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Newly Diagnosed Glioblastoma Multiforme and Unmethylated MGMT - CORE Study
CILENIGITIDE IN SUBJECTS WITH NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME AND UNMETHYLATED MGMT GENE PROMOTER (IRB #22908)
Cilengitide in subjects with newly diagnosed glioblastoma multiforme and unmethylated MGMT gene promoter--a multicenter, open-label Phase II study, investigating two cilengtide regimens in combination with standard treatment (temozolomide with concomitant radiation therapy, followed by temozolomide maintenance therapy). [The CORE study]
Gliomas account to 40% to 70% of all primary brain tumors. Glioblastoma multiforme (GBM) represent the most malignant of these tumors. Conventional treatment for primary disease includes surgery, radiotherapy, and chemotherapy. However, despite these various treatments, patients suffering from glioblastoma multiforme have a poor prognosis, with a median survival time of 12 to 15 months.
Cilengitide is an experimental drug that is being tested to see if it will extend progression free survival (PFS). Prior studies have suggested that cilengitide might cut off the blood supply to tumors, which may prevent tumor growth.
The primary objective of this study is to investigate the overall survival time in subjects receiving 2 different regimens of 2000 mg of cilengitide in combination with radiation therapy and temozolomide standard therapy. Secondary objectives of this study are (1) to evaluate progression free survival time, (2) to evaluate the safety and tolerability of the combination of cilengitide with standard radiation and temozolomide therapy in the overall study population, and (3) to evaluate the pharmacokinetic profile of cilengitide when given daily (5 out of 7 days) at 2000 mg in combination with radiation therapy and temozolomide on days of radiation therapy.
Participants have newly diagnosed, histologically proven GBM with proven unmethylated MGMT gene promoter status. 252 study participants will be treated at centers all over the world with approximately 10 patients being treated at Cedars-Sinai Medical Center.
A safety run-in was conducted to determine the safety and tolerability of the intense exposure treatment intended for Group B of the randomized part. The safety run-in was successfuly completed and determined the dose for Group B. Thus sections in the protocol abut safety run-in no longer apply, as future subjects will be enrolled in the randomized part of the study.
Patients will be randomized into one of three following groups:
Group A: Cilengitide will be given at a dose of 2000mg as an intravenous infusion (given by a drip in the vein of a patient's arm). Each infusion takes about an hour and patients will receive 2 infusions a week. One week after treatment start with cilengitide, patients will start the standard treatment of radiation and temozolomide (radiation 5 days a week and temozolomide 7 days a week for 6-7 weeks). Patients will continue to receive cilengitide 2 times a week for the entire duration of the standard treatment through Week 34, and subsequently as a maintenance therapy for another 10 months (cilengitide maintenance phase Week 35 through Week 77).
Group B: Treatment for group B is the same as for group A, except for the first 6-7 weeks of standard treatments patients will receive cilengitide 5 times a week (at 2000mg) instead of twice weekly as in group A. After the first 6-7 weeks of standard therapy, cilengitide will be administered again as group A on 2 days a week during standard treatment through Week 34 and for the next 10 months (cilengitide maintenance phase Week 35 through 77).
Group C: Standard treatment, which involves radiation therapy and chemotherapy with temozolomide. Subjects in the control group will receive standard therapy for 8 months (6 weeks of radiotherapy and temozolomide, followed by 6 four-week-cycles of temozolomide maintenance treatment).
Standard treatment up through Week 34: The standard treatment involves radiation therapy and chemotherapy with TMZ (temozolomide, also known as Temodal®, Temodar®). There are 2 phases to the treatment. The initial phase is 6-7 weeks of radiotherapy (5 days a week, Monday through Friday for a total of 30 sessions) and TMZ (7 days a week, even on Saturdays and Sundays when they do not have radiotherapy). After the end of radiotherapy, the TMZ maintenance phase will begin, during which TMZ chemotherapy will start again for 5 days every 4 weeks (=1 cycle) for a total of 6 cycles.
Study visits will occur every week during radiotherapy, and at least once a month thereafter through the end of standard therapy. After the end of standard therapy, the follow-up phase will begin during which study visits will occur every 12 weeks. After study completion, subjects will also be followed-up every 3 months for their survival/health status until death or for up to at least 3 years after randomization.
Treatment may stop earlier than planned due to occurrence of progressive disease (PD) or unacceptable toxicity, or withdrawal for any other reason. Subjects in the cilengitide group may continue receiving cilengitide after completion of 18 months of cilengitide treatment, until occurrence of PD or unacceptable toxicity, or until withdrawal for any other reason. A cross-over of subjects of the control group to cilengitide treatment is not allowed.
Separate consent will be obtained for the collection of the patient's tumor sample that will be analyzed to verify the patient has unmethylated MGMT status and is eligible to participate. Participants may participate in an optional pharmacogenetic sub-study, which involves a one-time blood draw of 5ml.
Pregnant women and children will not be eligible to receive the study intervention. Involvement of pregnant women will be limited to the adverse event in which a female subject (partner of male subject) becomes pregnant during the course study. If a woman (partner of male subject) becomes pregnant during the course of the research, information regarding the pregnancy as well as information regarding the outcome of her pregnancy will be monitored for research purposes. As the monitoring will be limited to obtaining data related to the course of the pregnancy and birth outcomes, there are no physical risks for pregnant woman and the newborns whose medical records may be reviewed. The collection of such information poses no greater than minimal risk for these populations and is described in the consent form. Consent/parental permission to review the medical records will be obtained from the pregnant women via the study consent form.Surasak Phuphanich, MD, FAAN
Director, Neuro-oncology Program