NCT02272998 - Ponatinib for Patients Whose Advanced Solid Tumor Cancer Has Activating Mutations Involving the Following Genes: FGFR1, FGFR2, FGFR3, FGFR4, RET, KIT.

Inclusion Criteria: - Patients with histologically or cytologically confirmed diagnosis of refractory metastatic solid tumor or chronic hematological malignancy who are eligible for investigational drug therapy - 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 if patients do not have a tumor suitable for biopsy but have another tissue available for molecular evaluation - Patients should have activating genomic alterations in FGFR (mutations, fusions or amplifications [> 6 copies]) or activating genomic alterations in KIT, platelet-derived growth factor receptor alpha [PDGFRα], 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; additional types of activating alterations in these genes can be approved by the principal investigator (PI) - Patients with advanced cancers should have had at least one prior therapy that is considered standard for that disease type - 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 - 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; anti-hypertensive medications are permitted - 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 randomization - 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) >= institutional lower limit of normal by echocardiogram (ECHO) or multi gated acquisition (MUGA) - Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients with acute hematological malignancies - Patients who have not received any prior treatment. - Patients with known ponatinib-resistant gene alterations - PDGFRA D842V mutation - cKIT D816V mutation - FLT3 D835V/Y/H/F or Y842C mutations - FGFR3 K652E mutation - Major surgery (e.g. thoracic, abdominal, vascular, neurosurgery) within 28 days prior to initiating therapy - History of acute pancreatitis within one year of study or history of chronic pancreatitis - History of alcohol abuse - Have uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL) - 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 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 - History of allergic reactions attributed to compounds of similar chemical or biologic composition to ponatinib - Patients with prolonged corrected QT interval, defined as QTc >450 msec - Use of antiplatelet agents other than low-dose aspirin as described - 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 - HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with ponatinib. - 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 taking medications or herbal supplements that are known to be strong cytochrome P450 3A4 (CYP3A4) inhibitors within at least 14 days before the first dose of ponatinib 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