Try the modernized beta website. Learn more about the modernization effort.
Working… Menu

Trial of Ponatinib in Patients With Bevacizumab-Refractory Glioblastoma

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. Identifier: NCT02478164
Recruitment Status : Completed
First Posted : June 23, 2015
Results First Posted : April 2, 2018
Last Update Posted : July 24, 2018
Information provided by (Responsible Party):
Eudocia Quant Lee, MD, Dana-Farber Cancer Institute

Brief Summary:
This research study is studying a chemotherapy as a possible treatment for recurrent glioblastoma that has not responded to bevacizumab. The name of the study drug involved in this study is Ponatinib.

Condition or disease Intervention/treatment Phase
Glioblastoma Drug: Ponatinib Phase 2

Detailed Description:

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved Ponatinib for your specific disease but it has been approved for other uses.

Ponatinib is a drug that may stop cancer cells from growing by affecting different kinds of proteins in cancer cells. Glioblastoma cells can be driven by mutated forms of a protein called c-kit (KIT) which are present in glioblastoma cells. Laboratory studies suggest that ponatinib has activity against mutated forms of (KIT) which is important in glioblastoma and therefore suggests that ponatinib may help to control the growth of glioblastoma. In this research study the study team is looking to see if ponatinib is safe and is able to control the growth of glioblastoma in people who have not responded to treatment with bevacizumab.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 17 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Ponatinib in Patients With Bevacizumab-Refractory Glioblastoma
Actual Study Start Date : July 13, 2015
Actual Primary Completion Date : July 8, 2017
Actual Study Completion Date : May 9, 2018

Arm Intervention/treatment
Experimental: Ponatinib
Drug will be administered once daily per cycle through oral ingestion.
Drug: Ponatinib
Other Names:
  • ponatinib hydrochloride
  • Iclusig

Primary Outcome Measures :
  1. 3-Month Progression-Free Survival (PFS3) [ Time Frame: 3 months ]
    PFS3 is the proportion of patients remaining alive and progression-free at 3-months from study entry. Progressive disease was established based on Response Assessment in Neuro-Oncology (RANO) criteria. RANO criteria has 5 potential categories: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive disease (PD) and Unknown. CR: disappearance of all enhancing lesions, stable or improved non-enhancing lesions, and stable or improved clinically. PR: >= 50% decrease in sum of perpendicular diameters of all measurable enhancing lesions, no progression of non-measurable disease, stable or improved non-enhancing lesions, and stable or improved clinically. PD: >25% increase in sum of perpendicular diameters of all measurable enhancing lesions, significant increase of non-enhancing lesions, any new lesions, clear clinical deterioration, failure to return for evaluation due to death or deteriorating condition. SD: does not qualify for CR,PR or PD.

Secondary Outcome Measures :
  1. Best Radiographic Response [ Time Frame: Disease was assessed radiographically for response every 8 weeks, assessed up to 24 weeks. ]
    Radiographic response was established based on Response Assessment in Neuro-Oncology (RANO) criteria with 5 potential categories: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive disease (PD) and Unknown status.

  2. Overall Survival (OS) [ Time Frame: 2 years ]
    OS based on Kaplan-Meier is defined as the time from study entry to death or date last known alive.

  3. Progression-Free Survival (PFS) [ Time Frame: 3 months ]
    PFS based on Kaplan-Meier is defined as the time from study entry to the earliest documentation of disease progression or death. Progressive disease was established based on Response Assessment in Neuro-Oncology (RANO) criteria.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Age ≥ 18 years
  • Karnofsky performance status ≥ 60
  • Participants must have histologically confirmed glioblastoma or variants. Subjects with initial diagnosis of a lower grade glioma are eligible if a subsequent biopsy is determined to be glioblastoma or variants.
  • Patients must have an unequivocal progression by magnetic resonance imaging (MRI) or computed tomography (CT) scan. A scan must be performed within 14 days prior to registration and on a steroid dose that has been stable or decreasing for at least 5 days. If the steroid dose is increased between the date of imaging and initiation of study treatment, a new baseline MRI/CT is required.
  • Participants must have bi-dimensionally measurable disease with a minimum measurement of 1 cm per dimension on MRI performed within 14 days prior to first treatment. If receiving corticosteroids, participants must be on a stable or decreasing dose of corticosteroids for at least 5 days prior to baseline MRI.
  • There is no limit on the number of prior relapses but the most recent relapse must be the first relapse on a bevacizumab-containing regimen.
  • Participants must have normal organ and marrow function as defined below:

    • Leukocytes ≥3,000/mcL (≥ 3,000/mm3)
    • Absolute neutrophil count ≥ 1,500/mcL (> 1,500/mm3)
    • Platelets ≥ 100,000/mcL (≥ 100,000/ mm3)
    • Total bilirubin ≤ 1.5 X institutional upper limit of normal, unless due to Gilbert's syndrome.
    • AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal
    • Serum Creatinine ≤ 1.5 X institutional upper limit of normal or or creatinine clearance > 60 mL/min/1.73 m2 (per 24 hour urine collection or calculated according to the Cockcroft-Gault formula) for subjects with creatinine levels above the institutional normal
    • Serum lipase and amylase ≤ 1.5 X institutional upper limit of normal.
  • Participants must have fully recovered (grade ≤ 1 or baseline or deemed irreversible) from any clinically significant acute toxicity related to prior therapy (with the exception of lymphopenia, which is common after therapy with temozolomide). Patients who discontinued bevacizumab previously due to a bevacizumab-related toxicity will not be allowed to participate.
  • The following time periods must have elapsed prior to the planned start date of study treatment:

    • ≥2 weeks or 6 half lives from any approved TKIs or investigational agent, whichever is longer
    • ≥4 weeks from prior cytotoxic therapy, except ≥ 3 weeks from last dose of temozolomide and ≥6 weeks from nitrosoureas or mitomycin C
    • ≥2 weeks from non-cytotoxic agents
    • ≥ 3 weeks from bevacizumab
  • Participants must have developed progressive disease after receiving prior radiation therapy and must have an interval of at least 12 weeks from the completion of any radiation therapy to study entry (unless progressive tumor growth is outside the radiation field or there is histopathological confirmation of recurrent tumor).
  • Participants may not have received prior therapy with any other Src, PDGFR, or FGFR inhibitor. Prior treatment with an anti-VEGFR or anti-VEGF agent is also allowed but only one relapse following a bevacizumab-containing regimen is allowed.
  • For females of childbearing potential, a negative serum pregnancy test must be documented prior to registration.

    --- NOTE: In addition to screening, serum pregnancy test must be performed on females of childbearing potential within 72 hours before the start of investigational product. When possible, these tests can be one-in-the-same (if screening pregnancy test was performed within 72 hours of first ponatinib dose, no need to repeat).

  • The effects of ponatinib on the developing human fetus are unknown. For this reason and because ponatinib is known to be teratogenic in animal models, 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, for the duration of study participation, and through 4 months after the end of treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  • Ability to understand and the willingness to sign a written informed consent document.

NOTE: Consent documents can be signed up to 30 days prior to registration. If >30 days has elapsed since patient signed the consent document, s/he must re-consent (new signature) before proceeding to register onto study.

  • Participants must have sufficient tissue from prior surgery for confirmation of diagnosis and correlative studies. The following amount of tissue is required:

    • 15 (5 μm thick) unstained formalin fixed paraffin embedded (FFPE) sections
    • 1-2 H&E stained slides, or additional unstained 5 μm slide(s) for staining
  • Protocol treatment plan must include beginning therapy within 5 consecutive days after registration.

Exclusion Criteria:

  • Participants may not be receiving any other investigational agents.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ponatinib.
  • Participants who have received prior treatment with interstitial brachytherapy, stereotactic radiosurgery, or implanted chemotherapy sources, such as wafers of polifeprosan 20 with carmustine
  • Participants with poorly controlled diabetes defined as a HgbA1c ≥ 7.0%
  • Participants with grade ≥ 3 peripheral motor or sensory neuropathy.
  • Participants receiving any medications or substances that are moderate and strong inhibitors or inducers of CYP3A4, including enzyme-inducing anti-epileptic drugs (EIAEDs) within 14 days before the first dose of ponatinib will be excluded. This category includes phenobarbital, phenytoin, fosphenytoin, primidone, carbamazepine, and oxcarbazepine. Lists including medications and substances known or with the potential to interact with CYP3A4 isoenzymes are provided in Appendix B.

    --- NOTE: Participants must avoid consumption of Seville orange (and juice), grapefruit or grapefruit juice, grapefruit hybrids, pummelos and exotic citrus fruits from 7 days prior to the first dose of study drug and during the entire study treatment period due to potential CYP3A4 interaction.

  • Participants taking medications that are known to be associated with Torsades de Pointes or QT prolongation. Refer to Tables C-1 and C-2 of Appendix C for a list of prohibited drugs.
  • Participants cannot take any herbal preparations/medications on study or within 7 days prior to first dose of study drug, including but not limited to: St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng.
  • Participants who underwent major surgery (including craniotomy) or significant traumatic injury within 28 days prior to initiating therapy. Baseline MRIs for participants who underwent salvage surgery must be obtained at least 4 weeks after procedure and there must be measurable disease.
  • Participants who underwent minor surgical procedure within 7 days prior to initiating therapy.
  • History of a bleeding disorder.
  • Patients with gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade >/= 3 within 30 days prior to study entry.
  • Patients whose MRI scan demonstrates intratumoral hemorrhage or peritumoral hemorrhage are not eligible for treatment if deemed significant by the treating physician. If there are questions, the treating physician should contact the study's Overall PI, Dr. Lee
  • History of acute pancreatitis within 1 year of study treatment or a history of chronic pancreatitis.
  • History of alcohol abuse.
  • Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL)
  • Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:

    • Any history of myocardial infarction
    • Any history of clinically significant (as determined by the treating physician) atrial arrhythmia
    • Any history of ventricular arrhythmia
    • Any history of Cerebrovascular accident or transient ischemic attack (TIA)
    • Any history of peripheral arterial occlusive disease requiring rvascularization
    • Unstable angina within 6 months prior to enrollment
    • Congestive heart failure within 6 months prior to enrollment
    • Venous thromboembolism including deep venous thrombosis or pulmonary embolism within 6 months prior to enrollment
    • Unacceptable Screening Baseline Cardiovascular Assessment:

      • Baseline MUGA or Echocardiogram demonstrating LVEF < 50 %
      • QTc > 480 msec on screening ECG (using the QTcF formula)
  • 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.
  • Ongoing or active infection. The requirement for intravenous (IV) antibiotics is considered active infection.
  • Known history of human immunodeficiency virus (HIV). Testing is not required in the absence of prior documentation or known history.
  • Pregnant or breastfeeding.

    -- Pregnant women are excluded from this study because ponatinib has potential for teratogenic or abortifacient effects in animal models. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with ponatinib, breastfeeding should be discontinued if the mother is treated with ponatinib. These potential risks may also apply to other agents used in this study.

  • Malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drugs.
  • Individuals with a history of a different malignancy, other than cervical cancer in situ, basal cell or squamous cell carcinoma of the skin, are ineligible, except if they have been disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy OR if the other primary malignancy is neither currently clinically significant nor requiring active intervention.
  • Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the drug.
  • HIV-positive individuals on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with ponatinib. In addition, these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02478164

Layout table for location information
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Dana-Farber Cancer Institute
Layout table for investigator information
Principal Investigator: Eudocia Lee, MD Dana-Farber Cancer Institute
  Study Documents (Full-Text)

Documents provided by Eudocia Quant Lee, MD, Dana-Farber Cancer Institute:
Layout table for additonal information
Responsible Party: Eudocia Quant Lee, MD, Eudocia Lee, MD, Dana-Farber Cancer Institute Identifier: NCT02478164    
Other Study ID Numbers: 15-163
First Posted: June 23, 2015    Key Record Dates
Results First Posted: April 2, 2018
Last Update Posted: July 24, 2018
Last Verified: June 2018

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action