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

Phase 1

Completed

Conditions: Adult Glioblastoma
Adult Gliosarcoma
Adult Giant Cell Glioblastoma

Interventions: Radiation: 3-Dimensional Conformal Radiation Therapy
Drug: Motexafin Gadolinium
Drug: Temozolomide

Registration Number: NCT00305864

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 118

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)

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase I: MGd 3 mg/kg	3-Dimensional Conformal Radiation Therapy	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.
Phase I: MGd 4 mg/kg	3-Dimensional Conformal Radiation Therapy	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.
Phase I: MGd 5 mg/kg	3-Dimensional Conformal Radiation Therapy	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.
Phase II: MGd 5 mg/kg	3-Dimensional Conformal Radiation Therapy	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.
Phase I: MGd 3 mg/kg	Temozolomide	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.
Phase I: MGd 4 mg/kg	Temozolomide	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.
Phase I: MGd 5 mg/kg	Temozolomide	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.
Phase II: MGd 5 mg/kg	Temozolomide	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.
Phase I: MGd 3 mg/kg	Motexafin Gadolinium	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.
Phase I: MGd 4 mg/kg	Motexafin Gadolinium	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.
Phase I: MGd 5 mg/kg	Motexafin Gadolinium	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.
Phase II: MGd 5 mg/kg	Motexafin Gadolinium	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.

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose of MGd (Phase I)	From start of radiation therapy to 90 days,	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
Median Overall Survival (Phase II)	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	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.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival (Phase II)	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.	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.

Trial Locations

Locations (106): Mobile Infirmary Medical Center
🇺🇸
Mobile, Alabama, United States
Arizona Oncology Services Foundation
🇺🇸
Scottsdale, Arizona, United States
The University of Arizona Medical Center-University Campus
🇺🇸
Tucson, Arizona, United States
East Bay Radiation Oncology Center
🇺🇸
Castro Valley, California, United States
Eden Hospital Medical Center
🇺🇸
Castro Valley, California, United States
Valley Medical Oncology Consultants-Castro Valley
🇺🇸
Castro Valley, California, United States
Bay Area Breast Surgeons Inc
🇺🇸
Emeryville, California, United States
Valley Medical Oncology Consultants-Fremont
🇺🇸
Fremont, California, United States
Saint Rose Hospital
🇺🇸
Hayward, California, United States
Los Angeles County-USC Medical Center
🇺🇸
Los Angeles, California, United States
Scroll for more (96 remaining)
Mobile Infirmary Medical Center
🇺🇸Mobile, Alabama, United States