Clinical trial NCT00813943: Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Unmethylated Gene Promoter Status
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]
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Glioblastoma
Keywords: Newly diagnosed Glioblastoma (WHO Grade IV)
Cilengitide
Temozolomide
Radiotherapy
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2008-12-23
Enrollment: 265
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Overall Survival (OS) Time
timeFrame: 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)
Secondary outcomes:
measure: Progression Free Survival (PFS) Time - Investigator and Independent Read
timeFrame: 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)
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: Days 1 and 5 of Week 1
measure: Time to Maximum Plasma Concentration (Tmax) and Terminal Elimination Half-Life (t1/2)
timeFrame: Days 1 and 5 of Week 1
measure: 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])
timeFrame: Days 1 and 5 of Week 1
measure: Plasma Concentration at Pre-dose (Cpre) and Plasma Concentration at End of Infusion (CT)
timeFrame: Days 1 and 5 of Week 1
measure: Apparent Terminal Rate Constant
timeFrame: Days 1 and 5 of Week 1
measure: Mean Residence Time From Time 0 to Infinity (MRT [0-infinity])
timeFrame: Days 1 and 5 of Week 1
measure: Plasma Clearance (CL)
timeFrame: Days 1 and 5 of Week 1
measure: Apparent Volume of Distribution During the Terminal Phase (Vz) and Apparent Volume of Distribution at Steady State (Vss)
timeFrame: Days 1 and 5 of Week 1
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) and Lab Parameters
timeFrame: 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)
Other outcomes:
Locations:
city: Rockland
country: United States
facility: Please Contact U.S. Medical Information Located in
state: Massachusetts
city: Darmstadt
country: Germany
facility: Please Contact the Merck KGaA Communication Center Located in
Study officials:
affiliation: Merck KGaA, Darmstadt, Germany
name: Andriy Markivskyy, MD
role: STUDY_DIRECTOR
affiliation: University of Alabama at Birmingham
name: Louis B. Nabors, Prof. Dr.
role: STUDY_CHAIR
References: