Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor
Conditions
Brief summary
Cilengitide may stop the growth of glioblastoma multiforme by blocking blood flow to the tumor. Giving cilengitide before and after surgery may be an effective treatment for glioblastoma multiforme. This phase II trial is studying how well cilengitide works in treating patients who are undergoing surgery for recurrent or progressive glioblastoma multiforme.
Detailed description
PRIMARY OBJECTIVES: I. Determine the 6-month progression-free survival rate in operative patients with recurrent or progressive glioblastoma multiforme treated with cilengitide. SECONDARY OBJECTIVES: I. Determine the safety and toxicity of this drug in these patients. OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment groups for the preoperative treatment component. Preoperative Treatment Group I: Patients receive high-dose cilengitide IV over 1 hour on days -8, -4, and -1. Preoperative Treatment Group II: Patients receive low-dose cilengitide IV over 1 hour on days -8, -4, and -1. Resection: All patients undergo tumor resection on day 0. Postoperative Treatment: Beginning within 2 weeks after surgery, all patients receive high-dose cilengitide IV over 1 hour twice weekly for 4 weeks. Treatment repeats every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months. PROJECTED ACCRUAL: A total of 44 patients (22 per preoperative treatment group) will be accrued for this study.
Interventions
DRUGcilengitide
Given IV
PROCEDUREtherapeutic conventional surgery
Undergo tumor resection
OTHERpharmacological study
Correlative studies
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed intracranial glioblastoma multiforme (GBM) * Original diagnosis of low-grade glioma with subsequent histological confirmation of GBM allowed * Recurrent disease * Failed prior radiotherapy * Must require a surgical procedure (gross total or near gross total resection) for tumor removal * Performance status - Karnofsky 60-100% * White Blood Count (WBC) ≥ 3,000/mm\^3 * Absolute neutrophil count ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Hemoglobin ≥ 10 g/dL (transfusion allowed) * Serum glutamic oxaloacetic transaminase (SGOT) \< 2 times upper limit of normal (ULN) * Bilirubin \< 2 times ULN * Creatinine \< 1.5 mg/dL * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective barrier contraception during and for ≥ 2 weeks after study participation (for female patients) or for 3 months after study participation (for male patients) * No other malignancy within the past 3 years except nonmelanoma skin cancer or carcinoma in situ of the cervix * No active infection * No other significant uncontrolled medical illness that would preclude study participation * At least 3 weeks since prior interferon * No prior cilengitide * No other prior targeted antiangiogenic treatment (e.g., vatalanib, SU5416, or thalidomide) * No concurrent anticancer immunotherapy * No concurrent routine prophylactic filgrastim (G-CSF) * At least 2 weeks since prior vincristine * At least 3 weeks since prior procarbazine * At least 6 weeks since prior nitrosoureas * No concurrent anticancer chemotherapy * At least 3 weeks since prior tamoxifen * No concurrent anticancer hormonal therapy * See Disease Characteristics * At least 4 weeks since prior radiotherapy * No concurrent anticancer radiotherapy * Recovered from all prior therapies * No more than 3 prior treatments for GBM (1 initial treatment; and treatment for 2 relapses) * For patients who received prior therapy for low-grade glioma, a subsequent surgical diagnosis of high-grade glioma is considered the first relapse * At least 4 weeks since prior investigational agents * At least 4 weeks since prior cytotoxic therapy * At least 3 weeks since other prior non-cytotoxic therapy (e.g., isotretinoin), except radiosensitizers * No other concurrent anticancer therapy * No other concurrent investigational agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6m-Progression-free Survival | 6 months | progression within 6 months (26 weeks) of treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in avb3 Integrin Expression on Tumor Cells and Endothelial Cells | Baseline and time of surgery | Will be performed between the untreated matched control tumor tissue and the tissue obtained from the post-treatment tumors using either a Fisher's Exact test or the Wilcoxon rank sum test depending on whether the assay provides a measurement or is yes/no. |
| Changes in Vitronectin Expression | Baseline and time of surgery | Will be performed between the untreated matched control tumor tissue and the tissue obtained from the post-treatment tumors using either a Fisher's Exact test or the Wilcoxon rank sum test depending on whether the assay provides a measurement or is yes/no. |
| Changes in Tumor Cell Apoptosis | Baseline and time of surgery | Will be performed between the untreated matched control tumor tissue and the tissue obtained from the post-treatment tumors using either a Fisher's Exact test or the Wilcoxon rank sum test depending on whether the assay provides a measurement or is yes/no. |
| Changes in Tumor Cell Proliferation | Baseline and time of surgery | Will be performed between the untreated matched control tumor tissue and the tissue obtained from the post-treatment tumors using either a Fisher's Exact test or the Wilcoxon rank sum test depending on whether the assay provides a measurement or is yes/no. |
| Changes in Endothelial Cell Apoptosis | Baseline and up to 4 years | Will be performed between the untreated matched control tumor tissue and the tissue obtained from the post-treatment tumors using either a Fisher's Exact test or the Wilcoxon rank sum test depending on whether the assay provides a measurement or is yes/no. |
| Plasma Concentration of EMD 121974 | 24 hour post concentration | 24 hour post dose concentration plasma, at time of resection |
| Tumor Tissue Concentrations | at time of surgery | a section of tumor of approximately 500mg will be snap frozen (immediately prepared and frozen) once removed from brain for analysis of the drug concentration in contrast -enhancing tumor. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Overall Progression Free Survival | 1 year | Kaplan-meier curve |
Countries
United States
Participant flow
Recruitment details
Patients were enrolled from March 2005 through October 2006. Patients were recruited in the outpatient setting, however patients did need surgery for this study.
Participants by arm
| Arm | Count |
|---|---|
| Low Dose 500mg Group 1 Preoperative Treatment: Patients receive low dose 500mg cilengitide IV over 1 hour on days -8, -4, and -1.
Resection: All patients undergo tumor resection on day 0.
Postoperative Treatment: Beginning within 2 weeks after surgery, all patients receive high-dose 2000mg cilengitide IV over 1 hour twice weekly for 4 weeks. Treatment repeats every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity.
cilengitide: Given IV
therapeutic conventional surgery: Undergo tumor resection
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies | 15 |
| High Dose 2000mg Group 2 Preoperative Treatment: Patients receive high-dose 2000mg cilengitide IV over 1 hour on days -8, -4, and -1.
Resection: All patients undergo tumor resection on day 0.
Postoperative Treatment: Beginning within 2 weeks after surgery, all patients receive high-dose 2000mg cilengitide IV over 1 hour twice weekly for 4 weeks. Treatment repeats every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity.
cilengitide: Given IV
therapeutic conventional surgery: Undergo tumor resection
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | did not start treatment post-op | 1 | 2 |
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | High Dose 2000mg Group 2 | Total | Low Dose 500mg Group 1 |
|---|---|---|---|
| Age, Continuous | 56 years | 55 years | 51 years |
| Histology - Glioblastoma | 15 participants | 30 participants | 15 participants |
| Prior Biopsy Only no | 15 participants | 29 participants | 14 participants |
| Prior Biopsy Only yes | 0 participants | 1 participants | 1 participants |
| Prior Chemotherapy | 15 participants | 30 participants | 15 participants |
| Prior Immunotherapy No | 13 participants | 27 participants | 14 participants |
| Prior Immunotherapy Yes | 2 participants | 3 participants | 1 participants |
| Prior Radiotherapy | 15 participants | 30 participants | 15 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized White | 14 participants | 29 participants | 15 participants |
| Sex: Female, Male Female | 8 Participants | 18 Participants | 10 Participants |
| Sex: Female, Male Male | 7 Participants | 12 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 26 / 26 |
| serious Total, serious adverse events | 0 / 26 |
Outcome results
Primary
6m-Progression-free Survival
progression within 6 months (26 weeks) of treatment
Time frame: 6 months
Population: 6months progression free survival based on the post surgical treatment. All patients received 2000mg post surgery. The pre-surgery dose was used for correlative purposes only. All patients received surgery and the doses pre-surgery have no relation to the primary objective.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Post-Operative Treatment 2000mg | 6m-Progression-free Survival | 12 percent |
Secondary
Changes in avb3 Integrin Expression on Tumor Cells and Endothelial Cells
Will be performed between the untreated matched control tumor tissue and the tissue obtained from the post-treatment tumors using either a Fisher's Exact test or the Wilcoxon rank sum test depending on whether the assay provides a measurement or is yes/no.
Time frame: Baseline and time of surgery
Population: Molecular analyses evaluating alterations after cilengitide treatments were planned as a component of this clinical trial, unfortunately, the majority of tumor samples were too small to do both measures of drug and molecular analysis or the sample was inadequate for both after removal of areas of necrosis and gliosis
Secondary
Changes in Endothelial Cell Apoptosis
Will be performed between the untreated matched control tumor tissue and the tissue obtained from the post-treatment tumors using either a Fisher's Exact test or the Wilcoxon rank sum test depending on whether the assay provides a measurement or is yes/no.
Time frame: Baseline and up to 4 years
Population: Molecular analyses evaluating alterations planned, unfortunately, majority of tumor samples were too small to do both measures of drug and molecular analysis or sample was inadequate for both after removal of areas of necrosis and gliosis
Secondary
Changes in Tumor Cell Apoptosis
Will be performed between the untreated matched control tumor tissue and the tissue obtained from the post-treatment tumors using either a Fisher's Exact test or the Wilcoxon rank sum test depending on whether the assay provides a measurement or is yes/no.
Time frame: Baseline and time of surgery
Population: Molecular analyses evaluating alterations planned, unfortunately, majority of tumor samples were too small to do both measures of drug and molecular analysis or sample was inadequate for both after removal of areas of necrosis and gliosis
Secondary
Changes in Tumor Cell Proliferation
Will be performed between the untreated matched control tumor tissue and the tissue obtained from the post-treatment tumors using either a Fisher's Exact test or the Wilcoxon rank sum test depending on whether the assay provides a measurement or is yes/no.
Time frame: Baseline and time of surgery
Population: Molecular analyses evaluating alterations planned, unfortunately, majority of tumor samples were too small to do both measures of drug and molecular analysis or sample was inadequate for both after removal of areas of necrosis and gliosis
Secondary
Changes in Vitronectin Expression
Will be performed between the untreated matched control tumor tissue and the tissue obtained from the post-treatment tumors using either a Fisher's Exact test or the Wilcoxon rank sum test depending on whether the assay provides a measurement or is yes/no.
Time frame: Baseline and time of surgery
Population: Molecular analyses evaluating alterations planned, unfortunately, majority of tumor samples were too small to do both measures of drug and molecular analysis or sample was inadequate for both after removal of areas of necrosis and gliosis
Secondary
Plasma Concentration of EMD 121974
24 hour post dose concentration plasma, at time of resection
Time frame: 24 hour post concentration
Population: 6 of 8 and 7 of 11 plasma samples at the 500mg and 2000mg dose level respectively, were below the lower level of quantitation (LLOQ) Of the 15 samples in the low dose group only 8 were evaluable and 11 of the 15 for the high dose group. Samples were either damaged or too small for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Post-Operative Treatment 2000mg | Plasma Concentration of EMD 121974 | 333 ng/ml | Standard Deviation 16.97 |
| Group II Pre-op (High-dose Cilengitide) 2000mg | Plasma Concentration of EMD 121974 | 386 ng/ml | Standard Deviation 184 |
Secondary
Tumor Tissue Concentrations
a section of tumor of approximately 500mg will be snap frozen (immediately prepared and frozen) once removed from brain for analysis of the drug concentration in contrast -enhancing tumor.
Time frame: at time of surgery
Population: 8 500mg dose tissue samples and 10 2000mg dose tissue samples were either too small or had large areas of necrosis and gliosis to do analysis/evaluation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Post-Operative Treatment 2000mg | Tumor Tissue Concentrations | 919 ng/g | Standard Deviation 1235 |
| Group II Pre-op (High-dose Cilengitide) 2000mg | Tumor Tissue Concentrations | 1413 ng/g | Standard Deviation 1335 |
Other Pre-specified
Overall Progression Free Survival
Kaplan-meier curve
Time frame: 1 year
Population: Overall survival based on the post surgical treatment. All patients received 2000mg post surgery. The pre-surgery dose was used for correlative purposes only. All patients received surgery and the doses pre-surgery have no relation to the this objective.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Post-Operative Treatment 2000mg | Overall Progression Free Survival | 8 weeks |