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

This study has been completed.
Sponsor:
Collaborator:
Merck KGaA
Information provided by (Responsible Party):
EMD Serono
ClinicalTrials.gov Identifier:
NCT00813943
First received: December 22, 2008
Last updated: September 24, 2013
Last verified: September 2013
  Purpose

CORE is a Phase 2 clinical trial in newly diagnosed glioblastoma in subjects with an unmethylated promoter of the O6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) gene 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.


Condition Intervention Phase
Glioblastoma
Drug: Cilengitide (2-times weekly)
Drug: cilengitide (5-times weekly)
Drug: Temozolomide
Radiation: Radiotherapy
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Cilengitide in Subjects With Newly Diagnosed Glioblastoma and Unmethylated MGMT Gene Promoter - a Multicenter, Open-label Phase II Study, Investigating Two Cilengitide Regimens in Combination With Standard Treatment (Temozolomide With Concomitant Radiation Therapy, Followed by Temozolomide Maintenance Therapy). [The CORE Study]

Resource links provided by NLM:


Further study details as provided by EMD Serono:

Primary Outcome Measures:
  • Overall survival time [ Time Frame: Follow up to 48 months after trial initiation ] [ Designated as safety issue: No ]
    Overall survival time will be measured from randomization to the date of death.


Secondary Outcome Measures:
  • Progression free survival (PFS) time [ Time Frame: Follow up to 48 months after trial initiation ] [ Designated as safety issue: No ]
    PFS will be measured from randomization to the first evidence of progressive disease (PD) or occurrence of death due to any cause.

  • Population pharmacokinetic parameter: Maximum observed plasma concentration (Cmax) [ Time Frame: Day 1 of Week -1, 1, 7 and 11 ] [ Designated as safety issue: No ]
  • Population pharmacokinetic parameters: Time to maximum plasma concentration (Tmax) and terminal elimination half-life (t1/2) [ Time Frame: Day 1 of Week -1, 1, 7 and 11 ] [ Designated as safety issue: No ]
  • Population pharmacokinetic parameters: Area under the plasma concentration curve, time 0 to infinity (AUC [0-infinity]) and time 0 to t (AUC [0-t]) [ Time Frame: Day 1 of Week -1, 1, 7 and 11 ] [ Designated as safety issue: No ]
  • Population pharmacokinetic parameter: plasma concentration at pre-dose (Cpre) [ Time Frame: Day 1 of Week -1, 1, 7 and 11 ] [ Designated as safety issue: No ]
  • Population pharmacokinetic parameter: plasma concentration at end of infusion (CT) [ Time Frame: Day 1 of Week -1, 1, 7 and 11 ] [ Designated as safety issue: No ]
  • Population pharmacokinetic parameter: apparent terminal rate constant (λz) [ Time Frame: Day 1 of Week -1, 1, 7 and 11 ] [ Designated as safety issue: No ]
  • Population pharmacokinetic parameters: mean residence time, time 0 to infinity (MRT [0-infinity]) [ Time Frame: Day 1 of Week -1, 1, 7 and 11 ] [ Designated as safety issue: No ]
  • Population pharmacokinetic parameter: plasma clearance (CL) [ Time Frame: Day 1 of Week -1, 1, 7 and 11 ] [ Designated as safety issue: No ]
  • Population pharmacokinetic parameters: apparent volume of distribution during the terminal phase (Vz) and at steady state (Vss) [ Time Frame: Day 1 of Week -1, 1, 7 and 11 ] [ Designated as safety issue: No ]
  • Number of subjects with adverse events (AEs), Serious AEs, treatment emergent AEs, AEs leading to death, and AEs with National Cancer Institute-Common Toxicity Criteria (NCI−CTC) toxicity Grade 3 or 4 [ Time Frame: Screening up to 28 days after the last dose of study treatment ] [ Designated as safety issue: Yes ]
  • Number of subjects with adverse events belonging to Standardized MedDRA Queries (SMQs) thromboembolic event and hemorrhages with NCI−CTC toxicity Grade 3 or 4 [ Time Frame: Screening up to 28 days after the last dose of study treatment ] [ Designated as safety issue: Yes ]
  • Number of subjects with clinically significant abnormal Electrocardiogram (ECG) and lab parameters [ Time Frame: Screening up to 28 days after the last dose of study treatment ] [ Designated as safety issue: Yes ]

Enrollment: 265
Study Start Date: January 2009
Study Completion Date: August 2013
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cilengitide (2-times weekly) + Temozolomide + Radiotherapy Drug: 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.
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.
Radiation: 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.
Experimental: Cilengitide (5-times weekly) + Temozolomide + Radiotherapy 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.
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.
Radiation: 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.
Active Comparator: Temozolomide + Radiotherapy 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.
Radiation: 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00813943

Locations
United States, Massachusetts
Please Contact U.S. Medical Information Located in
Rockland, Massachusetts, United States
Germany
Please Contact the Merck KGaA Communication Center Located in
Darmstadt, Germany
Sponsors and Collaborators
EMD Serono
Merck KGaA
Investigators
Study Director: Andriy Markivskyy, MD Merck KGaA
Study Chair: Louis B. Nabors, Prof. Dr. University of Alabama at Birmingham
  More Information

No publications provided

Responsible Party: EMD Serono
ClinicalTrials.gov Identifier: NCT00813943     History of Changes
Other Study ID Numbers: EMD 121974-012
Study First Received: December 22, 2008
Last Updated: September 24, 2013
Health Authority: United States: Food and Drug Administration
European Union: European Medicines Agency

Keywords provided by EMD Serono:
Newly diagnosed Glioblastoma (WHO Grade IV)
Cilengitide
Temozolomide
Radiotherapy

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Dacarbazine
Temozolomide
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014