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

NCT ID: NCT00813943

Last Updated: 2017-01-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 265 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-03-31
• Study Completion Date: 2013-08-31

Brief 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.

Conditions

Glioblastoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cilengitide (2-times weekly) + Temozolomide + Radiotherapy

Group Type: EXPERIMENTAL

Cilengitide (2-times weekly)

Intervention Type: DRUG

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.

Temozolomide

Intervention Type: DRUG

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.

Radiotherapy

Intervention Type: RADIATION

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.

Cilengitide (5-times weekly) + Temozolomide + Radiotherapy

Group Type: EXPERIMENTAL

cilengitide (5-times weekly)

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Radiotherapy

Intervention Type: RADIATION

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.

Temozolomide + Radiotherapy

Group Type: ACTIVE_COMPARATOR

Temozolomide

Intervention Type: DRUG

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.

Radiotherapy

Intervention Type: RADIATION

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.

Interventions

Cilengitide (2-times weekly)

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.

Intervention Type: DRUG

cilengitide (5-times weekly)

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.

Intervention Type: DRUG

Temozolomide

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.

Intervention Type: DRUG

Radiotherapy

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 Type: RADIATION

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)

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck KGaA, Darmstadt, Germany

INDUSTRY

Sponsor Role: collaborator

EMD Serono

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Andriy Markivskyy, MD

Role: STUDY_DIRECTOR

Merck KGaA, Darmstadt, Germany

Louis B. Nabors, Prof. Dr.

Role: STUDY_CHAIR

University of Alabama at Birmingham

Locations

Please Contact U.S. Medical Information Located in

Rockland, Massachusetts, United States

Please Contact the Merck KGaA Communication Center Located in

Darmstadt, , Germany

Countries

United States; Germany

References

Seliger C, Oppong FB, Lefranc F, Chinot O, Stupp R, Nabors B, Gorlia T, Weller M; EORTC Brain Tumor Group. Association of antidepressant drug use with outcome of patients with glioblastoma. Int J Cancer. 2023 Apr 1;152(7):1348-1359. doi: 10.1002/ijc.34344. Epub 2022 Nov 17.

Reference Type: DERIVED

PMID: 36346112 (View on PubMed)

Other Identifiers

EMD121974-012

Identifier Type: -

Identifier Source: org_study_id