the population of patients have not previously had carcinoma in situ. In some embodiments, the patient has visible disease at the time that the erdafitinib is administered. In some embodiments, the population of patients have visible disease at the time that the erdafitinib is administered. In some embodiments, the patient has Ta or T1 bladder cancer. In some embodiments, the population of patients have Ta or T1 bladder cancer. In some embodiments, the patient has not undergone TURBT prior to administering the erdafitinib. In some embodiments, the population of patients have not undergone TURBT prior to administering the erdafitinib. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR-NMIBC as described herein.

[0281] In some embodiments, the method comprises administering about 2 mg / day of erdafitinib to the patient. In some embodiments, the method comprises administering about 4 mg / day of erdafitinib to the patient.

[0282] In some embodiments, the method of treating HR-NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR- NMIBC) in a patient comprising administering about 2 mg / day to about 4 mg / day, more in particular about 3 mg / day, of erdafitinib for at least about 90 days locally to the bladder of the patient, wherein the erdafitinib formulation is Formula 4B formulation as described herein. In some embodiments, 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 solidpharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, in particular wherein the delivery system comprises AC- 4075 A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed.

[0283] In other aspects, provided herein is a method of treating IR-NMIBC, e.g., recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising administering about 2 mg / day to about 4 mg / day, more in particular about 3 mg / day, of erdafitinib for at least about 90 days locally to the bladder of the patient, wherein the erdafitinib formulation is Formula 4B formulation as described herein. In some embodiments, 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 some embodiments, the formulation is contained within an intravesical drug delivery system, in particular wherein the delivery system comprises AC- 4075 A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed.

[0284] In some embodiments, the method of treating HR-NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR- NMIBC) in a patient comprising administering about 2 mg / day to about 4 mg / day, more in particular about 3 mg / day, of erdafitinib for at least about 90 days locally to the bladder of the patient, wherein the erdafitinib formulation is Formulation 3.4 as described herein. In some embodiments, 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 some embodiments, the formulation is contained within an intravesical drug delivery system, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed.

[0285] In other aspects, provided herein is a method of treating IR-NMIBC, e.g., recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patientcomprising administering about 2 mg / day to about 4 mg / day of erdafitinib, more in particular about 3 mg / day, for at least about 90 days locally to the bladder of the patient, wherein the erdafitinib formulation is Formulation 3.4 as described herein. Accordingly, Formulation 3.4 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) 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 some embodiments, the formulation is contained within an intravesical drug delivery system, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed.

[0286] In some embodiments, the method of treating HR-NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR- NMIBC) in a patient comprising administering about 2 mg / day to about 4 mg / day, more in particular about 3 mg / day, of erdafitinib for at least about 90 days locally to the bladder of the patient, wherein the erdafitinib formulation is Formulation 4.1 as described herein. In some embodiments, 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 some embodiments, the formulation is contained within an intravesical drug delivery system, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed.

[0287] In other aspects, provided herein is a method of treating IR-NMIBC, e.g., recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising administering about 2 mg / day to about 4 mg / day, more in particular about 3 mg / day, of erdafitinib for at least about 90 days locally to the bladder of the patient, wherein the erdafitinib formulation is Formulation 4.1 as described herein. 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 some embodiments, the formulation is contained within an intravesical drug delivery system, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed.

[0288] In some embodiments, the method of treating HR-NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR- NMIBC) in a patient comprises deploying an intravesical drug delivery system as described herein. In some embodiments, the drug delivery system comprises 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 the first and second wall structures being are one another at two interface edges and together forming a tube defining the closed drug reservoir; 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.

[0289] In some embodiments, the method of treating IR-NMIBC, e.g., recurrent intermediate risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprises deploying an intravesical drug delivery system as described herein. In some embodiments, the drug delivery system comprises 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 the first and second wall structures being are one another at two interface edges and together forming a tube defining the closed drug reservoir; 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.

[0290] In some embodiments, the method of treating HR-NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprises deploying an intravesical drug delivery system as described herein, wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed.

[0291] In some embodiments, the method of treating IR-NMIBC, e.g., recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprises deploying an intravesical drug delivery system as described herein, wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the device are closed.

[0292] In some embodiments, the method comprises administering about 2 mg / day to about 4 mg / day of erdafitinib for at least about 90 days locally to the bladder of the patient, wherein the patient has not had prior treatment with an FGFR inhibitor. In some embodiments, the population of patients have not had prior treatment with an FGFR inhibitor.

[0293] In some embodiments, the patient harbors at least one FGFR2 genetic alteration. In some embodiments, the patient harbors at least one FGFR3 genetic alteration. In some embodiments, the patient harbors at least one FGFR2 and at least one FGFR3 genetic alteration. In some embodiments, the population of patients harbor at least one FGFR2 genetic alteration. In some embodiments, the population of patients harbor at least one FGFR3 genetic alteration. In some embodiments, the population of patients harbor at least one FGFR2 and at least one FGFR3 genetic alteration.

[0294] In some embodiments, the FGFR2 genetic alteration comprises an activating tumor FGFR2 mutation or fusion. In some embodiments, the FGFR2 genetic alteration comprises an activating tumor FGFR2 fusion. In some embodiments, the FGFR3 genetic alteration comprises an activating tumor FGFR3 mutation or fusion. In some embodiments, the FGFR3 genetic alteration comprises an activating tumor FGFR3 mutation. In some embodiments, the FGFR3 genetic alteration comprises an activating tumor FGFR3 fusion. In some embodiments, the FGFR2 genetic alteration and the FGFR3 genetic alteration comprise activating tumor FGFR2 or 3 mutations or fusions. In some embodiments, the FGFR3 genetic alteration is an FGFR3 mutation selected from the group consisting of FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, and FGFR3 G370C. In some embodiments, the FGFR3 genetic alteration is a gene fusion comprising FGFR3:TACC3 VI. In some embodiments, the FGFR genetic alteration is detected using a PCR or NGS assay of a urine sample obtained from the patient. In some embodiments the FGFR genetic alteration is detected using a PCR or NGS assay of a tumor tissue sample obtained from the patient. In some embodiments theFGFR genetic alteration is detected using a histopathological image of the tumor tissue via digital histopathology analysis.

[0295] 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 some embodiments, a urine sample assay identifies about 29% 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 PredicineCare™ (NGS) 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.

[0296] In some embodiments, at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of treated patients identified by a urine sample assay alone were recurrence-free or achieved a complete response. In some embodiments, between about 50% and 100%, 55% and 95%, 60% and 90%, 65% and 85%, or 70% and 80% of treated patients identified by a urine sample assay alone were recurrence-free or achieved a complete response. In some embodiments, at least about 80%, 90%, 95%, or 100% of treated patients identified by a urine sample assay alone were recurrence-free or achieved a complete response. In some embodiments, at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of treated patients identified by a urine sample assay alone were recurrence-free or achieved a complete response. In some embodiments, all of the treated patients identified by a urine sample assay alone were recurrence-free or achieved a complete response. In an embodiment, the urine sample assay is a NGS (next-generation sequencing) assay, in particular the PredicineCare™ (NGS) assay.

[0297] In some embodiments, the method comprising administering erdafitinib comprises deploying an intravesical drug delivery system comprising erdafitinib to the bladder of thepatient. In some embodiments, the method comprises administering about 2 mg / day to about 4 mg / day of erdafitinib, where administering erdafitinib comprises deploying an intravesical drug delivery system as described herein. In some embodiments, the method comprises removing the drug delivery system about 90 days later. In some embodiments, the drug delivery system comprises about 400, about 450, about 500, about 550, or about 600 mg erdafitinib. In some embodiments, the drug delivery system comprises about 480, about 485, about 490, about 495, about 500, about 505, about 510, about 515, or about 520 mg erdafitinib. In some embodiments, the drug delivery system comprises about 500 mg erdafitinib.

[0298] In some embodiments, the method comprises administering about 2 mg / day to about 4 mg / day of erdafitinib, where administering erdafitinib comprises deploying an intravesical drug delivery system as described herein. In some embodiments, the method comprises administering about 2.5 mg / day to about 3.5 mg / day of erdafitinib, where administering erdafitinib comprises deploying an intravesical drug delivery system as described herein. In some embodiments, the method comprises administering about 2 mg / day, about 3 mg / day, or about 4 mg / day of erdafitinib, where administering erdafitinib comprises deploying an intravesical drug delivery system as described herein.

[0299] In some embodiments, the drug delivery system comprises a dual lumen tube comprising a drug reservoir lumen comprising the erdafitinib and a small lumen comprising an elastic nitinol wire. In some embodiments, the drug reservoir lumen is bounded by a first wall structure formed of a first material and a second wall structure formed of a second material. In some embodiments, the first and second wall structures being adjacent to one another at two interface edges and together forming a tube defining a closed drug reservoir lumen, 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 by diffusion through the second wall structure. In some embodiments, the second wall structure forms a longitudinal strip extending along the length of the tube. In some embodiments, the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the two interface edges are disposed at an arc angle of 45 degrees to 90 degrees, in particular 90 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the two interface edges are disposed at an arc angle of 150 degrees to 270 degrees, in particular 180 degrees, ofa circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the two interface edges are disposed at an arc angle of 125 degrees to 145 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the two interface edges are disposed at an arc angle of 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

[0300] In some embodiments, the drug delivery system is elastically deformable. In some embodiments, the drug delivery system has a bi-oval retention shape. In some embodiments, the drug delivery system is elastically deformable and has a bi-oval retention shape.

[0301] In some embodiments, the erdafitinib is in the form of a plurality of mini-tablets serially arranged in the drug lumen. In some embodiments, the drug lumen comprises about 40 to 43 erdafitinib containing minitablets. In some embodiments, the drug lumen comprises 40 erdafitinib containing minitablets. In some embodiments, the drug lumen comprises 41 erdafitinib containing minitablets. In some embodiments, the drug lumen comprises 42 erdafitinib containing minitablets. In some embodiments, the drug lumen comprises 43 erdafitinib containing minitablets. In some embodiments, the plurality of mini-tablets are arranged in the drug lumen of an intravesical drug delivery system, wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. In some embodiments, the erdafitinib containing minitablet comprises (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% vinylpyrrolidonevinyl 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 minitablet. In some embodiments, the erdafitinib containing minitablet comprises (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 minitablet. In some embodiments, the erdafitinib containing minitablet comprises (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 acetatecopolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 2.0 wt% magnesium stearate, wherein these weight percentages are relative to the entire minitablet.

[0302] 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 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 harboringone 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 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 whereinerdafitinib 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 2 mg / day to about 4 mg / day, as described herein). In an aspect the patient, in particular a human, is a recurrent BCG-experienced HR-NMIBC 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 / Tl) 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 / Tl) cancer patient, scheduled for Rcy. In an aspect the patient, in particular a human, is a recurrent, intermediate-risk NMIBC (Ta and Tl) cancer patient with a previous history of only low-grade disease.

[0303] 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 moreFGFR 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 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 thepresence 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 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 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 2 mg / day to about 4 mg / day, as described herein). In an aspect the patient, in particular a human, is a recurrent BCG- experienced HR-NMIBC 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 / Tl) 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 / Tl) cancer patient, scheduled for Rcy. In an aspect the patient, in particular a human, is a recurrent, intermediate-risk NMIBC (Ta and Tl) cancer patient with a previous history of only low-grade disease.

[0304] In some embodiments, provided herein is a method of treating recurrent, BCG- experienced HR-NMIBC in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of 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 joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, 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, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later, wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the drug delivery system comprises Formula 4B formulation, wherein 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 some embodiments, the delivery system comprises AC- 4075 A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed.

[0305] In some embodiments, provided herein is a method of treating recurrent, BCG- experienced HR-NMIBC in a patient comprising deploying an intravesical drug deliverysystem to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of 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 joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, 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, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later, wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the drug delivery system comprises Formulation 4.1, wherein Formula 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.

[0306] In some embodiments, provided herein is a method of treating recurrent, BCG- experienced HR-NMIBC in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of 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 joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, arepermeable 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, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later, wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the drug delivery system comprises Formulation 3.4, wherein Formula 3.4 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) 1 wt% meglumine; (d) 17.5 wt% microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidonevinyl 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.

[0307] In some embodiments, the method of treating recurrent, IR-NMIBC in a patient comprises deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of 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 joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, 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, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first materialforming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later, wherein such treatment results in a complete response of at least 50% in a population of patients receiving such treatment. In some embodiments, the drug delivery system comprises Formula 4B formulation, wherein 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 some embodiments, the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed.

[0308] In some embodiments, the method of treating recurrent, IR-NMIBC in a patient comprises deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of 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 joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, 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, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later, wherein such treatment results in a complete response of at least 50% in a population of patients receiving such treatment. In some embodiments, the drug delivery system comprises Formu...

Claims

CLAIMSWhat is claimed is:

1. 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, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 2.5 mg / day to about 3.5 mg / day, and wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure.

2. 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 theerdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 3 mg / day and wherein the two interface edges are disposed at an arc angle of about 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure.

3. The drug delivery system of claim 1 or claim 2, comprising 42-46 erdafitinib mini tablets.

4. The drug delivery system of claim 3, comprising 43 erdafitinib minitablets.

5. The drug delivery system of any one of claims 1-4, wherein the first material comprises AC-4075A and the second material comprises EG-80-A, optionally wherein the first material comprises AC-4075A-B20.

6. The drug delivery system of any one of claims 1-5, wherein the drug formulation comprises:(a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl-17T- pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the drug formulation;(b) hydroxypropyl -beta-cyclodextrin in a concentration of 10 wt% of the drug formulation;(c) meglumine in a concentration of 1 wt% of the drug formulation;(d) microcrystalline cellulose in a concentration of 17.5 wt% of the drug formulation;(e) silicified microcrystalline cellulose in a concentration of 10.75 wt% of the drug formulation;(f) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.5 wt% of the drug formulation;(g) colloidal silicon dioxide in a concentration of 0.25 wt% of the drug formulation;(h) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the drug formulation; and(i) magnesium stearate in a concentration of 1.5 wt% of the drug formulation; or(a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl-lJT- pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the drug formulation;(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.

7. The drug delivery system of any one of claims 1-5, wherein the drug formulation comprises:(a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl-lJT- pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the drug formulation;(b) hydroxypropyl -beta-cyclodextrin in a concentration of 10 wt% of the drug formulation;(c) microcrystalline cellulose in a concentration of 17.5 wt% of the drug formulation;(d) silicified microcrystalline cellulose in a concentration of 11.75 wt% of the drug formulation;(e) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.5 wt% of the drug formulation;(f) colloidal silicon dioxide in a concentration of 0.25 wt% of the drug formulation;(g) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the drug formulation; and(h) magnesium stearate in a concentration of 1.5 wt% of the drug formulation; or(a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl- l / / - pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the drug formulation;(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.

8. The drug delivery system of any one of claims 1-5, wherein the drug formulation comprises:(a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl-lJT- pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the drug formulation;(b) hydroxypropyl -beta-cyclodextrin in a concentration of 10 wt% of the drug formulation;(c) meglumine in a concentration of 1 wt% of the drug formulation;(d) microcrystalline cellulose in a concentration of 24.5 wt% of the drug formulation;(e) silicified microcrystalline cellulose in a concentration of 6 wt% of the drug formulation;(f) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 6 wt% of the drug formulation;(g) colloidal silicon dioxide in a concentration of 0.5 wt% of the drug formulation;(h) magnesium stearate in a concentration of 2 wt% of the drug formulation; or(a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl-lJT- pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the drug formulation;(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.

9. The drug delivery system of any one of claims 1-8, wherein the first wall structure and the second wall structure have a thickness between about 0.2 mm to about 1.0 mm.

10. The drug delivery system of any one of claims 1-9, wherein the second wall structure has a thickness, wherein the thickness of the second wall structure is from about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib.

11. The drug delivery system of any one of claims 1-10, wherein the drug formulation comprises minitablets, wherein each minitablet has a weight that is between about 22 mg and about 24 mg.

12. The drug delivery system of any one of claims 1-11, wherein the drug formulation comprises minitablets, wherein each minitablet has a weight that is about 23 mg.

13. The drug delivery system of any one of claims 1-12, wherein the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm.

14. The drug delivery system of any one of claims 1-13, wherein the drug formulation comprises minitablets, wherein each minitablet has a thickness that is about 3.2 mm.

15. The drug delivery system of any one of claims 1-14, wherein the drug formulation comprises minitablets, wherein each minitablet has a diameter is that between about 2.60 mm to about 2.66 mm.

16. The drug delivery system of any one of claims 1-15, wherein the drug formulation comprises minitablets, wherein each minitablet has a diameter that is about 2.63 mm.

17. The drug delivery system of any one of claims 1-16, wherein the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm.

18. The drug delivery system of any one of claims 1-17, wherein the housing of the drug delivery system comprises a retention frame lumen and a wireform disposed in the retention frame lumen.

19. The drug delivery system of claim 18, wherein the wireform has a diameter that is about 0.305 mm and a length that is about 156 mm.

20. The drug delivery system of claim 18 or 19, wherein the wireform is a nitinol wire.

21. The drug delivery system of any one of claims 1-20, comprising a plurality of the minitablets arranged in series and defining a drug core length between a first face of a first minitablet and an opposed second face of a last minitablet.

22. The drug delivery system of claim 21, wherein the drug core length is about 15 cm.

23. The drug delivery system of any one of claims 1-22, wherein the second material of the drug delivery system defines a wall thickness extending along the diameter of the drug reservoir lumen that is 0.2 ± 0.04 mm.

24. The drug delivery system of any one of claims 1-23, wherein the drug reservoir lumen defines an inner diameter that is 2.64 ± 0.05 mm.

25. The drug delivery system of any one of claims 1-24, wherein the drug delivery system is elastically deformable between a coiled retention shape and a relatively straightened insertion shape.

26. The drug delivery system of claim 25, wherein the coiled retention shape comprises a bi-oval shape.

27. The drug delivery system of claim 25 or 26, wherein, when in the coiled retention shape, the drug delivery system has a maximum dimension in any direction that is equal to or less than about 6 cm.

28. The drug delivery system of any one of claims 25-27, wherein, when in the coiled retention shape, the drug delivery system has a maximum dimension in any direction that is equal to or less than about 5.5 cm.

29. The drug delivery system of any one of claims 25-28, wherein, when in the coiled retention shape, the drug delivery system fits within an envelope of 5.5 cm by 4.5 cm.

30. The drug delivery system of any one of claims 1-29, wherein the erdafitinib is erdafitinib free base.

31. The drug delivery system of any one of claims 1-30, wherein both the first wall structure and the second wall structure are permeable to water.

32. A method of treating non-muscle invasive bladder cancer in a patient comprising: deploying the drug delivery system according to any one of claims 1-31 to the bladder of the patient; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; and removing the drug delivery system at least about 90 days later.

33. The method of claim 32, wherein the cancer is intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC).

34. The method of claim 32, wherein the cancer is newly diagnosed intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC).

35. The method of claim 32, wherein the cancer is recurrent intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC).

36. The method of any one of claims 32 to 35, wherein the cancer harbors an FGFR alteration.

37. The method of claim 35, wherein the FGFR alteration is a FGFR2 alteration or a FGFR3 alteration.

38. The method of claim 36 or 37, wherein the FGFR alteration is a FGFR3 alteration, in particular a FGFR3 mutation or a FGFR3 fusion.

39. The method of claim 38, wherein the FGFR3 alteration is at least one of FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, in particular FGFR3-TACC3 variant 1 (FGFR3-TACC3 VI) or FGFR3-TACC3 variant 3 (FGFR3- TACC3 V3), FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

40. The method of any one of claims 32-39, wherein the patient did not receive recent bacillus Calmette-Guerin (BCG) treatment.

41. The method of any one of claims 32-40, wherein the patient has 1 or more of the following risk factors: multiple low grade (LG) tumors, solitary LG tumor >3 cm, early recurrence of LG tumor (<1 year), frequent recurrence (> 1 per year), or recurrence after prior intravesical chemotherapy.

42. The method of any one of claims 32-41, wherein such treatment results in a median duration of response of at least 12 months, or is about 12 months.

43. The method of any one of claims 33-40, wherein such treatment results in a complete response rate of about 90% in the population of patients treated with about 2 mg / day to about 4 mg / day of erdafitinib, the complete response rate assessed at 12 weeks.

44. The method of any one of claims 33-40, wherein such treatment results in a complete response rate of about 85% in the population of patients treated with about 2 mg / day to about 4 mg / day of erdafitinib, the complete response rate assessed at 12 weeks.

45. The method of claim 32, wherein the cancer is high-risk non-muscle invasive bladder cancer (HR.-NMIBC).

46. The method of claim 45, wherein the cancer harbors an FGFR alteration.

47. The method of claim 46, wherein the FGFR alteration is a FGFR2 alteration or a FGFR3 alteration.

48. The method of claim 46 or 47, wherein the FGFR alteration is a FGFR3 alteration, in particular a FGFR3 mutation or a FGFR3 fusion.

49. The method of claim 48, wherein the FGFR3 alteration is at least one of FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, in particular FGFR3-TACC3 variant 1 (FGFR3-TACC3 VI) or FGFR3-TACC3 variant 3 (FGFR3- TACC3 V3), FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

50. The method of any one of claims 45-49, wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg / day to about 4 mg / day of erdafitinib, in particular about 3 mg / day of erdafitinib, and in particular the 12-month RFS rate, is about 90%.

51. The method of any one of claims 45-49, wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg / day to about 4 mg / day of erdafitinib, in particular about 3 mg / day of erdafitinib, and in particular the 12-month RFS rate, is about 75% or about 79% or about 80%.

52. A method of treating intermediate-risk non-muscle invasive bladder cancer (IR- NMIBC) in a patient comprising administering about 2 mg / day to about 4 mg / day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein: i) the patient is newly diagnosed or recurrent IR-NMIBC; ii) the patient is determined to have intermediate risk of recurrence or progression; iii) the patient has select FGFR genetic alterations; iv) the patient is without prior bacillus Calmette-Guerin (BCG) treatment; andv) the patient comprises one or more of the following risk factors selected from the list consisting of: a) multiple low grade (LG) tumors, b) solitary LG tumor >3 cm, c) frequent recurrence (> 1 per year), and d) recurrence after prior intravesical chemotherapy.

53. The method of claim 52, wherein the patient and / or population of patients have histologically confirmed diagnosis of IR-NMIBC with at least one of the following disease characterizations: i) Ta LG / G1 : recurrent; ii) Ta LG / G1 : primary & (multifocal or > 3 cm); and / or iii) Ta G2: primary or recurrent.

54. A method of treating recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising administering about 2 mg / day to about 4 mg / day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein such treatment results in an at least 50% complete response rate in a population of patients receiving such treatment.

55. A method of treating recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising: deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of 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 joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure;releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; and removing the drug delivery system at least about 90 days later; wherein such treatment results in an at least 50% complete response rate in a population of patients receiving such treatment.

56. The method of any one of claims 52-55, wherein such treatment results in a median duration of response of at least 12 months, or is about 12 months.

57. The method of any one of claims 52-56, wherein such treatment results in a complete response rate of about 90% in the population of patients treated with about 2 mg / day to about 4 mg / day of erdafitinib, the complete response rate assessed at 12 weeks.

58. The method of any one of claims 52-57, wherein such treatment results in a complete response rate of about 85% in the population of patients treated with about 2 mg / day to about 4 mg / day of erdafitinib, the complete response rate assessed at 12 weeks.

59. The method of any one of claims 52-58, comprising administering about 2.5 mg / day to about 3.5 mg / day of erdafitinib to the patient.

60. The method of any one of claims 52-59, comprising administering about 3 mg / day of erdafitinib to the patient.

61. A method of treating recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising administering about 2 mg / day to about 4 mg / day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment.

62. A method of treating recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoirlumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of 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 joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; removing the drug delivery system at least about 90 days later; wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment.

63. The method of any one of claim 61 or 62, wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg / day to about 4 mg / day of erdafitinib, in particular about 3 mg / day of erdafitinib, and in particular the 12-month RFS rate, is about 90%.

64. The method of any one of claim 61 or 62, wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg / day to about 4 mg / day of erdafitinib, in particular about 3 mg / day of erdafitinib, and in particular the 12-month RFS rate, is about 75% or about 79% or about 80%.

65. The method of any one of claims 61-64, comprising administering about 2.5 mg / day to about 3.5 mg / day of erdafitinib to the patient.

66. The method of any one of claims 61-65, comprising administering about 3 mg / day of erdafitinib to the patient.

67. The method of any one of claims 52-66, wherein the method further comprises using a urine sample assay to select patients for treatment.

68. The method of claim 67, wherein the urine sample assay is a urine sample NGS or PCR assay, in particular a urine sample NGS assay.

69. The method of claim 67 or 68, wherein the urine sample assay detects the presence of at least one FGFR2 genetic alteration and / or FGFR3 genetic alteration.

70. The method of claim 69, wherein the FGFR2 genetic alteration and / or the FGFR3 genetic alteration comprises an activating tumor FGFR2 or FGFR3 mutation or fusion.

71. The method of claim 69 or 70, wherein the FGFR2 genetic alteration and / or the FGFR3 genetic alteration is selected from FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, in particular FGFR3-TACC3 VI or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof, in particular wherein the FGFR2 genetic alteration and / or the FGFR3 genetic alteration is selected from FGFR3-TACC3 variant 1 (FGFR3-TACC3 VI) , FGFR3 G370C, FGFR3 S249C, FGFR3 Y373C, and FGFR3 R248C.

72. The method of any one of claims 67-71, wherein at least 50%, 60%, 70%, 80%, or 90% of treated patients selected by the urine sample assay were recurrence-free or achieved a complete response.

73. The method of any one of claims 67-71, wherein at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% of treated patients selected by the urine sample assay were recurrence-free or achieved a complete response.

74. The method of claim 55 or 62, wherein the drug formulation comprises about 480 mg to about 510 mg of erdafitinib, optionally wherein the erdafitinib is erdafitinib free base.

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