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Ponatinib Hydrochloride in Treating Patients With Advanced Biliary Cancer With FGFR2 Fusions

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02265341
Recruitment Status : Completed
First Posted : October 15, 2014
Results First Posted : August 6, 2019
Last Update Posted : August 6, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Tracking Information
First Submitted Date  ICMJE October 9, 2014
First Posted Date  ICMJE October 15, 2014
Results First Submitted Date  ICMJE June 3, 2019
Results First Posted Date  ICMJE August 6, 2019
Last Update Posted Date August 6, 2019
Actual Study Start Date  ICMJE December 2014
Actual Primary Completion Date May 1, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 12, 2019)
Clinical Benefit Rate (Percentage), Which Includes Confirmed Tumor Response (Complete Response [CR] or Partial Response [PR]) or Stable Disease (SD) [ Time Frame: Up to 10 months of treatment ]
A confirmed tumor response is defined to be either a CR or PR noted as the objective status on 2 consecutive evaluations at least 8 weeks apart. The proportion of clinical benefit rate will be estimated by the number of patients with clinical benefit (confirmed CR, confirmed PR, or SD for 4 or more cycles) divided by the total number of evaluable patients. Complete Response (CR): All of the following must be true:a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to <1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the BSD (see Section 11.41). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD taking as reference the MSD. Please refer to RECIST v1.1 response criteria for more details.
Original Primary Outcome Measures  ICMJE
 (submitted: October 9, 2014)
Clinical benefit rate, which includes confirmed tumor response (complete response [CR] or partial response [PR]) or stable disease (SD) [ Time Frame: Up to 5 years ]
A confirmed tumor response is defined to be either a CR or PR noted as the objective status on 2 consecutive evaluations at least 8 weeks apart. The proportion of clinical benefit rate will be estimated by the number of patients with clinical benefit (confirmed CR, confirmed PR, or SD for 4 or more cycles) divided by the total number of evaluable patients. A confidence interval for the true clinical benefit rate will be calculated using the approach of Duffy and Santner.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 12, 2019)
  • CA 19-9 Response [ Time Frame: Up to 10 months of treatment ]
    This test measures the amount of a protein called CA 19-9 (cancer antigen 19-9) in the blood. CA 19-9 is a type of tumor marker. Tumor markers are substances made by cancer cells or by normal cells in response to cancer in the body.CA 19-9 was collected at baseline and on day one of each cycle. A CA 19-9 response is defined to be a >= 50% reduction from baseline. The CA 19-9 response rate (percentage) will be estimated by the number of CA 19-9 responses divided by the total number of evaluable patients.
  • Overall Toxicity Rate, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) [ Time Frame: Up to 10 months of treatment ]
    The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.
  • Progression-free Survival [ Time Frame: Time from registration to the earliest date of documentation of disease progression, assessed up to maximum 3.3 years from registration. ]
    Progression free survival (PFS) is defined as the time from the date of registration to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
  • Survival Time [ Time Frame: Time from registration to death due to any cause, assessed up to a maximum of 3.3 years ]
    Overall survival time is defined as the time from registration to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 9, 2014)
  • Progression-free Survival [ Time Frame: Time from registration to the earliest date of documentation of disease progression, assessed up to 5 years ]
    The distribution of progression-free survival time will be estimated using the method of Kaplan-Meier.
  • Survival Time [ Time Frame: Time from registration to death due to any cause, assessed up to 5 years ]
    The distribution of survival time will be estimated using the method of Kaplan-Meier.
  • Change in CA 19-9 response, defined to be a >= 50% reduction from baseline [ Time Frame: Baseline to up to 5 years ]
    The CA 19-9 response rate will be estimated by the number of CA 19-9 responses divided by the total number of evaluable patients. A confidence interval will be calculated based on the binomial distribution.
  • Incidence of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 5 years ]
    The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.
Current Other Pre-specified Outcome Measures
 (submitted: July 12, 2019)
  • Changes in Patient-reported Outcomes (Quality of Life and Symptoms), Assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30, EORTC QLQ-BIL21, Skindex-16, and Bowel Function Questionnaire [ Time Frame: Up to a maximum follow-up of 3.3 years ]
    The Uniscale assessment of overall quality of life will be used. The Was It Worth It questionnaire will determine patient's satisfaction with the study. Scale score trajectories over time will be examined using stream plots and mean plots with standard deviation error bars overall. Changes from baseline at each cycle will be statistically tested using paired t-tests, and standardized response means will be interpreted using Cohen's (1988) cut-offs. Correlation between outcomes will employ Pearson and/or Spearman correlations at individual time points.
  • Rate of Circulating-free Tumor Deoxyribonucleic Acid Mutations [ Time Frame: Up to a maximum follow-up of 3.3 years ]
    Will be described, and association with confirmed tumor response and/or clinical benefit will be investigated using a Fisher's exact test.
  • Rate of FGFR Fusions [ Time Frame: Up to a maximum follow-up of 3.3 years ]
    Will be described, and association with confirmed tumor response and/or clinical benefit will be investigated using a Fisher's exact test.
Original Other Pre-specified Outcome Measures
 (submitted: October 9, 2014)
  • Rate of FGFR Fusions [ Time Frame: Up to 5 years ]
    Will be described, and association with confirmed tumor response and/or clinical benefit will be investigated using a Fisher's exact test.
  • Rate of Circulating-free Tumor Deoxyribonucleic Acid Mutations [ Time Frame: Up to 5 years ]
    Will be described, and association with confirmed tumor response and/or clinical benefit will be investigated using a Fisher's exact test.
  • Changes in Patient-reported Outcomes (Quality of Life and Symptoms), Assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30, EORTC QLQ-BIL21, Skindex-16, and Bowel Function Questionnaire [ Time Frame: Baseline to up to 5 years ]
    The Uniscale assessment of overall quality of life will be used. The Was It Worth It questionnaire will determine patient's satisfaction with the study. Scale score trajectories over time will be examined using stream plots and mean plots with standard deviation error bars overall. Changes from baseline at each cycle will be statistically tested using paired t-tests, and standardized response means will be interpreted using Cohen's (1988) cut-offs. Correlation between outcomes will employ Pearson and/or Spearman correlations at individual time points.
 
Descriptive Information
Brief Title  ICMJE Ponatinib Hydrochloride in Treating Patients With Advanced Biliary Cancer With FGFR2 Fusions
Official Title  ICMJE Pilot Study of Ponatinib in Biliary Cancer Patients With FGFR2 Fusions
Brief Summary This pilot phase II trial studies how well ponatinib hydrochloride works in treating patients with biliary cancer that has spread to other places in the body and that have alterations (fusions) in a gene known as fibroblast growth factor receptor 2 (FGFR2). Ponatinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed Description

PRIMARY OBJECTIVES:

I. To assess the clinical benefit rate (confirmed complete or partial response or stable disease for 4 or more cycles) of ponatinib (ponatinib hydrochloride) in fibroblast growth factor receptor (FGFR) aberrant advanced biliary cancers.

SECONDARY OBJECTIVES:

I. To estimate progression free survival, overall survival, and cancer antigen 19-9 (CA19-9) response rate of these patients.

II. To estimate the adverse event profile of ponatinib.

TERTIARY OBJECTIVES:

I. Establish preliminary correlations between FGFR2 fusions and evidence of any clinical benefit.

II. Assess preliminary evaluation of FGFR2 pathway perturbation with ponatinib. III. To describe patient-reported health-related quality of life and symptoms.

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 6 months for at least 2 years.

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 Hepatobiliary Neoplasm
Intervention  ICMJE
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Ponatinib Hydrochloride
    Given PO
    Other Name: AP24534 HCl
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
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:
  • Other: Laboratory Biomarker Analysis
  • Drug: Ponatinib Hydrochloride
  • Other: Quality-of-Life Assessment
Publications * Borad MJ, Gores GJ, Roberts LR. Fibroblast growth factor receptor 2 fusions as a target for treating cholangiocarcinoma. Curr Opin Gastroenterol. 2015 May;31(3):264-8. doi: 10.1097/MOG.0000000000000171. Review.

*   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 Completed
Actual Enrollment  ICMJE
 (submitted: September 29, 2017)
12
Original Estimated Enrollment  ICMJE
 (submitted: October 9, 2014)
30
Actual Study Completion Date  ICMJE June 14, 2019
Actual Primary Completion Date May 1, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histological/cytological confirmation of biliary cancer
  • Confirmation of advanced biliary cancer that is refractory or intolerant to gemcitabine or fluoropyrimidine based therapy with FGFR2 fusion [using next-gen sequencing assays (such as Foundation One) or fluorescent in situ hybridization (FISH) break-apart assays] or FGFR pathway mutation/amplification [using next-gen sequencing assays (such as Foundation One)]; assays must be performed in a Clinical Laboratory Improvement Amendments [CLIA] certified laboratory and done as a CLIA validated test or research use only [RUO] in a CLIA laboratory
  • Measurable disease
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
  • Absolute neutrophil count (ANC) >= 1500/mm^3
  • Platelet count >= 100,000/mm^3
  • Hemoglobin >= 9.0 g/dL
  • Total bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome
  • Aspartate transaminase (AST) and alanine aminotransferase (ALT) < 3 x ULN
  • Creatinine =< 1.5 x ULN
  • Serum lipase and amylase =< 2.5 x ULN; NOTE: if subject has tumor involvement in the liver =< 3 x ULN
  • Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
  • Recovered from prior radiotherapy and/or systemic therapy related toxicities to grade =< 1
  • Provide informed written consent
  • Life expectancy >= 3 months
  • Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study); Note: during the Active Monitoring Phase of a study (i.e., active treatment and observation), participants must be willing to return to the consenting institution for follow-up
  • Female and male patients who are fertile agree to use an effective form of contraception with their sexual partners from registration through 4 months after the end of treatment
  • Ability to complete questionnaire(s) by themselves or with assistance

Exclusion Criteria:

  • Any of the following:

    • Pregnant women
    • Nursing women
    • Men or women of childbearing potential who are unwilling to employ adequate contraception
  • Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
  • Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy; NOTE: patients with a known history of HIV infection are not eligible for this trial
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
  • Prior systemic chemotherapy, radiation therapy or major surgery =< 30 days prior to registration
  • Concurrent use of any other approved or investigational anticancer agents, including hormonal agents
  • Prior nitrosourea or mitomycin C =< 6 weeks prior to registration
  • Patients with gastrointestinal comorbidities that would affect intake or absorption of ponatinib
  • Untreated or progressive brain metastases
  • Prior treatment with or allergic reactions attributed to compounds of similar chemical or biologic composition to ponatinib
  • Clinically uncontrolled hypertension (diastolic blood pressure > 90 mm mercury [Hg]; systolic > 140 mm Hg); Note: patients with hypertension should be undergoing treatment at study entry for blood pressure control
  • Previous or concurrent malignancy except adequately treated basal or squamous cell skin cancer, in situ carcinoma of the cervix, or other solid tumor treated curatively and without evidence of recurrence for at least 5 years
  • History of significant bleeding disorder unrelated to cancer
  • History of acute pancreatitis within 1 year prior to registration, chronic pancreatitis, alcohol abuse or uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)
  • Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:

    • Any history of myocardial infarction, stroke, or revascularization
    • Unstable angina or transient ischemic attack within 6 months prior to registration
    • Congestive heart failure within 6 months prior to registration, or left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards within 6 months prior to registration
    • History of clinically significant (as determined by the treating physician) atrial arrhythmia
    • Any history of ventricular arrhythmia
    • Active venous thromboembolism including deep venous thrombosis or pulmonary embolism that is not amenable to treatment with anticoagulants
    • Patients with congenital prolonged QT syndromes and abnormal baseline prolonged corrected QT (QTc) (> 450 ms in men and > 470 ms in women)
    • Patients with an ejection fraction =< 50% as assessed by a baseline echocardiogram
  • Taking medications that are known to be associated with torsades de pointes
  • Taking any medications or herbal supplements that are known to be strong inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) =< 14 days prior to registration
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 information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02265341
Other Study ID Numbers  ICMJE MC1345
NCI-2014-02075 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC1345 ( Other Identifier: Mayo Clinic in Arizona )
P30CA015083 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mayo Clinic
Study Sponsor  ICMJE Mayo Clinic
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Mitesh Borad Mayo Clinic
PRS Account Mayo Clinic
Verification Date April 2019

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