Emory Urology Bladder Cancer Research & Trials

Diagnosis of superficial bladder cancer

Scheduled for BCG intravesical therapy tab

Willing and able to give blood sample

Willing and able to fill out a pill diary to ensure compliance

Pregnant patients

Diagnosis of invasive bladder cancer

HIV positive or immunocompromised

Presence of concurrent second cancer (active, not history)

Pathologically demonstrated BCG-unresponsive*, high-risk NMIBC defined as carcinoma in situ (CIS) with or without papillary component, any T1, or Ta high-grade lesions; diagnosis required within 8 weeks (56 days) prior to starting treatment and must be confirmed by the Pathology Review Committee (PRC)

Predominant histologic component (> 50%) must be urothelial (transitional cell) carcinoma

ECOG performance status of 0-1

Participants with an active, known or suspected autoimmune disease

Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll

Prior malignancy active within the previous three years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, prostate cancer with evidence of undetectable Prostate Specific Antigen (PSA), or carcinoma in situ of the cervix or breast

Participants with a personal or family (ie, in a first-degree relative) history of cytochrome b5 reductase deficiency (previously called methemoglobin reductase deficiency) or other diseases that put them at risk of methemoglobinemia. All participants will be screened for methemoglobin levels prior to randomization

Participants with a history of G6PD deficiency or other congenital or autoimmune hemolytic disorders. All participants will be screened for G6PD deficiency prior to randomization

Evidence of locally advanced disease or metastatic bladder cancer as seen in crosssectional images of the chest, abdomen, and pelvis

Urothelial cancer (UC) in the upper genitourinary tract (kidneys, renal collecting systems, ureters) within 24 months of enrollment

UC and/or CIS in the prostatic urethra within 12 months of enrollment

Locally advanced disease demonstrated by pelvic examination, preferably performed under anesthesia

Previous or concurrent muscle invasive or disseminated/metastatic bladder cancer

Histologically confirmed, recurrent, non-muscle-invasive urothelial carcinoma of the bladder

Any UCC variant is allowed

At least one of the following tumor FGFR mutations or fusions as determined by local or central testing at the time of recurrence after BCG therapy: FGFR3 mutations (R248C, S249C, G370C, Y373C) or FGFR2 and FGFR3 gene fusions (FGFR2-BICC1, FGFR2-CASP7, FGFR3-TACC3, FGFR3-BAIAP2L1)

BCG-unresponsive subjects must meet at least one of the following:
– Persistent or recurrent CIS alone or with recurrent Ta/T1 disease within 12 months of adequate BCG therapy (Cohort 2 only).
– Recurrent high-grade Ta/T1 disease within six months of completion of adequate BCG therapy.
– T1 high-grade at the first disease assessment following an induction BCG course.

BCG experienced subjects must meet the following:
– Recurrent high-grade Ta/T1 disease within 12 months of completion of BCG therapy (At least five of six full doses of an initial induction course OR at least five of six full doses of an initial induction course plus at least 1 maintenance (two of three weekly doses) in a six-month period)

Cohort 1: may be BCG-unresponsive or BCG experienced

Cohort 2: must be BCG-unresponsive

Histologically confirmed, muscle-invasive (T2 or higher stage) urothelial carcinoma of the bladder

Histopathology demonstrating any small cell component, pure adenocarcinoma, pure squamous cell carcinoma, or pure squamous CIS of the bladder

Prior treatment with an FGFR inhibitor

Active malignancies (i.e., progressing or requiring treatment change in the last 24 months) other than the disease being treated under study (UTUC is included in this)

At least 18 years of age

Non-muscle invasive (T1, high-grade Ta and/or CIS) transitional cell carcinoma (TCC) of bladder

Treated with only one course of BCG induction (defined as at least five of six intravesical instillations of BCG over a 10 week period)

After BCG induction, (1) persistent Ta and/or CIS or (2) recurrent T1, Ta and/or CIS (recurrence must be within 24 months of last exposure to BCG)

ECOG Score of 0, 1, or 2

Persistent T1 within three to six months after start of BCG induction

Muscle-invasive urothelial carcinoma

Concurrent extra-vesical non-muscle invasive TCC of urothelium, upper tract, or prostate

Pregnant or breastfeeding

History of HIV infection, Hepatitis B, active tuberculosis

Has received prior systemic anti-cancer therapy including investigational agents within four weeks of start of study treatment

Histologically confirmed diagnosis of muscle invasive bladder cancer (T2-T4aN0M0) with predominant (≥50%) urothelial histology (histology and presence of muscle invasion to be confirmed by BICR)

Clinically non-metastatic bladder cancer (N0M0) determined by imaging (CT chest and CT or MRI of the abdomen/pelvis), confirmed by BICR

Deemed eligible for RC + PLND by his/her urologist and/or oncologist and agree to undergo curative intent standard RC + PLND (including prostatectomy if applicable)

Be ineligible for treatment with cisplatin, as defined by meeting at least one of the following criteria:
– Impaired renal function with measured or calculated CrCl 30 to 59 mL/min (calculated by Cockcroft-Gault method or measured by 24-hour urine collection)
– ECOG Performance Status 2
– CTCAE v.4 Grade ≥2 audiometric hearing loss (25 dB in two consecutive wave ranges)
– CTCAE v.4 Grade ≥2 peripheral neuropathy
– NYHA Class III heart failure

ECOG Score of 0, 1, or 2

Known additional non-urothelial malignancy that is progressing or has required active treatment ≤3 years of study randomization

Any prior systemic anti-neoplastic treatment for MIBC

An abdomino-pelvic lymph node ≥15 mm in the short axis

Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor

Prior systemic anti-cancer therapy including investigational agents within three years prior to randomization

Has received prior systemic anti-cancer therapy including investigational agents within four weeks of start of study treatment

Any prior radiotherapy to the bladder

Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within seven days prior the first dose of study drug

Histologically or cytologically confirmed, invasive urothelial carcinoma with susceptible FGFR3 alterations within 120 days following nephroureterectomy, distal ureterectomy, or cystectomy

If status post neoadjuvant chemotherapy, pathologic stage at surgical resection must be AJCC Stage ≥ ypT2 and/or yN+

If not status post neoadjuvant chemotherapy, is ineligible to receive cisplatin-based adjuvant chemotherapy based on Galsky, et al. (2011):
– Creatinine clearance ≤60 mL/min, or
– CTCAE Grade ≥2 hearing loss, or
– CTCAE Grade ≥2 neuropathy

If cisplatin ineligible, must meet the following criteria:
– Upper tract disease should be AJCC Stage ≥pT2 pN0-2 M0
– UBC should be AJCC Stage ≥pT3 or pN+

Must have a centrally reviewed negative postoperative CT or negative biopsy within 28 days before randomization to confirm absence of disease at baseline

ECOG performance status of ≤2

Presence of positive surgical margins following nephroureterectomy, distal ureterectomy, or cystectomy

Have received BCG or other intravesical therapy for NMIBC within previous 30 days

Are currently receiving or are planning to receive during participation in this study, treatment with agents that are known strong inducers or inhibitors of CYP3A4, and medications which increase serum phosphorus and/or calcium concentration

Have a history of primary malignancy within the past 3 years

Have current evidence of corneal or retinal disorder/keratopathy

Have a history and/or current evidence of extensive tissue calcification

Have impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral infigratinib

Have amylase or lipase >2.0 × ULNHave insufficient hepatic and renal function

Have any other concurrent disease or condition that, in the view of the investigator, would interfere with study participation