Cilengitide in Treating Patients Who Are Undergoing Surgery for Recurrent or Progressive Glioblastoma Multiforme

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase II Trial of EMD 121974 for Recurrent Glioblastoma: A Clinical Trial With Tissue Correlates of Response

Conditions
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Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor

Intervention / Treatment
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* Drug: cilengitide
* Procedure: therapeutic conventional surgery
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (high-dose cilengitide) 2000mg<br>Preoperative Treatment: Patients receive high-dose cilengitide IV over 1 hour on days -8, -4, and -1. (High dose 2000mg) 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. | Drug: cilengitide<br>* Given IV<br>* Other names: EMD 121974;Procedure: therapeutic conventional surgery<br>* Undergo tumor resection<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Group II (low-dose cilengitide) 500mg<br>Preoperative Treatment: Patients receive low-dose cilengitide IV over 1 hour on days -8, -4, and -1. (500mg) 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 | Drug: cilengitide<br>* Given IV<br>* Other names: EMD 121974;Procedure: therapeutic conventional surgery<br>* Undergo tumor resection<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6m-Progression-free Survival | progression within 6 months (26 weeks) of treatment | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and time of surgery | 
| 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. | Baseline and time of surgery | 
| 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. | Baseline and time of surgery | 
| 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. | Baseline and time of surgery | 
| 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. | Baseline and up to 4 years | 
| Plasma Concentration of EMD 121974 | 24 hour post dose concentration plasma, at time of resection | 24 hour post concentration | 
| 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. | at time of surgery |