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

  • STATUS
    Recruiting
  • days left to enroll
    68
  • participants needed
    45
  • sponsor
    Sameek Roychowdhury
Updated on 23 January 2021
hematologic malignancy
tyrosine
measurable disease
growth factor
x-rays
gilbert's syndrome
FGFR1
KIT
neutrophil count
RET
primary tumor
primary cancer
solid tumour
solid tumor
metastatic solid tumor
FGFR2
solid neoplasm
FGFR3
advanced malignant solid tumor

Summary

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), has failed 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.

Description

PRIMARY OBJECTIVES:

I. To evaluate the response of ponatinib (ponatinib hydrochloride) in patients with fibroblast growth factor receptor (FGFR) altered cancers.

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 vs. amplifications vs. mutations).

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 for 52 weeks.

Details
Condition Cancer, Cancer/Tumors, Ewing's Family Tumors, Cancer (Pediatric), Neoplasms, primary cancer, primary malignant neoplasm, malignancy, cancers, malignancies, malignant tumor, malignant tumors
Treatment laboratory biomarker analysis, Ponatinib Hydrochloride
Clinical Study IdentifierNCT02272998
SponsorSameek Roychowdhury
Last Modified on23 January 2021

Eligibility

Yes No Not Sure

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 [PDGFR], 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
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