Trial of Ponatinib in Patients With Bevacizumab-Refractory Glioblastoma

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 mont