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

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ClinicalTrials.gov Identifier: NCT02272998
Recruitment Status : Recruiting
First Posted : October 23, 2014
Last Update Posted : February 17, 2020
Sponsor:
Information provided by (Responsible Party):
Sameek Roychowdhury, Ohio State University Comprehensive Cancer Center

Tracking Information
First Submitted Date  ICMJE October 21, 2014
First Posted Date  ICMJE October 23, 2014
Last Update Posted Date February 17, 2020
Actual Study Start Date  ICMJE February 24, 2015
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 21, 2014)
Overall response, defined as the number of patients who achieve any response according to disease type in the first 6 courses of treatment [ Time Frame: Up to 6 months ]
The proportion of responses for the purposes of the decision rule will be calculated out of all eligible patients who receive any treatment. Assuming the number of responses is binomially distributed, 95% binomial confidence intervals will also be calculated for the estimate of the proportion of responses.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 21, 2014)
  • Incidence of toxicity, defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 30 days after last dose of study drug ]
    Frequency and severity of adverse events will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns for each of the cohorts as well as across cohorts. In addition, all adverse event data that is graded as 3, 4, or 5 will be reviewed and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing.
  • Tolerability of the regimen, assessed by the number of patients who required dose modifications and/or dose delays [ Time Frame: Up to 30 days after last dose of study drug ]
    Collected and summarized by descriptive statistics. In addition, the proportion of patients who go off treatment due to adverse reactions or even those who refuse further treatment for lesser toxicities that inhibit their willingness to continue participation on the trial will be captured.
  • Overall survival [ Time Frame: The time from treatment initiation to death, assessed up to 52 weeks ]
    Kaplan-Meier curves will be used to estimate the survival distribution.
  • Progression free survival [ Time Frame: The time from treatment initiation to progression or death, assessed up to 52 weeks ]
    Kaplan-Meier curves will be used to estimate the survival distribution.
  • Clinical benefit rate (CBR) [ Time Frame: 6 months ]
    Calculated by the number of patients who have achieve a response and/or are progression-free and alive at 6 months divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for CBR will be calculated.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: October 21, 2014)
Correlative gene and protein markers [ Time Frame: Up to 3 years (time of progression) ]
Correlative gene and protein markers will be summarized univariately in a quantitative manner and also summarized by clinical outcome group (e.g. response vs. no response). Graphical analyses will be largely used to assess potential patterns and relationships; e.g. side-by-side boxplots to assess differences in continuous marker levels between those with vs. without the clinical improvement (e.g. response vs. no response). Overall, hypothesis testing will largely be avoided given the sample size limitations.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Ponatinib for Patients Whose Advanced Solid Tumor Cancer Has Activating Mutations Involving the Following Genes: FGFR1, FGFR2, FGFR3, FGFR4, RET, KIT.
Official Title  ICMJE 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)
Brief 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.
Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Malignant Neoplasm
Intervention  ICMJE
  • Drug: ponatinib hydrochloride
    Given PO
    Other Names:
    • AP24534
    • Iclusig
    • multitargeted tyrosine kinase inhibitor AP24534
  • Other: laboratory biomarker analysis
    Correlative studies
Study Arms  ICMJE Experimental: Treatment (ponatinib hydrochloride)
Patients receive ponatinib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: ponatinib hydrochloride
  • Other: laboratory biomarker analysis
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 21, 2014)
45
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: The Ohio State University Comprehensive Cancer Center 1-800-293-5066 Jamesline@osumc.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02272998
Other Study ID Numbers  ICMJE OSU-14078
NCI-2014-01499 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Sameek Roychowdhury, Ohio State University Comprehensive Cancer Center
Study Sponsor  ICMJE Sameek Roychowdhury
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Sameek Roychowdhury, MD, PhD Ohio State University Comprehensive Cancer Center
PRS Account Ohio State University Comprehensive Cancer Center
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP