Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Unmethylated Gene Promoter Status (CORE)

Merck KGaA (EMD Serono)

Status and phase: Completed; Phase 2

Conditions: Glioblastoma

Treatments: Drug: Temozolomide; Drug: cilengitide (5-times weekly); Drug: Cilengitide (2-times weekly); Radiation: Radiotherapy

Study type: Interventional

Funder types: Industry

Identifiers

NCT00813943

EMD121974-012

Details and patient eligibility

About

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.

Enrollment: 265 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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265 participants in 3 patient groups

Cilengitide (2-times weekly) + Temozolomide + Radiotherapy

Experimental group

Treatment:

Radiation: Radiotherapy

Drug: Cilengitide (2-times weekly)

Drug: Temozolomide

Cilengitide (5-times weekly) + Temozolomide + Radiotherapy

Experimental group

Treatment:

Drug: cilengitide (5-times weekly)

Radiation: Radiotherapy

Drug: Temozolomide

Temozolomide + Radiotherapy

Active Comparator group

Treatment:

Radiation: Radiotherapy

Drug: Temozolomide