Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

Ponatinib Hydrochloride in Treating Patients with Refractory Metastatic Cancers and Genetic Alterations

Protocol: OSU-14078

Full Title

Phase II study of ponatinib for advanced cancers with genomic alterations in fibroblastic growth factor receptor (FGFR) and other genomic targets (KIT, PDGFRá, RET FLT3, ABL1)

Purpose

This phase II trial studies how well ponatinib hydrochloride 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 hydrochloride 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.

Study Objective

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

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.

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 3 months for 52 weeks.

Are you eligible?

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 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

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 acute 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 or history of chronic pancreatitis

History of alcohol abuse

Have uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)

Patients who are receiving any other investigational therapeutic agents

Patients with gastrointestinal stromal tumor (GIST)

Patients with history of clinically significant bleeding disorder

Pregnant women are excluded from this study; breastfeeding should 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) 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