PRIMARY OBJECTIVES:
I. To assess the clinical benefit rate (confirmed complete or partial response or stable
disease for 4 or more cycles) of ponatinib (ponatinib hydrochloride) in fibroblast growth
factor receptor (FGFR) aberrant advanced biliary cancers.
SECONDARY OBJECTIVES:
I. To estimate progression free survival, overall survival, and cancer antigen 19-9 (CA19-9)
response rate of these patients.
II. To estimate the adverse event profile of ponatinib.
TERTIARY OBJECTIVES:
I. Establish preliminary correlations between FGFR2 fusions and evidence of any clinical
benefit.
II. Assess preliminary evaluation of FGFR2 pathway perturbation with ponatinib. III. To
describe patient-reported health-related quality of life and symptoms.
OUTLINE:
Patients receive ponatinib hydrochloride orally (PO) once daily (QD) on days 1-28. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for at least 2
years.
Inclusion Criteria:
- Histological/cytological confirmation of biliary cancer
- Confirmation of advanced biliary cancer that is refractory or intolerant to
gemcitabine or fluoropyrimidine based therapy with FGFR2 fusion [using next-gen
sequencing assays (such as Foundation One) or fluorescent in situ hybridization (FISH)
break-apart assays] or FGFR pathway mutation/amplification [using next-gen sequencing
assays (such as Foundation One)]; assays must be performed in a Clinical Laboratory
Improvement Amendments [CLIA] certified laboratory and done as a CLIA validated test
or research use only [RUO] in a CLIA laboratory
- Measurable disease
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
- Absolute neutrophil count (ANC) >= 1500/mm^3
- Platelet count >= 100,000/mm^3
- Hemoglobin >= 9.0 g/dL
- Total bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome
- Aspartate transaminase (AST) and alanine aminotransferase (ALT) < 3 x ULN
- Creatinine =< 1.5 x ULN
- Serum lipase and amylase =< 2.5 x ULN; NOTE: if subject has tumor involvement in the
liver =< 3 x ULN
- Negative pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only
- Recovered from prior radiotherapy and/or systemic therapy related toxicities to grade
=< 1
- Provide informed written consent
- Life expectancy >= 3 months
- Willing to return to enrolling institution for follow-up (during the Active Monitoring
Phase of the study); Note: during the Active Monitoring Phase of a study (i.e., active
treatment and observation), participants must be willing to return to the consenting
institution for follow-up
- Female and male patients who are fertile agree to use an effective form of
contraception with their sexual partners from registration through 4 months after the
end of treatment
- Ability to complete questionnaire(s) by themselves or with assistance
Exclusion Criteria:
- Any of the following:
- Pregnant women
- Nursing women
- Men or women of childbearing potential who are unwilling to employ adequate
contraception
- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens
- Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
positive and currently receiving antiretroviral therapy; NOTE: patients with a known
history of HIV infection are not eligible for this trial
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm
- Prior systemic chemotherapy, radiation therapy or major surgery =< 30 days prior to
registration
- Concurrent use of any other approved or investigational anticancer agents, including
hormonal agents
- Prior nitrosourea or mitomycin C =< 6 weeks prior to registration
- Patients with gastrointestinal comorbidities that would affect intake or absorption of
ponatinib
- Untreated or progressive brain metastases
- Prior treatment with or allergic reactions attributed to compounds of similar chemical
or biologic composition to ponatinib
- Clinically uncontrolled hypertension (diastolic blood pressure > 90 mm mercury [Hg];
systolic > 140 mm Hg); Note: patients with hypertension should be undergoing treatment
at study entry for blood pressure control
- Previous or concurrent malignancy except adequately treated basal or squamous cell
skin cancer, in situ carcinoma of the cervix, or other solid tumor treated curatively
and without evidence of recurrence for at least 5 years
- History of significant bleeding disorder unrelated to cancer
- History of acute pancreatitis within 1 year prior to registration, chronic
pancreatitis, alcohol abuse or uncontrolled hypertriglyceridemia (triglycerides > 450
mg/dL)
- Clinically significant, uncontrolled, or active cardiovascular disease, specifically
including, but not restricted to:
- Any history of myocardial infarction, stroke, or revascularization
- Unstable angina or transient ischemic attack within 6 months prior to
registration
- Congestive heart failure within 6 months prior to registration, or left
ventricular ejection fraction (LVEF) less than lower limit of normal per local
institutional standards within 6 months prior to registration
- History of clinically significant (as determined by the treating physician)
atrial arrhythmia
- Any history of ventricular arrhythmia
- Active venous thromboembolism including deep venous thrombosis or pulmonary
embolism that is not amenable to treatment with anticoagulants
- Patients with congenital prolonged QT syndromes and abnormal baseline prolonged
corrected QT (QTc) (> 450 ms in men and > 470 ms in women)
- Patients with an ejection fraction =< 50% as assessed by a baseline
echocardiogram
- Taking medications that are known to be associated with torsades de pointes
- Taking any medications or herbal supplements that are known to be strong inhibitors of
cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) =< 14 days prior to
registration
