Clinical Trial Details
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NCT02478164 : Trial of Ponatinib in Patients With Bevacizumab-Refractory Glioblastoma
PhasePhase 2
AgesMin: 18 Years Max: N/A
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

- ?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

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 ?m thick) unstained formalin fixed paraffin embedded (FFPE) sections

- 1-2 H&E stained slides, or additional unstained 5 ?m 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

- 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

- 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

- 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.
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