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: December 4, 2014
Last verified: December 2014
  Purpose

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.


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 (OS) Time [ Time Frame: Time from randomization to death or last day known to be alive, reported between day of first participant randomized, that is, Jun 2009 until cut-off date, (07 Feb 2013) ] [ Designated as safety issue: No ]
    The OS time is defined as the time (in months) from randomization to death or last day known to be alive. Participants without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier.


Secondary Outcome Measures:
  • Progression Free Survival (PFS) Time - Investigator and Independent Read [ Time Frame: Time from randomization to disease progression, death or last tumor assessment, reported between day of first participant randomized, that is, Jun 2009 until cut-off date, (07 Feb 2013) ] [ Designated as safety issue: No ]
    The PFS time is defined as the duration from randomization to either first observation of progressive disease (PD) or occurrence of death due to any cause. Investigator read is the assessment of all imaging by the treating physician at the local trial site. Independent Read is the assessment of all imaging centrally by an Independent Review Committee (IRC).

  • Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Days 1 and 5 of Week 1 ] [ Designated as safety issue: No ]
    The Cmax for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2. Cilengitide plasma concentrations were determined after dosing on Day 1 (single dose) and Day 5 (repeated doses) of Week 1.

  • Time to Maximum Plasma Concentration (Tmax) and Terminal Elimination Half-Life (t1/2) [ Time Frame: Days 1 and 5 of Week 1 ] [ Designated as safety issue: No ]
    The Tmax and t1/2 for cilengitide were calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2. Cilengitide plasma concentrations were determined after dosing on Day 1 (single dose) and Day 5 (repeated doses) of Week 1.

  • Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC [0-infinity]) and Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC [0-24]) [ Time Frame: Days 1 and 5 of Week 1 ] [ Designated as safety issue: No ]
    The AUC (0-infinity) and AUC (0-24) for cilengitide were calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2. Cilengitide plasma concentrations were determined after dosing on Day 1 (single dose) and Day 5 (repeated doses) of Week 1.

  • Plasma Concentration at Pre-dose (Cpre) and Plasma Concentration at End of Infusion (CT) [ Time Frame: Days 1 and 5 of Week 1 ] [ Designated as safety issue: No ]
    The Cpre and CT for cilengitide were calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2. Cilengitide plasma concentrations were determined after dosing on Day 1 (single dose) and Day 5 (repeated doses) of Week 1.

  • Apparent Terminal Rate Constant [ Time Frame: Days 1 and 5 of Week 1 ] [ Designated as safety issue: No ]
    The apparent terminal rate constant for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2. Cilengitide plasma concentrations were determined after dosing on Day 1 (single dose) and Day 5 (repeated doses) of Week 1.

  • Mean Residence Time From Time 0 to Infinity (MRT [0-infinity]) [ Time Frame: Days 1 and 5 of Week 1 ] [ Designated as safety issue: No ]
    The MRT (0-infinity) for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2. Cilengitide plasma concentrations were determined after dosing on Day 1 (single dose) and Day 5 (repeated doses) of Week 1.

  • Plasma Clearance (CL) [ Time Frame: Days 1 and 5 of Week 1 ] [ Designated as safety issue: No ]
    The CL for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2. Cilengitide plasma concentrations were determined after dosing on Day 1 (single dose) and Day 5 (repeated doses) of Week 1.

  • Apparent Volume of Distribution During the Terminal Phase (Vz) and Apparent Volume of Distribution at Steady State (Vss) [ Time Frame: Days 1 and 5 of Week 1 ] [ Designated as safety issue: No ]
    The Vz (after single dose) and Vss (after repeated doses) for cilengitide were calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2. Cilengitide plasma concentrations were determined after dosing on Day 1 (single dose) and Day 5 (repeated doses) of Week 1.

  • Number of Participants With Adverse Events (AEs), Serious AEs, Treatment-Related AEs, Treatment-Related Serious AEs, AEs Leading to Death, Treatment-Related AEs Leading to Death, AEs of Grade 3 or 4 and Treatment-Related AEs of Grade 3 or 4 [ Time Frame: Time from first dose up to 28 days after last dose of study treatment, reported between day of first participant randomized, that is, Jun 2009 until cut-off date (07 Feb 2013) ] [ Designated as safety issue: Yes ]
    An AE is defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. Treatment-emergent AEs are the events between first dose of study drug and up to 28 days after last dose of study treatment. A Serious AE is an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Treatment-related AEs are the AEs which are suspected to be reasonably related to the study treatment (cilengitide, or radiotherapy, or temozolomide) as per investigator assessment. The severity of AEs was assessed according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTCAE) (Version 3.0): Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling. Note: Death (Grade 5) was regarded as an outcome.

  • Number of Participants With AEs Belonging to Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) Thromboembolic Events and Hemorrhage With NCI−CTC Toxicity Grade 3 or 4 [ Time Frame: Time from first dose up to 28 days after last dose of study treatment, reported between day of first participant randomized, that is, Jun 2009 until cut-off date (07 Feb 2013) ] [ Designated as safety issue: Yes ]
    Thromboembolic events (standardized MedDRA query [SMQ]) Grade 3 or 4 AEs encompassed hemiparesis and cerebrovascular accident, pulmonary embolism, and deep vein thrombosis. Thromboembolic events (SMQ) of any grade and of Grade 3 or 4 were generally more frequent in the Cilengitide + Temozolomide/Radiotherapy group than in the Temozolomide/Radiotherapy group but were still in the expected range of this patient population The severity of AEs was assessed according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTCAE) (version 3.0): Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling. Note: Death (Grade 5) was regarded as an outcome.

  • Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) and Lab Parameters [ Time Frame: Time from first dose up to 28 days after last dose of study treatment, reported between day of first participant randomized, that is, Jun 2009 until cut-off date (07 Feb 2013) ] [ Designated as safety issue: Yes ]

Enrollment: 265
Study Start Date: March 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, total dose 60 Gy.
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, total dose 60 Gy.
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, total dose 60 Gy.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
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

Responsible Party: EMD Serono
ClinicalTrials.gov Identifier: NCT00813943     History of Changes
Other Study ID Numbers: EMD 121974-012 
Study First Received: December 22, 2008
Results First Received: August 29, 2014
Last Updated: December 4, 2014
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, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dacarbazine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents

ClinicalTrials.gov processed this record on August 28, 2016