| Eligibility |
Inclusion Criteria:
- Written informed consent and any locally-required authorization (e.g. HIPAA) obtained
from the patient prior to performing any protocol-related procedures, including
screening evaluations
- Age = 18 years at time of study entry (no safety data in pediatric patients is
available for infigratinib).
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (See Appendix
A).
- Histologically confirmed bladder transitional cell carcinoma (TCC)
-- Patients with mixed histology are required to have a component of TCC, and no
component of small cell histology
- cT2-T4a N0 M0 disease after radiographic staging of chest, abdomen and pelvis,
considered appropriate and planned for radical cystectomy as assessed by a Urologic
Oncologist.
- Presence of the following FGFR3/2 activating alterations, as detected by either plasma
or urine cfDNA or cfRNA or by tissue-based NGS (Predicine, Hayward, CA):
- Mutations in exon 7 (R248C, S249C)
- Mutations in exon 10 (G372C, A393E, Y375C)
- Mutations in exon 15 (K652M/T, K652E/Q)
- Any FGFR3/2 gene fusion (Availability of baseline archival tumor tissue for
identification of FGFR3/2 alterations is not required, but tissue will be
obtained when available including either FFPE tumor tissue block or a minimum of
fifteen 5µm unstained FFPE slides and fifteen 10µm unstained FFPE slides with an
associated pathology report is required)
- Ineligibility for cisplatin-based chemotherapy, defined by any of the following:
- Creatinine clearance (CL) <60 mL/min. GFR should be calculated from serum/plasma
creatinine using the Cockcroft-Gault formula.
- CTCAE v5.0 Grade > 1 hearing loss
- CTCAE v5.0 Grade > 1 neuropathy
- NYHA Class > II cardiac dysfunction
- Patients not meeting the above criteria are eligible if he/she declines
neoadjuvant cisplatin-based chemotherapy after specific informed consent
describing the known benefits of cisplatin-based chemotherapy. The reason for
cisplatin-ineligibility based on the above criteria or cisplatin refusal should
be documented on the case report form.
- Adequate organ function laboratory values as defined below:
- Hemoglobin = 9.0 g/dL
- Absolute neutrophil count (ANC) 1.5 x (> 1500 per mm3)
- Platelet count =100 x 109/L (>75,000 per mm3)
- International Normalized Ratio (INR) or activated partial thromboplastin time
(aPTT) < 1.5 x ULN, unless the patient is receiving anticoagulation therapy
provided INR or PTT is within the therapeutic range of the intended anticoagulant
therapy.
- Serum bilirubin =1.5 x institutional upper limit of normal (ULN)
-- This will not apply to patients with confirmed Gilbert's syndrome (persistent or
recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of
hemolysis or hepatic pathology), who will be allowed only in consultation with their
physician.
- AST (SGOT)/ALT (SGPT) =1.5 x institutional upper limit of normal
- Measured creatinine CL >30 mL/min or Calculated creatinine CL>30 mL/min by the
Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine
clearance:
- Males: Creatinine CL (mL/min) = Weight (kg) x (140 - Age)/72 x serum creatinine
(mg/dL)
- Females: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85/ 72 x serum
creatinine (mg/dL)
- Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
agespecific requirements apply:
- Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).
- Women =50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
hysterectomy).
- Patient has ability and willingness to sign a written informed consent document and is
willing and able to comply with the protocol for the duration of the study including
undergoing treatment and scheduled visits and examinations including follow up.
Exclusion Criteria:
- Patients with primary TCC of the ureter, urethra, or renal pelvis without TCC of the
bladder
- Inoperable tumor(s) with fixation to the pelvic wall on clinical exam
- Any previous systemic chemotherapy or radiotherapy for TCC of bladder
- Participation in another clinical study with an investigational product during the
last 6 months
- Any prior participation in a study involving an FGFR inhibitor.
- Concurrent enrolment in another clinical study, unless it is an observational
(noninterventional) clinical study or during the follow-up period of an interventional
study
- History of another primary malignancy except for:
- Malignancy treated with curative intent and with no known active disease =5 years
before the first dose of study drug and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
- Adequately treated carcinoma in situ without evidence of disease (e.g. cervical
cancer in situ)
- Receipt of the last dose of intravesical chemotherapy or biologic therapy = 42 days (6
weeks) prior to the first dose of study drug for patients who have received prior
intravesical chemotherapy or biologic therapy (e.g. BCG)
- Any unresolved toxicity NCI CTCAE version 5.0 Grade =2 from previous anticancer
therapy with the exception of alopecia, vitiligo, and the laboratory values defined in
the inclusion criteria
- Patients currently receiving treatment with drugs that are known to be strong CYP3A4
inducers or inhibitors, including anti-epileptic drugs.
- Use of medications that are known to prolong the QT interval and/or associated with a
risk of torsade de pointes 7 days prior to the first dose of infigratinib.
- Use of amiodarone within 90 days prior to first dose of infigratinib.
- Use of medications that increase serum levels of calcium and/or phosphorus.
- Concurrent use of warfarin or other coumadin-derivative anticoagulants; heparin and/or
low molecular-weight heparins are permitted.
- Inorganic phosphorus and/or total/ionized serum calcium outside normal limits prior to
study entry.
- Have clinically significant cardiac disease, including any of the following:
- New York Heart Association (NYHA) Class =2B; subjects with known history or
current symptoms of cardiac disease, or history of treatment with cardiotoxic
agents, should have a clinical risk assessment of cardiac function using the NYHA
classification.
- Presence of Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grade =2
ventricular arrhythmias, atrial fibrillation, bradycardia, or conduction
abnormality
- Unstable angina pectoris or acute myocardial infarction =3 months prior to first
dose of study drug
- QTcF >470 msec (males and females). Note: If the QTcF is >470 msec in the first
ECG, a total of 3 ECGs separated by at least 5 minutes should be performed. If
the average of these 3 consecutive results for QTcF is =470 msec, the subject
meets eligibility in this regard
- Known history of congenital long QT syndrome.
- Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
Concurrent use of hormonal therapy for non-cancer-related conditions (e.g. hormone
replacement therapy) is acceptable.
- Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose of infigratinib. NB: local surgery of isolated lesions for palliative
intent is acceptable.
- History of allogeneic organ transplantation
- Current evidence of corneal or retinal disorder/keratopathy
- Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially increase
risk of incurring AEs or compromise the ability of the patient to give written
informed consent
- Female patients who are pregnant or breastfeeding, or patients of reproductive
potential who are not willing to employ effective birth control from screening to 90
days after the last dose of infigratinib monotherapy.
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients
- Inability to swallow oral medications
- Judgement by the investigator that the patient is unsuitable to participate in the
study and the patient is unlikely to comply with study procedures, restrictions and
requirements.
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