Clinical trial NCT00093964: Cilengitide (EMD 121974) for Recurrent Glioblastoma Multiforme (Brain Tumor)
Official title: A Multicenter, Open-label, Randomized, Uncontrolled, Phase IIa Trial in Subjects With Recurrent Glioblastoma Multiforme to Investigate the Clinical Activity, Safety, and Tolerability of Cilengitide (EMD 121,974) Administered as a Single Agent.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Glioblastoma Multiforme
Keywords: Brain cancer
Brain tumor
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
First posted: 2004-10-11
Enrollment: 81
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: This study will investigate clinical activity, safety, and tolerability of the anti-angiogenic compound cilengitide (EMD 121974) in the treatment of first recurrence of glioblastoma multiforme (GBM).


Eligibility criteria: Inclusion Criteria:

* Written informed consent obtained before undergoing any study-related activities.
* Males or females 18 years of age or older who can be treated in an outpatient setting.
* Histologically proven GBM, which is recurrent or progressive following surgery or biopsy, external beam radiation therapy, and 1 previous regimen of systemic chemotherapy (Gliadel wafer therapy is not considered systemic chemotherapy). Malignancy is to be documented with a previous histopathological report.
* Subjects initially diagnosed with other conditions similar to GBM (such as anaplastic astrocytoma \[AA\] or low grade glioma) that subsequently progressed to histologically proven GBM and have had surgery or biopsy, external beam radiation therapy, and 1 previous regimen of systemic chemotherapy for the original diagnosis are eligible if they meet all inclusion criteria.
* GBM recurring only in the contralateral hemisphere must be histologically confirmed by biopsy. GBM recurring bilaterally does not need to be histologically confirmed by biopsy (i.e., if recurrence is ipsilateral and contralateral).
* Archived tumor tissue specimens from the GBM surgery or biopsy must be available for central pathology review and exploratory analysis of angiogenic markers (e.g. αvβ3 and αvβ5 integrins).
* Measurable disease (solid contrast-enhancing lesion greater than or equal to (\>=)1 cm in any dimension) evaluated by gadolinium-enhanced magnetic resonance imaging (Gd MRI) within 2 weeks prior to the first dose of EMD 121974.
* At least 12 weeks have elapsed since the last radiation treatment, and at least 4 weeks have elapsed since the last chemotherapy dose (at least 6 weeks for nitrosourea-containing chemotherapy) prior to the first dose of EMD 121974.
* If the subject underwent recent surgery, status must be \>=2 weeks post surgery or \>=1 week post biopsy, in stable condition, and maintained on a stable corticosteroid regimen for \>=5 days prior to first dose of EMD 121974.
* Karnofsky Performance Score (KPS) of \>=70%.
* Subjects with the potential for pregnancy or impregnating their partner must agree to follow acceptable methods of birth control to avoid conception during the study and for at least 6 months after receiving the last dose of study drug.
* Women of childbearing potential must have a negative pregnancy test at screening.
* Laboratory values (within 1 week prior to the first dose of EMD 121974, except for blood count and Prothrombin time (PT)/Partial thromboplastin time (PTT), which are to be within 72 hours of the first dose): Absolute neutrophil count \>=1500/millimeter (mm)\^3. Platelets \>=100,000/mm\^3. Creatinine less than or equal to (\<=) 1.5 milligram/deciliter (mg/dL) or creatinine clearance \>=60 mL/min. Hematocrit \>=30%. Prothrombin time (PT) and partial thromboplastin time (PTT) within normal limits. Hemoglobin \>=10 mg/dL. Total bilirubin \<=1.5 times the upper limit of normal. Aspartate aminotransferase and alanine aminotransferase \<=2.5 times above upper limit of normal.
* No more than 8 weeks have elapsed since recurrence was detected

Exclusion Criteria:

* Prior radiation therapy greater than (\>) 66 Gray.
* Subject anticipates undergoing elective surgery, dental extraction, or invasive dental procedures.
* History of recent peptic ulcer disease (endoscopically proven gastric ulcer, duodenal ulcer, or esophageal ulcer) within 6 months of enrollment.
* History of prior 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.
* History of coagulation disorder associated with bleeding or recurrent thrombotic events.
* Concurrent illness, including severe infection, which may jeopardize the ability of the subject to receive the procedures outlined in this protocol with reasonable safety.
* Subject is pregnant, anticipates becoming pregnant within 6 months after study participation, or is currently breast-feeding.
* Receiving concurrent investigational agents or has received an investigational agent within the past 30 days prior to the first dose of EMD 121974.
* Prior antiangiogenic therapy.
* Placement of Gliadel wafer at surgery for recurrence.
* Unable to undergo Gd MRI.
* Current known alcohol dependence or drug abuse.
* Requiring concomitant chemotherapy.
* Treatment with a prohibited concomitant medication.
* Known hypersensitivity to the study treatment.
* Legal incapacity or limited legal capacity.

Primary outcomes:
measure: Percentage of Subjects With Progression-free Survival
timeFrame: Month 6
Secondary outcomes:
measure: Percentage of Subjects With Overall Response Rate
timeFrame: From the start of treatment up to 6 years
measure: Time to Disease Progression
timeFrame: From the start of treatment until disease progression (assessed up to a maximum of 6 years)
measure: Overall Survival Time
timeFrame: From the start of treatment until death (assessed up to a maximum of 6 years)
measure: Percentage of Subjects With 1-year of Survival Rate
timeFrame: From the start of treatment up to 1 year
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: Pre-dose, 1, 1.5, 2, 3, 4, 8, 24 hours post-infusion on Day 1 of Week 1 in Cycle 1 and 2
measure: Time to Reach Maximum Plasma Concentration (Tmax)
timeFrame: Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity After Administration (AUC 0-infinity)
timeFrame: Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2
measure: Apparent Terminal Rate Constant (Lambda z)
timeFrame: Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2
measure: Terminal Half-life (t1/2)
timeFrame: Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2
measure: Mean Residence Time of Drug in the Body (MRT)
timeFrame: Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2
measure: Total Body Clearance (CL) of Drug From Plasma/Cerebro Spinal Fluid (CSF)
timeFrame: Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2
measure: Apparent Volume of Distribution During the Terminal Phase (Vz)
timeFrame: Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2
measure: Apparent Volume of Distribution at Steady State (Vss)
timeFrame: Pre-dose, 1, 1.5, 2, 3, 4, 8, 24 hours post-infusion on Day 1 of Week 1 in Cycle 1 and 2
measure: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From the start of treatment up to 6 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Aurora
country: United States
facility: Denise Damek
state: Colorado
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Medical Center
state: Indiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Good Samaritan Hospital/Tri Health Hatton Center
state: Ohio
city: Dallas
country: United States
facility: Baylor University Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Burlington
country: United States
facility: University of Vermont/Fletcher Allen Healthcare
state: Vermont
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
Study officials:
affiliation: EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: Reardon DA, Fink KL, Mikkelsen T, Cloughesy TF, O'Neill A, Plotkin S, Glantz M, Ravin P, Raizer JJ, Rich KM, Schiff D, Shapiro WR, Burdette-Radoux S, Dropcho EJ, Wittemer SM, Nippgen J, Picard M, Nabors LB. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol. 2008 Dec 1;26(34):5610-7. doi: 10.1200/JCO.2008.16.7510. Epub 2008 Nov 3.