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

Study Overview
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Brief Summary
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This phase I/II trial is studying the side effects and best dose of motexafin gadolinium when given together with temozolomide and radiation therapy and to see how well they work in treating patients with newly diagnosed supratentorial glioblastoma multiforme or gliosarcoma. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Motexafin gadolinium may help temozolomide work better by making tumor cells more sensitive to the drug. Radiation therapy uses high-energy x-rays to kill tumor cells. Motexafin gadolinium may also make tumor cells more sensitive to radiation therapy. Giving motexafin gadolinium together with temozolomide and radition therapy may kill more tumor cells.

Detailed Description
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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.

Official Title
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A PHASE I/II TRIAL OF TEMOZOLOMIDE, MOTEXAFIN GADOLINIUM, AND 60 GY FRACTIONATED RADIATION FOR NEWLY DIAGNOSED SUPRATENTORIAL GLIOBLASTOMA MULTIFORME

Conditions
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Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma

Intervention / Treatment
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* Radiation: 3-Dimensional Conformal Radiation Therapy
* Drug: Motexafin Gadolinium
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed glioblastoma multiforme (GBM) or gliosarcoma Newly diagnosed by surgical biopsy or excision within the past 5 weeks Supratentorial location, as determined by the following: Contrast-enhanced MRI performed preoperatively MRI performed postoperatively within 28 days prior to study entry (preferably within 72 hours of surgery) Postoperative scan not required if diagnosed by stereotactic biopsy and pre-operative MRI was performed No gliomas graded < GBM No recurrent malignant gliomas No tumor foci detected below the tentorium or beyond the cranial vault No multifocal disease or leptomeningeal spread Zubrod performance status 0-1 Neurologic function status 0-2 Absolute neutrophil count ≥ 1,800 cells/mm^3 Platelet count ≥ 100,000 cells/mm^3 Hemoglobin ≥ 8 g/dL (transfusion allowed) BUN ≤ 25 mg/dL Creatinine ≤ 1.5 mg/dL Bilirubin ≤ 1.5 mg/dL ALT or AST ≤ 2 times upper limit of normal Fertile patients must use effective contraception during and for 2 months after completion of study treatment Negative pregnancy test Not pregnant or nursing No prior invasive malignancies, except for nonmelanomatous skin cancer and carcinoma in situ of the uterine cervix or bladder, unless disease-free for ? 3 years No severe, active comorbidity, defined as follows: Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months Transmural myocardial infarction within the past 6 months Acute bacterial or fungal infection requiring intravenous antibiotics at study entry Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days prior to study entry Coagulation defects Known AIDS No prior allergic reaction to the study drugs No history of porphyria or G6PD deficiency No allergy to gadolinium or contraindications to MRI No other concurrent chemotherapy Recovered from effects of surgery or postoperative infection and other complications No prior systemic chemotherapy, including polifeprosan 20 with carmustine implant (Gliadel wafer), for the current GBM Prior chemotherapy for a different cancer allowed No prior radiotherapy to the head and neck (except for T1 glottic cancer) that would result in overlap of radiation therapy fields No prophylactic filgrastim (G-CSF) during the first course of study treatment No concurrent sargramostim (GM-CSF)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I: MGd 3 mg/kg<br>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. | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Undergo radiotherapy<br>* Other names: Radiation Conformal Therapy;Drug: Motexafin Gadolinium<br>* Given IV<br>* Other names: Xcytrin;Drug: Temozolomide<br>* Given orally<br>* Other names: Temomedac;|
| Experimental: Phase I: MGd 4 mg/kg<br>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. | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Undergo radiotherapy<br>* Other names: Radiation Conformal Therapy;Drug: Motexafin Gadolinium<br>* Given IV<br>* Other names: Xcytrin;Drug: Temozolomide<br>* Given orally<br>* Other names: Temomedac;|
| Experimental: Phase I: MGd 5 mg/kg<br>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. | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Undergo radiotherapy<br>* Other names: Radiation Conformal Therapy;Drug: Motexafin Gadolinium<br>* Given IV<br>* Other names: Xcytrin;Drug: Temozolomide<br>* Given orally<br>* Other names: Temomedac;|
| Active Comparator: Phase II: MGd 5 mg/kg<br>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. | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Undergo radiotherapy<br>* Other names: Radiation Conformal Therapy;Drug: Motexafin Gadolinium<br>* Given IV<br>* Other names: Xcytrin;Drug: Temozolomide<br>* Given orally<br>* Other names: Temomedac;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of MGd (Phase I) | 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 maximum tolerated dose (MTD). The MTD would be used for the Phase II arm. Rating scale: 0 = not the MTD, 1 = MTD | From start of radiation therapy to 90 days, | 
| Median Overall Survival (Phase II) | 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. | From randomization to date of death or last follow-up. Analysis occurs after all patients have been potentially followed for at least 18 months. Patients were followed up to 54.3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (Phase II) | Progression will be defined as a > 25% increase in tumor area. Progression-free 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. | From randomization to date of progression, death, or last follow-up. Analysis occurs after all patients have been potentially followed for at least 18 months. Patients were followed up to 54.3 months. |