Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma
Conditions
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.
Interventions
RADIATION3-Dimensional Conformal Radiation Therapy
Undergo radiotherapy
DRUGMotexafin Gadolinium
Given IV
DRUGTemozolomide
Given orally
Sponsors
Radiation Therapy Oncology Group
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Pre-assignment details
In multicenter clinical trials the accrual closure date must be predicted so that sites can be notified weeks in advance. As expected, this process often results in a final number of patients differing from the planned accrual.
Participants by arm
| Arm | Count |
|---|---|
| Phase I: MGd 3 mg/kg 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. | 7 |
| Phase I: MGd 4 mg/kg 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. | 10 |
| Phase I: MGd 5 mg/kg 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. | 7 |
| Phase II: MGd 5 mg/kg 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. | 94 |
| Total | 118 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Ineligible / No protocol treatment | 0 | 1 | 1 | 13 |
Baseline characteristics
| Characteristic | Phase I: MGd 3 mg/kg | Phase I: MGd 4 mg/kg | Phase I: MGd 5 mg/kg | Phase II: MGd 5 mg/kg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 56 years | 57.5 years | 58 years | 57.5 years | 57 years |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 1 Participants | 33 Participants | 44 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 6 Participants | 61 Participants | 74 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 7 | 9 / 9 | 6 / 6 | 80 / 81 |
| serious Total, serious adverse events | 3 / 7 | 6 / 9 | 4 / 6 | 48 / 81 |
Outcome results
Primary
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
Time frame: From start of radiation therapy to 90 days,
Population: Eligible patients who received protocol treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: MGd 3 mg/kg | Maximum Tolerated Dose of MGd (Phase I) | 0 units on a scale |
| Phase I: MGd 4 mg/kg | Maximum Tolerated Dose of MGd (Phase I) | 0 units on a scale |
| Phase I: 5 mg/kg | Maximum Tolerated Dose of MGd (Phase I) | 1 units on a scale |
Primary
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.
Time frame: 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
Population: All eligible patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: MGd 3 mg/kg | Median Overall Survival (Phase II) | 15.6 Months |
Comparison: A one-sided one-sample log-rank test at significance level of 0.10 was predicted to have 85% power to detect a survival difference against the historical control (13.7 vs. 18.5 months) with 60 deaths.p-value: 0.27Log Rank
Secondary
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.
Time frame: 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.
Population: All eligible patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: MGd 3 mg/kg | Progression-free Survival (Phase II) | 7.6 months |