Clinical trial NCT00689221: Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Methylated Gene Promoter Status
Official title: Cilengitide for Subjects With Newly Diagnosed Glioblastoma and Methylated MGMT Gene Promoter - A Multicenter, Open-label, Controlled Phase III Study, Testing Cilengitide in Combination With Standard Treatment (Temozolomide With Concomitant Radiation Therapy, Followed by Temozolomide Maintenance Therapy) Versus Standard Treatment Alone (CENTRIC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Glioblastoma
Keywords: newly diagnosed Glioblastoma (WHO Grade IV)
Cilengitide
Temozolomide
Radiotherapy
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: European Organisation for Research and Treatment of Cancer - EORTC
name: Merck KGaA, Darmstadt, Germany
First posted: 2008-06-03
Enrollment: 545
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: CENTRIC is a Phase 3 clinical trial assessing efficacy and safety of the investigational integrin inhibitor, cilengitide, in combination with standard treatment versus standard treatment alone in newly diagnosed glioblastoma subjects with a methylated 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 be a predictive marker for benefit from temozolomide (TMZ) treatment.


Eligibility criteria: Inclusion Criteria:

1. Tumor tissue specimens from the glioblastoma surgery or open biopsy (formalin-fixed, paraffin-embedded block; stereotactic biopsy not allowed) must be available for MGMT status analysis and central pathology review
2. Newly diagnosed histologically proven supratentorial glioblastoma (World Health Organization \[WHO\] Grade IV)
3. Proven methylated MGMT gene promoter methylation status
4. Available post-operative gadolinium-enhanced magnetic resonance imaging (Gd-MRI) performed within less than (\<) 48 hours after surgery (in case it was not possible to obtain a Gd-MRI within \<48 hours post surgery, a Gd-MRI is to be performed prior to randomization)
5. Stable or decreasing dose of steroids for greater than or equal to (\>=) 5 days prior to randomization
6. Eastern Cooperative Oncology Group performance score (ECOG PS) of 0-1
7. Meets 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)
8. Other protocol defined inclusion criteria could apply

Exclusion Criteria:

1. Prior chemotherapy within the last 5 years
2. Prior RTX of the head
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 antiangiogenic therapy
5. Placement of Gliadel® wafer at surgery
6. Inability to undergo Gd-MRI.
7. Planned surgery for other diseases
8. History of recent peptic ulcer disease (endoscopically proven gastric ulcer, duodenal ulcer, or esophageal ulcer) within 6 months of enrollment
9. 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
10. History of coagulation disorder associated with bleeding or recurrent thrombotic events
11. Clinically manifest myocardial insufficiency (New York Heart Association \[NYHA\] III, IV) or history of myocardial infarction during the past 6 months; uncontrolled arterial hypertension
12. 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, Sep 2008 until cut-off date, (19 Nov 2012)
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, Sep 2008 until cut-off date, (19 Nov 2012)
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: Day 1 of Week -1
measure: Time to Maximum Plasma Concentration (Tmax)
timeFrame: Day 1 of Week -1
measure: Area Under the Plasma Concentration Curve From Time 0 to 6 Hours (AUC [0-6]) After Dose
timeFrame: Day 1 of Week -1
measure: European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores
timeFrame: Up to 50 months
measure: European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Brain Module (EORTC QLQ-BN20) Sub-scale Scores
timeFrame: Up to 50 months
measure: EuroQol 5-Dimensions (EQ-5D) Questionnaire Index
timeFrame: Up to 50 months
measure: Number of Participants With Change From Baseline in Work Status at End of Study
timeFrame: Baseline, End of study (up to cut-off date, [19 Nov 2012])
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, Sep 2008 until cut-off date (19 Nov 2012)
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, Sep 2008 until cut-off date (19 Nov 2012)
measure: Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) and Lab Parameters
timeFrame: Up to 50 months
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: University of Lausanne Medical Center (CHUV)
name: Roger Stupp, Prof. Dr.
role: STUDY_CHAIR
affiliation: Merck KGaA, Darmstadt, Germany
name: Andriy Markivskyy, MD
role: STUDY_DIRECTOR
References:
citation: Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial Roger Stupp, Monika E Hegi, Thierry Gorlia, Sara C Erridge, James Perry, Yong-Kil Hong, Kenneth D Aldape, Benoit Lhermitte, Torsten Pietsch, Danica Grujicic, Joachim Peter Steinbach, Wolfgang Wick, Rafał Tarnawski, Do-Hyun Nam, Peter Hau, Astrid Weyerbrock, Martin J B Taphoorn, Chiung-Chyi Shen, Nalini Rao, László Thurzo, Ulrich Herrlinger, Tejpal Gupta, Rolf-Dieter Kortmann, Krystyna Adamska, Catherine McBain, Alba A Brandes, Joerg Christian Tonn, Oliver Schnell, Thomas Wiegel, Chae-Yong Kim, Louis Burt Nabors, David A Reardon, Martin J van den Bent, Christine Hicking, Andriy Markivskyy, Martin Picard, Michael Weller The Lancet Oncology 20 August 2014(Article in Press DOI: 10.1016/S1470-2045(14)70379-1)
citation: Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, Aldape KD, Lhermitte B, Pietsch T, Grujicic D, Steinbach JP, Wick W, Tarnawski R, Nam DH, Hau P, Weyerbrock A, Taphoorn MJ, Shen CC, Rao N, Thurzo L, Herrlinger U, Gupta T, Kortmann RD, Adamska K, McBain C, Brandes AA, Tonn JC, Schnell O, Wiegel T, Kim CY, Nabors LB, Reardon DA, van den Bent MJ, Hicking C, Markivskyy A, Picard M, Weller M; European Organisation for Research and Treatment of Cancer (EORTC); Canadian Brain Tumor Consortium; CENTRIC study team. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1100-8. doi: 10.1016/S1470-2045(14)70379-1. Epub 2014 Aug 19.