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Ponatinib in Treating Patients with Refractory Metastatic Cancers and Genetic Alterations

Trial Status: Closed to Accrual

This phase II trial studies how well ponatinib works in treating patients with cancer that has spread to other parts of the body (metastatic), did not respond to previous treatment (refractory), and has one of several alterations, or mutations, in its deoxyribonucleic acid (DNA) sequence. Ponatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether a patient's genetic alterations may affect how well ponatinib hydrochloride works.

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


Ann Arbor
University of Michigan Comprehensive Cancer Center
Contact: Ajjai Alva


Ohio State University Comprehensive Cancer Center
Contact: Sameek Roychowdhury
Phone: 614-685-5841


I. To evaluate the response of ponatinib in solid tumor patients with fibroblast growth factor receptor (FGFR) alterations.


I. To assess the safety and tolerability of ponatinib in advanced solid tumors with genomic FGFR alterations.

II. To assess progression free survival (PFS) and overall survival (OS) with ponatinib.

III. To determine candidate genomic and proteomic biomarkers of sensitivity and resistance to ponatinib using unbiased high throughput approaches (exome, transcriptome, reverse phase protein array [RPPA]).

IV. To assess response of ponatinib in advanced cancers with subsets of genomic FGFR alterations (fusions versus [vs.] amplifications vs. mutations).

V. To assess response of ponatinib by tumor type.


Patients receive ponatinib hydrochloride orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 52 weeks.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Ohio State University Comprehensive Cancer Center

Principal Investigator
Sameek Roychowdhury

  • Primary ID OSU-14078
  • Secondary IDs NCI-2014-01499, 14078, 2014C0143
  • ID NCT02272998