A Safety Run-in/Randomized Phase II Trial of EMD 121974 in Conjunction With Concomitant and Adjuvant Temozolomide With Radiation Therapy in Patients With Newly Diagnosed Glioblastoma Multiforme

PRIMARY OBJECTIVES: I. To assess the safety profile of EMD 121974 (cilengitide) when administered as a one-hour infusion twice a week concurrently with concomitant and adjuvant temozolomide with radiation therapy for newly diagnosed glioblastoma multiforme. (Safety Run-In) II. To estimate overall survival in newly diagnosed patients with glioblastoma multiforme treated with EMD 121974 concurrently with concomitant and adjuvant temozolomide with radiation therapy. (Phase II) SECONDARY OBJECTIVES: I. To estimate and compare overall survival between a low dose treatment group and a high dose treatment group in newly diagnosed patients with glioblastoma multiforme treated with EMD 121974 concurrently with concomitant and adjuvant temozolomide with radiation therapy. (Phase II) II. To determine the toxicity of EMD 121974 (cilengitide) when it is administered in conjunction with concomitant and adjuvant temozolomide with radiation therapy in patients with newly diagnosed glioblastoma multiforme. (Phase II) III. To evaluate the molecular profile of individual patients and correlate molecular expression profiles with clinical outcomes. (Phase II) IV. To characterize tumor blood volume, tumor blood flow, and permeability ratios using perfusion MR in newly diagnosed glioblastoma multiforme and follow these parameters during treatment with EMD 121974 (cilengitide). (Phase II) OUTLINE: This is an open-label, multicenter, safety run-in study of cilengitide followed by a randomized phase II study. Safety Run-In: INITIATION COURSE: Patients receive cilengitide IV over 1 hour on days 1 and 4. Treatment repeats weekly for 10 weeks. Patients also receive oral temozolomide and undergo radiotherapy one hour later on days 1-5 of weeks 1-6. MAINTENANCE COURSES: Patients receive oral temozolomide once daily on days 1-5 in courses 1-6. Patients also receive cilengitide IV on days 1, 4, 8, 11, 15, 18, 22, and 25. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of cilengitide (3 Pre-defined study dose levels are defined as: 500, 1000 and 2000mg). The MTD is defined as the dose preceding that at which 2 of 3 or 3 of 6 patients experience dose-limiting toxicity. If no MTD (maximum tolerable dose) is defined through three steps of the dose escalation process, we will pursue the phase II safety/efficacy study with randomized treatment allocation. Patients will be randomized into one of two pre-specified treatment dosage arms, 500mg group or 2000mg group. PHASE II: Patients are stratified according to age (50 and under vs over 50), Karnofsky performance score (60%-80% vs 90%-100%), and tumor status (measurable vs nonmeasurable). Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive radiotherapy and temozolomide as in safety run-in initiation course and cilengitide at the lower dose as in safety run-in initiation and maintenance courses. ARM II: Patients receive radiotherapy and temozolomide as in safety run-in initiation course and cilengitide at the higher dose as in safety run-in initiation and maintenance courses. Patients are followed every 2 months. PROJECTED ACCRUAL: A total of 9-112 patients (9-18 for safety run-in and 94 \[47 per treatment arm\] for phase II) will be accrued for this study within 1.5-37 months