This research study is studying the safety, tolerability, and tumor activity of the study
drug known as rogaratinib as a possible treatment for bladder cancer.
- Male or female patients ≥ 18 years of age (at least age of legal maturity)
- Have a histologically-confirmed diagnosis of high risk non-muscle-invasive (T1, High
Grade Ta and/or CIS) transitional cell carcinoma of the bladder. Subjects with tumors
of mixed transitional/non-transitional cell histology are not allowed.
- In subjects with Ta and T1, have undergone complete TURBT as characterized by:
- Attainment of a visually complete resection
- Residual CIS not amenable to complete transurethral resection is acceptable
- The most recent cystoscopy / TURBT must have been performed within 8 weeks prior
to the first dose of trial treatment
- Have been treated with adequate BCG therapy and have developed NMIBC that is
unresponsive to BCG therapy. Adequate BCG therapy must include: An induction course
with at least 5 instillations of BCG (adequate induction); and at least 7
instillations of BCG within 9 months of the first instillation of adequate induction
therapy. BCG unresponsive high risk NMIBC is defined as: Stage progression at 3 months
(±4 weeks) despite adequate induction therapy (e.g., Ta to T1, or CIS to T1; note:
adequate induction therapy only, defined above, is required in this case); or
Persistent high risk NMIBC at 6 months (±4 weeks) after adequate BCG therapy or
Recurrent high risk NMIBC within 9 months of the last BCG instillation despite
adequate BCG therapy.
- Have elected not to undergo, or are considered ineligible for radical cystectomy, as
determined by the treating surgeon. Reasons for ineligibility or refusal of radical
cystectomy should be discussed with the subject as part of the informed consent
process and should be captured on the appropriate case report form. Ineligibility
factors for radical cystectomy may include, but are not limited to:
- Cardiovascular disease (e.g. recent acute coronary syndrome, arrhythmia, heart
- Chronic obstructive pulmonary disease that would preclude a safe surgical
procedure, as determined by the treating surgeon
- Poor performance status (e.g. ECOG >2)
- Prior major abdominal and pelvic surgery, that would preclude a safe surgical
procedure, as determined by the treating surgeon
- High FGFR 1/3 mRNA expression levels (RNAscope score of 3+ or 4+; measurement is part
of the protocol) in archival or fresh tumor biopsy specimen
- Existence of archival or fresh tumor biopsy specimen for FGFR1/3 mRNA expression
testing. Patients who don't have archival tissue specimens meeting eligibility
requirements may undergo a biopsy. Acceptable samples include core needle biopsies for
deep tumor tissue (minimum three cores) or excisional, incisional, punch, or forceps
biopsies for cutaneous, subcutaneous, or mucosal lesions.
- Ability to understand and signing of the written patient information/informed consent
form (PI/ICF) for FGFR testing
- Ability to understand and signing of the written PI/ICF for study treatment
eligibility. Signed informed consent form must be available before any study-specific
procedure for the respective study parts may begin.(PI/ICF for study treatment
eligibility must be offered only after positive results in FGFR testing study received
- Eastern Cooperative Oncology Group performance status 0 or 1
- Adequate bone marrow, liver and renal function as assessed by laboratory requirements
conducted within 14 days before registration:
- Absolute neutrophil count (ANC) ≥ 1,500/mm3 (without granulocyte
colony-stimulating factor support within 2 weeks before the first study drug
- Hemoglobin ≥ 10 g/dL (without transfusion or erythropoietin within 4 weeks before
the first study drug administration)
- Platelet count ≥ 100,000/mm3 (without transfusion within 2 weeks before the first
study drug administration)
- Total bilirubin ≤ 1.5 x the upper limit of normal (ULN). Total bilirubin ≤ 3 x
ULN for patients with known Gilbert syndrome.
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN
- Alkaline phosphatase ≤ 2.5 times ULN
- Lipase and amylase ≤ 2 x ULN
- Serum albumin ≥ 2.5 g/dl
- Glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m2 according to the
modification of diet in renal disease (MDRD) abbreviated formula.
Note: at the investigator's discretion, an estimated creatinine clearance result <60
mL/min/1.73m² may be verified by measurement of creatinine clearance based on 24-hour urine
collection or using EDTA, inulin, GFR scan. INR ≤ 1.5 x ULN and PTT or activated PTT (aPTT)
≤ 1.5 x ULN. Patients being treated with anticoagulant, e.g. warfarin or heparin, will be
allowed to participate provided no prior evidence of an underlying abnormality in these
parameters exists and they are on a stable dose as defined by the local standard of care.
- Negative serum pregnancy test in women of childbearing potential (performed within 7
days before the first treatment). Negative results must be available before the first
study drug administration. Females are considered of childbearing potential unless
they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation,
or bilateral oophorectomy) or they are naturally postmenopausal for at least 12
- Women and men of reproductive potential must agree to use adequate contraception when
sexually active. This applies for the time period between signing of the informed
consent form and until at least 5 months after the last study drug administration. The
definition of adequate contraception will be based on the judgment of the investigator
and on local requirements. Acceptable methods of contraception include, but are not
limited to, (i) condoms (male or female) with or without a spermicidal agent; (ii)
diaphragm or cervical cap with spermicide; (iii) intra-uterine device; (iv)
- Recovery to National Cancer Institute's Common Terminology Criteria for Adverse
Events, version 5.0 (NCI CTCAE v.5.0) Grade 0 or 1 level or recovery to baseline
preceding the prior treatment from any previous drug / procedure-related toxicity
(patients with persistent alopecia of any grade, and/or anemia [hemoglobin ≥ 10 g/dL]
can be included)
- Has muscle invasive (i.e. T2, T3, T4) locally advanced non-resectable or metastatic
- Has concurrent extra-vesical (i.e. urethra, ureter or renal pelvis) non-muscle
invasive transitional cell carcinoma of the urothelium.
- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment.
- Has undergone any intervening intravesical chemotherapy or immunotherapy from the time
of most recent cystoscopy/TURBT to starting trial treatment. (Note: intravesical
treatment given as part of the most recent cystoscopy / TURBT is allowed.)
- Previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase
inhibitors including rogaratinib or FGFR-specific antibodies).
- Previous or concurrent cancer except: cervical carcinoma in situ, treated basal-cell
carcinoma or squamous cell skin cancer, localized prostate cancer treated with
curative intent and known absence of prostate-specific antigen (PSA) relapse or
incidental prostate cancer (T1/T2a, Gleason score ≤ 6, and PSA ≤ 10 ng/mL undergoing
active surveillance and treatment-naïve), or any other cancer curatively treated > 3
years before the first study drug administration.
- History or current condition of an uncontrolled cardiovascular disease including any
of the following conditions:
- Congestive heart failure (CHF) NYHA Class 2 or greater, unstable angina (symptoms
of angina at rest)
- New-onset angina (within last 3 months before the first study drug
- Myocardial infarction (MI) within past 6 months before the first study drug
- Unstable cardiac arrhythmias requiring anti-arrhythmic therapy. Patients with
arrhythmia not requiring therapy or under control with anti-arrhythmic therapy
such as beta-blockers or digoxin are eligible.
- Patients with known coronary artery disease, or congestive heart failure not meeting
the above criteria, must be on a stable medical regimen that is optimized in the
opinion of the treating physician, in consultation with a cardiologist if appropriate.
- Known human immunodeficiency virus (HIV) infection.
- Active hepatitis B virus (HBV; chronic or acute; defined as having a known positive
hepatitis B surface antigen [HBsAg] test at the time of screening) or hepatitis C
infection requiring treatment. Patients with past HBV infection or resolved HBV
infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of
HBsAg) are eligible if HBV DNA is negative. Patients positive for hepatitis C virus
(HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
- Active tuberculosis.
- Treatment with therapeutic oral or I.V. antibiotics within 2 weeks before the first
study drug administration. Patients receiving prophylactic antibiotics (e.g. for
prevention of a urinary tract infection or to prevent chronic obstructive pulmonary
disease exacerbation) are eligible.
- Any hemorrhage / bleeding event CTCAE v.5.0 ≥ Grade 3 within 4 weeks before the first
study drug administration.
- Serious, non-healing wound, ulcer, or bone fracture.
- Known hypersensitivity to any of the study drugs, study drug classes, or excipients in
- Any malabsorption condition.
- Current diagnosis of any retinal disorders including retinal detachment, retinal
pigment epithelial detachment (RPED), serous retinopathy or retinal vein occlusion. An
ophthalmological exam with optical coherence tomography is required within 30 days of
the date of registration.
- Peripheral sensory neuropathy of CTCAE v.5.0 Grade 2 or higher.
- Current evidence of endocrine alteration of calcium phosphate homeostasis (e.g.
parathyroid disorder, history of parathyroidectomy, tumor lysis, tumoral calcinosis,
- Concomitant therapies that are known to increase serum phosphate levels (i.e.
antacids, laxatives oral/rectal, oral phosphate binders, potassium phosphate) and that
cannot be discontinued or switched to a different medication before the first study
- Any condition that is unstable or could jeopardize the safety of the patient and their
compliance in the study.
- Clinically active infections (CTCAE v. 5.0 ≥ Grade 1) within 2 weeks before the first
study drug administration.
- Seizure disorder requiring medication.
- History of organ allograft.
- Evidence or history of bleeding diathesis or coagulopathy.
- Women who are actively breastfeeding.
- Use of strong inhibitors of CYP3A4 and strong inducers of CYP3A4 are not permitted for
2 weeks before the first study drug administration or during the study.
- Autologous bone marrow transplant or stem cell rescue within 4 months before the first
study drug administration.
- Major surgery, open biopsy, or significant traumatic injury within 4 weeks before the
first study drug administration (central line surgery is not considered major
- Renal failure requiring peritoneal dialysis or hemodialysis.
- Systolic/diastolic blood pressure ≤ 100/60 mmHg and concurrent heart rate ≥ 100/min.
- Inability to swallow oral tablets.
- Close affiliation with the investigational site; e.g. a close relative of the
investigator or a dependent person (e.g. employee of or student at the investigational
- Substance abuse, medical, psychological or social conditions that may interfere with
the patient's participation in the study or evaluation of the study results.
- Arterial or venous thrombotic events or embolic events such as cerebrovascular
accident (including transient ischemic attacks), deep vein thrombosis or pulmonary
embolism within 6 months before the first study drug administration.
- Those who have not recovered from adverse events due to agents administered more than
4 weeks earlier.
- Concomitant therapy with the following medication is prohibited
- Concomitant use of strong inhibitors of CYP3A4 and strong inducers of CYP3A4 are
not permitted for 2 weeks prior to start of study treatment or during the study.
- Concomitant use of moderate and weak CYP3A4 inducers should be avoided as
clinically significant decrease in plasma concentrations of rogaratinib cannot be
- Concomitant use of herbal preparations containing CYP3A4 inducers (e.g. St John's
Wort) are not permitted during the study.
- Grapefruit and grapefruit juice (CYP3A4 inhibitor) consumption is not permitted
during the study.
- Therapies that are known to increase serum calcium or phosphate levels (i.e.
antacids, phosphate-containing laxatives oral/rectal, potassium phosphate)
- Patients may not receive other investigational treatment or other approved
anti-tumor therapy while on this protocol (excluding anti-VEGF therapy for
- Concomitant therapies that should be avoided:
- Narrow therapeutic index drugs that are CYP3A4, P-gp, and BCRP substrates (e.g.
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide,
quinidine, sirolimus, and tacrolimus) should be avoided, because drug
interactions caused by irreversible inhibition of CYP3A4, P-gp, and BCRP by
rogaratinib cannot be ruled out.
- Fluconazole is considered a moderate to strong inhibitor of CYP2C9 and should be
avoided, if possible.
- No results are available from human interaction studies between rogaratinib and
other chemotherapies. No data are available to evaluate the interaction between
rogaratinib and radiation. Therefore, when administering these agents after study
drug has been withdrawn, it should be taken into consideration that rogaratinib
plasma concentrations may be detectable for a few days (depending on half-life)
and the physiologic consequences that could interact with chemotherapy and
radiotherapy may last even longer following discontinuation of rogaratinib.