PPX and Concurrent Radiation for Newly Diagnosed Glioblastoma Without MGMT Methylation

To obtain preliminary data in a randomized phase II study whether PPX/RT improves progression-free survival as compared to temozolomide/RT for patients with GBM without MGMT methylation.

To evaluate the toxicities of PPX/RT To evaluate neuro-cognitive functional assessments of patients with GBM receiving PPX/RT To obtain preliminary data in a randomized phase II study whether PPX/RT improves overall survival as compared to temozolomide /RT for patients with GBM without MGMT methylation to facilitate planning a phase III study.

• Drug: PPX (CT2103)
  XRT: 60 Gy at 2 Gy/fraction x 30 fractions PPX: 50 mg/m2/week x 6 weeks during radiation Temozolomide maintenance: Beginning 4 weeks after completion of chemoradiation, temozolomide d1-5 of 28 day cycle for 12 cycle maximum.
• Drug: Temozolomide
  XRT: 60 Gy at 2 Gy/fraction x 30 fractions Temozolomide, 75 mg/m2/day, 7 days per week, from the first to the last day of radiotherapy Temozolomide maintenance: Beginning 4 weeks after completion of chemoradiation, temozolomide d1-5 of 28 day cycle for 12 cycle maximum

• Experimental: radiation plus PPX(CT2103

  Radiation therapy, Monday through Friday, for 6 weeks for a total of 30 treatments

  + intravenous PPX every week x 6 weeks for a total of 6 treatments

  Intervention: Drug: PPX (CT2103)
• Active Comparator: radiation + Temozolomide

  Radiation therapy, Monday through Friday, for 6 weeks for a total of 30 treatments

  + Daily oral temozolomide(TMZ) (7 days) x 6 wks for a total of 42 days

  Intervention: Drug: Temozolomide

Inclusion Criteria:

• Histologically proven diagnosis of glioblastoma or gliosarcoma (WHO grade IV)
• GBM must have unmethylated MGMT as determined by central laboratory
• Diagnosis of GBM must be made by biopsy or surgical excision, either partial or complete; as long as there is sufficient tissue to determine MGMT status
• No prior chemotherapy or radiation for brain tumor

• Must be able to tolerate brain MRIs.

  *A diagnostic contrast-enhanced MRI must be performed postoperatively within 42 days prior to study registration.

• KPS >60.
• Age > 18
• Life expectancy of at least 3 months.
• Absolute neutrophil count > 1500/mm3, Platelets > 100,000/mm,
• Creatinine < 2 x ULN
• ALT or AST < 3 x upper limit of normal (ULN) and total bilirubin < 1.5x ULN.
• Patients with a prior history of low grade glioma who did not receive prior radiation or chemotherapy with transformation to grade IV brain tumor are eligible.
• Women must be non-lactating, and surgically sterile, post-menopausal or have a negative serum pregnancy test and agree to use adequate birth control. Males must agree to use adequate birth control.
• Voluntary, signed informed consent.

Exclusion Criteria:

• Acute infection or other medical condition that would impair study treatment
• No other active invasive malignancy unless disease free for at least 3 years.
• Prior temozolomide or PPX.
• Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are not permitted.
• Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields.
• No diffuse leptomeningeal disease, or gliomatosis cerebri.
• Use of any other experimental chemotherapy drug within the 60 days prior to randomization and during the trial. (Use of a non-chemotherapy investigational agent must be approved by the Brown University Oncology Group)

• Rhode Island Hospital
• Milton S. Hershey Medical Center
• University of Washington
• University of Massachusetts, Worcester
• Maine Medical Center
• University of California, San Diego