Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Unmethylated Gene Promoter Status
Condition: Glioblastoma
MeSH terms: Glioblastoma
Intervention: Cilengitide (2-times weekly); cilengitide (5-times weekly); Temozolomide; Radiotherapy
Intervention description: Cilengitide 2000 milligram (mg) will be administered intravenously twice weekly over 1 hour infusion from Weeks -1 to 77 or until occurrence of progressive disease, unacceptable toxicity, or withdrawal for any other reason. If considered beneficial in the opinion of the Investigator, continuation of cilengitide treatment will be optional in subjects without disease progression and after Week 77 since start of treatment.; Cilengitide 2000 milligram (mg) will be administered intravenously 5-times weekly over 1 hour infusion from Weeks -1 to 77 or until occurrence of progressive disease, unacceptable toxicity, or withdrawal for any other reason. If considered beneficial in the opinion of the Investigator, continuation of cilengitide treatment will be optional in subjects without disease progression and after Week 77 since start of treatment.; Temozolomide (TMZ) 75 milligram per square meter [mg/m^2] will be administered intravenously once daily from Week 1 to 6. From Week 11 onwards, TMZ will be given as maintenance treatment at a dose of 150-200 mg/m^2 for consecutive 5 days every 4 weeks until Week 34 or until disease progression.; Radiation therapy (RTX) at a dose of 2 gray (Gy) per fraction will be given once daily, 5 days per week from Week 1 to 6, total dose 60 Gy.
Intervention MeSH terms: Temozolomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 265.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Newly diagnosed Glioblastoma (WHO Grade IV); Cilengitide; Temozolomide; Radiotherapy

Summary:

      CORE is a Phase 2 clinical trial in newly diagnosed glioblastoma in subjects with an
      unmethylated O6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) gene promoter in
      the tumor tissue.

      The MGMT gene promoter is a section of deoxyribonucleic acid (DNA) that acts as a controlling
      element in the expression of MGMT. Methylation of the MGMT gene promoter has been found to
      appear to be a predictive marker for benefit from temozolomide (TMZ) treatment.

      In a safety run-in period in dedicated study centers, the safety and tolerability of
      Cilengitide given as an intense treatment in combination with the first part of standard
      therapy will be assessed. Thereafter the trial will investigate the overall survival and
      progression-free survival in subjects receiving two different regimens of Cilengitide in
      combination with standard treatment versus standard treatment alone.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Newly diagnosed histologically proven supratentorial glioblastoma (World Health
             Organization [WHO] Grade IV, including glioblastoma subtypes, for example,
             gliosarcoma). The histological diagnosis has to be obtained from a neurosurgical
             resection of the tumor or by an open biopsy (stereotactic biopsy is not allowed)

          2. Tumor tissue specimens from the glioblastoma surgery or open biopsy (formalin-fixed
             paraffin-embedded) must be available for MGMT gene promoter status analysis and
             central pathology review

          3. Proven unmethylated MGMT gene promoter status (that is, cut-off ratio less than (<) 2
             by means of applied test to determine MGMT gene promoter status)

          4. Males or females greater than or equal to (>=) 18 years of age

          5. Interval of >= 2 weeks but less than or equal to (=<) 7 weeks after surgery or biopsy
             before first administration of study treatment

          6. Available post-operative gadolinium-enhanced magnetic resonance imaging (Gd-MRI)
             performed within < 48 hours after surgery

          7. Stable or decreasing dose of steroids for >= 5 days prior to randomization

          8. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1

          9. Has to meet 1 of the following recursive partitioning analysis (RPA) classifications:

               -  Class III (Age < 50 years and ECOG PS 0)

               -  Class IV (meeting one of the following criteria: a) Age < 50 years and ECOG PS 1
                  or b) Age >= 50 years, underwent prior partial or total tumor resection, Mini
                  Mental State Examination [MMSE] >= 27)

               -  Class V (meeting one of the following criteria: a) Age >= 50 years and underwent
                  prior partial or total tumor resection, MMSE < 27 or b) Age >= 50 years and
                  underwent prior tumor biopsy only)

         10. Other protocol defined inclusion criteria could apply

        Exclusion Criteria:

          1. Prior chemotherapy within the last 5 years

          2. Prior RTX of the head (except for low dose RTX for tinea capitis)

          3. Receiving concurrent investigational agents or has received an investigational agent
             within the past 30 days prior to the first dose of cilengitide

          4. Prior systemic anti-angiogenic therapy

          5. Placement of Gliadel® wafer at surgery

          6. Planned surgery for other diseases

          7. History of recent peptic ulcer disease (endoscopically proven gastric ulcer, duodenal
             ulcer, or esophageal ulcer) within 6 months of enrollment

          8. History of malignancy. Subjects with curatively treated cervical carcinoma in situ or
             basal cell carcinoma of the skin, or subjects who have been free of other malignancies
             for >= 5 years are eligible for this study

          9. History of coagulation disorder associated with bleeding or recurrent thrombotic
             events

         10. Clinically manifest myocardial insufficiency (New York Heart Association [NYHA] III,
             IV) or history of myocardial infarction during the past 6 months; or uncontrolled
             arterial hypertension

         11. Inability to undergo Gd-MRI

         12. Concurrent illness, including severe infection (for example, human immunodeficiency
             virus), which may jeopardize the ability of the subject to receive the procedures
             outlined in this protocol with reasonable safety

         13. Subject is pregnant (positive serum beta human chorionic gonadotropin [b-HCG] test at
             screening) or is currently breast-feeding, anticipates becoming pregnant/impregnating
             their partner during the study or within 6 months after study participation, or
             subject does not agree to follow acceptable methods of birth control, such as hormonal
             contraception, intra-uterine pessar, condoms or sterilization, to avoid conception
             during the study and for at least 6 months after receiving the last dose of study
             treatment

         14. Current alcohol dependence or drug abuse

         15. Known hypersensitivity to the study treatment

         16. Legal incapacity or limited legal capacity

         17. Presence of any psychological, familial, sociological, or geographical condition
             potentially hampering compliance with the study protocol and follow-up schedule

         18. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family
             members who suffer(ed) from such

         19. Other protocol defined exclusion criteria could apply