Motexafin Gadolinium, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma

• Maximum Tolerated Dose of MGd (Phase I) [ Time Frame: From start of radiation therapy to 90 days, ] [ Designated as safety issue: Yes ]

  Patients were to be followed for a minimum of 90 days from the start of radiation therapy (RT) and carefully evaluated with respect to treatment morbidity. A dose limiting toxicity (DLT) was defined as a grade 4 neurologic adverse event (AE) considered to be related to treatment occurring within 21 days of the conclusion of RT. For each dose level, up to seven patients were to be accrued to assure that there would be six eligible for treatment adverse event evaluation. A dose level of MGd was considered acceptable if no more than 1 patient of the 6 experience a DLT. If the current level was considered acceptable, then dose escalation occurred. Otherwise, the preceding dose level would be declared the MTD. The MTD would be used for the Phase II arm.

  Rating scale: 0 = not the MTD, 1 = MTD

  
  
• Median Overall Survival (Phase II) [ Time Frame: From randomization to date of death or last follow-up. Analysis occurs after all patients have been potentially forllowed for at least 18 months. ] [ Designated as safety issue: No ]
  Survival time was defined as the time from baseline to date of death from any cause. Patients last known to be alive are censored at date of last contact.
  
  

• Progression-free Survival (Phase II) [ Time Frame: From randomization to date of progression, death, or last follow-up. Analysis occurs at the same time as the primary outcome analysis. ] [ Designated as safety issue: No ]
  Progression will be defined as a > 25% increase in tumor area.
  
  

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of motexafin gadolinium (MGd) when given concurrently with temozolomide and radiotherapy in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM) or gliosarcoma.

II. Estimate the overall survival of patients treated with concurrent radiotherapy, temozolomide, and MGd followed by post-radiation temozolomide.

III. Determine the short- and long-term adverse effects in patients treated with this treatment.

IV. Estimate the progression-free survival of patients with newly diagnosed supratentorial GBM or gliosarcoma treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of motexafin gadolinium (MGd).

PHASE I: Patients undergo radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Beginning the night before the first dose of radiotherapy and ending the night before the last dose of radiotherapy, patients receive concurrent oral temozolomide once daily on days 0-39. Patients also receive MGd IV over 30 minutes prior to radiotherapy once daily on days 1-5 and 8-12 and then on days 15, 17, 19, 22, 24, 26, 29, 31, 33, 36, 38, and 40. Beginning 28 days after the completion of radiotherapy, patients receive oral temozolomide once daily on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-7 patients receive escalating doses of MGd until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which no more than 6 eligible patients experience dose-limiting toxicity.

PHASE II: Patients undergo radiotherapy and receive temozolomide as in phase I. Patients also receive MGd as in phase I at the MTD determined in phase I.

After completion of study treatment, patients are followed every 2 months for 1 year, every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.