Ponatinib in Treating Patients with Refractory Metastatic Cancers and Genetic Alterations

Inclusion Criteria

• Patients with histologically or cytologically confirmed diagnosis of refractory metastatic solid tumor for whom no other standard treatment options are available
• Patients must have tumor suitable for biopsy (as assessed by trained specialists in interventional radiology) and medically fit to undergo a biopsy or surgical procedure; OR archival tumor specimen of biopsied tumor; OR if patients do not have a tumor suitable for biopsy but have another tissue (preferably progressive metastatic site) available for molecular evaluation (biopsy will be performed through Ohio State University [OSU]-13053 study or the University of Michigan [UM] Precision Cancer Study)
• Patients must have activating genomic alterations in FGFR (mutations, fusions or amplifications [> 6 copies]) or activating genomic alterations in mast/stem cell growth factor receptor kit (KIT), platelet-derived growth factor receptor alpha (PDGFR alpha), ret proto-oncogene (RET), ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1) and fms-related tyrosine kinase 3 (FLT3) by any validated Clinical Laboratory Improvement Amendments (CLIA)-certified molecular testing (fluorescent in situ hybridization [FISH], polymerase chain reaction [PCR] or sequencing data are acceptable); CLIA validated results from other institutions; diagnostic labs (e.g. foundation medicine) are acceptable
• Patients with solid tumors must have measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1), defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam; Note: this trial is open only to patients with solid tumors
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 80%)
• Life expectancy of greater than 3 months
• Patients with multiple malignancies remain eligible
• Patients with an inherited cancer syndrome or a medical history suggestive of an inherited cancer syndrome remain eligible
• Patients must have controlled blood pressure with a systolic blood pressure < 140 mmHg and diastolic < 90 mmHg (for patients with an elevated initial blood pressure (BP) reading [hypertensive range], a repeat measurement at least 2 minutes later should be performed, and the two readings should be averaged to obtain a BP reading); any hypertensive at-home blood pressure reading will be confirmed in clinic; patients on anti-hypertensive medications are eligible, if blood pressure is controlled; study drug dosing will be interrupted for any reading >= 160/100
• Ponatinib can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals; for this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and through 4 months after the end of treatment; for females of childbearing potential, a negative pregnancy test must be documented prior to registration
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 75,000/mcL
• Total bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert’s syndrome (< 5 if liver involvement with primary tumor)
• Serum lipase and amylase =< 1.5 x ULN
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
• Left ventricular ejection fraction (LVEF) >= 50% by echocardiogram (ECHO) or multi gated acquisition (MUGA) scan
• Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 60 mL/min OR 24-hour urine creatinine clearance >= 60 mL/min
• Patient has the ability to swallow oral medication and keep a pill diary
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Patients with hematological malignancies
• Patients who have not received any prior treatment
• Patients with known ponatinib-resistant gene alterations * Platelet derived growth factor receptor, alpha polypeptide (PDGFRA) D842V mutation * Mast/stem cell growth factor receptor Kit (cKIT) D816V mutation * FLT3 D835V/Y/H/F or Y842C mutations * Fibroblast growth factor receptor 3 (FGFR3) K652E mutation
• Major surgery (e.g. thoracic, abdominal, vascular, neurosurgery) within 28 days prior to registration on the study
• History of acute pancreatitis within one year of study entry or history of chronic pancreatitis
• History of alcohol abuse
• Have uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)
• Patients who are receiving any other investigational agents
• Patients with history of clinically significant bleeding disorder
• Pregnant women are excluded from this study because ponatinib can affect embryo-fetal development; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ponatinib breastfeeding must be discontinued
• Patients who are incarcerated are not eligible
• Patients with any history of arterial thromboembolic disease; any patient with a history of myocardial infarction (MI), stroke, transient ischemic attack (TIA), unstable angina or peripheral vascular disease will not be eligible
• Patients with history of recurrent venous thromboembolism (deep venous thrombosis or pulmonary embolism) or history of venous thromboembolism within 6 months prior to registration on study will not be eligible
• Patients with history of active hepatitis B or C infection or chronic hepatitis with Child Pugh B or C hepatic dysfunction
• Patients with prolonged corrected QT interval, defined as corrected QT (QTc) > 450 msec
• Use of antiplatelet agents other than low-dose aspirin
• Gastrointestinal (GI) bleed within 30 days prior to registration on study
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ponatinib
• Patients with history of atrial arrhythmia (requiring any anti-arrhythmic therapy) or patients with any history of ventricular arrhythmia are excluded
• Clinically significant, uncontrolled intercurrent illness including, but not limited to: * Symptomatic or active infection * Uncontrolled hypertension (diastolic blood pressure > 90 mm Hg; systolic > 140 mm Hg); patients with hypertension should be under treatment on study entry to effect blood pressure control * Psychiatric illness/social situations that would limit compliance with study requirements
• Patients with history of congestive heart failure are excluded
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
• Patients on medications known to be associated with torsades de pointes
• Patients who received the last administration of an anti-cancer therapy including, chemotherapy, immunotherapy/biologic therapy, targeted therapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) or within 5 half-lives, whichever is shorter, prior to entering the study
• Patients who have not recovered (=< Common Terminology Criteria for Adverse Events [CTCAE] grade 1) from adverse events (with the exception of alopecia) due to agents administered more than 4 weeks earlier
• Patients taking medications or herbal supplements that are known to be strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors within at least 14 days prior to registration are excluded
• Patients with symptomatic or progressive brain metastases are ineligible; subjects with treated brain metastases are eligible if they have no radiographic or other signs of progression in the brain for >= 4 weeks after completion of local therapy
• Patients with macular edema, retinal vein occlusion or retinal hemorrhage are excluded
• Patients who have received prior FGFR targeted therapy