Clinical Trials /

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

NCT02272998

Description:

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.

Related Conditions:
  • Cancer
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: OSU-14078
  • SECONDARY ID: NCI-2014-01499
  • NCT ID: NCT02272998

Conditions

  • Malignant Neoplasm

Interventions

DrugSynonymsArms
ponatinib hydrochlorideAP24534, Iclusig, multitargeted tyrosine kinase inhibitor AP24534Treatment (ponatinib hydrochloride)

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), 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ponatinib hydrochloride)ExperimentalPatients receive ponatinib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • ponatinib hydrochloride

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Overall survival
Time Frame:The time from treatment initiation to death, assessed up to 52 weeks
Safety Issue:
Description:Kaplan-Meier curves will be used to estimate the survival distribution.
Measure:Progression free survival
Time Frame:The time from treatment initiation to progression or death, assessed up to 52 weeks
Safety Issue:
Description:Kaplan-Meier curves will be used to estimate the survival distribution.
Measure:Clinical benefit rate (CBR)
Time Frame:6 months
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sameek Roychowdhury

Trial Keywords

  • FGFR, RET, KIT

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