Trial of Ponatinib in Patients With Bevacizumab-Refractory Glioblastoma
Condition: Glioblastoma
MeSH terms: Glioblastoma
Intervention: Ponatinib
Intervention MeSH terms: Ponatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 17.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        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.