Cilengitide in Treating Younger Patients With Recurrent or Progressive High-Grade Glioma That Has Not Responded to Standard Therapy

Study Overview
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Brief Summary
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This phase II trial studies how well cilengitide works in treating younger patients with recurrent or progressive high-grade glioma that has not responded to standard therapy. Cilengitide may stop the growth of tumor cells by blocking blood flow to the tumor.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the objective response rate to cilengitide in younger patients with recurrent or progressive high-grade glioma that is refractory to standard therapy. SECONDARY OBJECTIVES: I. To estimate the distribution of time to progression, time to treatment failure, and time to death in these patients. II. To estimate the rate of toxicity, especially symptomatic intratumoral hemorrhage, in these patients. III. To evaluate the pharmacokinetics of cilengitide in plasma using a limited sampling strategy. IV. To evaluate the pharmacogenetic polymorphisms in drug transporters (eg, breast cancer resistance protein [BCRP], P-glycoprotein [P-gp]) and relate to cilengitide disposition. OUTLINE: Patients receive cilengitide IV over 1 hour on days 1, 4, 8, 11, 15, 18, 22, and 25. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years and then periodically for 3 years.

Official Title
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Cilengitide (EMD 121974) (IND# 59073) in Recurrent or Progressive and Refractory Childhood High-Grade Glioma

Conditions
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Childhood High-grade Cerebellar Astrocytoma, Childhood High-grade Cerebral Astrocytoma, Recurrent Childhood Anaplastic Astrocytoma, Recurrent Childhood Anaplastic Oligoastrocytoma, Recurrent Childhood Anaplastic Oligodendroglioma, Recurrent Childhood Brain Tumor, Recurrent Childhood Cerebellar Astrocytoma, Recurrent Childhood Cerebral Astrocytoma, Recurrent Childhood Glioblastoma, Recurrent Childhood Visual Pathway and Hypothalamic Glioma

Intervention / Treatment
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* Drug: cilengitide
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed primary central nervous system (CNS) high-grade glioma, including any of the following: Glioblastoma multiforme Anaplastic astrocytoma Anaplastic oligodendroglioma High-grade astrocytoma not otherwise specified (i.e., anaplastic ganglioglioma, anaplastic mixed glioma, or anaplastic mixed glioneuronal tumors) No diffuse pontine gliomas, gliomatosis cerebri, and primary spinal cord high-grade astrocytoma Gliosarcoma Recurrent or progressive disease that is refractory to standard therapy Radiographically documented measurable disease Lesion must be at least twice the thickness of the image from which it is derived (e.g., 10 mm for a 5 mm slice thickness) No diffuse pontine gliomas No evidence of prior CNS bleeding Karnofsky performance status (PS) 50-100% (patients > 16 years of age) Lansky PS 50-100% (patients =< 16 years of age) Life expectancy >= 8 weeks Absolute neutrophil count (ANC) >= 1,000/μL Platelet count >= 100,000/μL (transfusion independent) Hemoglobin >= 8.0 g/dL (red blood cell [RBC] transfusions allowed) Creatinine clearance or radioisotope glomerular filtration rate >= 70mL/min OR serum creatinine based on age/gender as follows: 0.4 mg/dL (1 month to < 6 months of age) 0.5 mg/dL (6 months to < 1 year of age) 0.6 mg/dL (1 to < 2 years of age) 0.8 mg/dL (2 to < 6 years of age) 1.0 mg/dL (6 to < 10 years of age) 1.2 mg/dL (10 to < 13 years of age) 1.5 mg/dL (male) or 1.4mg/dL (female) (13 to < 16 years of age) 1.7 mg/dL (male) or 1.4mg/dL (female) (>= 16 years of age) Total bilirubin =< 1.5 times upper limit of normal (ULN) for age Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 times ULN for age No evidence of dyspnea at rest No exercise intolerance Pulse oximetry > 94%, if determination is clinically indicated Seizure disorder is allowed provided it is well-controlled with anticonvulsants No uncontrolled infection Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Recovered from all prior therapy No more than two prior treatments for high-grade glioma (i.e., one initial treatment and one treatment for relapse) More than 2 weeks since prior myelosuppressive chemotherapy (>= 6 weeks for nitrosoureas) At least 1 week since prior non-myelosuppressive chemotherapy, immunotherapy, or biologic therapy At least 2 weeks since prior local palliative radiotherapy (i.e., small port) to a symptomatic non-target lesion only At least 3 months since prior craniospinal radiotherapy At least 6 weeks since prior substantial bone marrow radiotherapy At least 6 months since prior allogeneic stem cell transplant (SCT) or rescue Patients who have undergone prior allogeneic SCT and who have graft-versus-host disease (GVHD) must have controlled GVHD that is =< grade 2 At least 1 month since prior autologous SCT More than 1 week since prior growth factors (> 3 weeks for pegfilgrastim [Neulasta®]) No other concurrent anticancer therapy, including chemotherapy or immunomodulating agents No other concurrent experimental agents or therapies No concurrent alternative or complimentary therapies No concurrent homeopathic medicines No concurrent nonsteroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (aspirin) No concurrent steroids as anti-emetics Concurrent steroids for treatment of increased intracranial pressure allowed if on a stable or decreasing dose for >= 1 week before study entry Concurrent radiotherapy to localized painful lesions allowed provided >= 1 measurable lesion is not irradiated

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (cilengitide)<br>Patients receive cilengitide IV over 1 hour on days 1, 4, 8, 11, 15, 18, 22, and 25. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: cilengitide<br>* Given IV<br>* Other names: EMD 121974;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response to Cilengitide | Objective response is defined as a complete response or partial response at 4 weeks that is sustained for at least another 4 weeks, or a stable disease at 4 weeks that is sustained for at least 12 weeks while on stable or decreasing dose of corticosteroids, except when corticosteroids are being used to control hydrocephaly unrelated to tumor progression. | Up to 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Tumor Progression (TTP) | The distribution of TTP will be analyzed separately using product limit (PL) estimate. | Time from study enrollment to radiographically determined tumor progression or recurrence, assessed up to 5 years | 
| Time to Treatment Failure (TTF) | The distribution of TTF will be analyzed separately using PL estimate. | Time from study enrollment to tumor progression, tumor recurrence, death from any cause, or occurrence of a second malignant neoplasm, assessed up to 5 years | 
| Time to Death (TTD) | The distribution of TTD will be analyzed separately using PL estimate. | Time from study enrollment to death from any cause, assessed up to 5 years | 
| Rate of Toxicity, Especially That of Symptomatic Intratumoral Hemorrhage (ITH) Assessed by Common Terminology Criteria for Adverse Events Version 4.0 | Rate of individual toxicity including that of symptomatic ITH will be summarized in each course of treatment using standard descriptive statistical methods. | Up to 5 years | 
| Pharmacokinetic Parameter of Cilengitide in Plasma: Volume of Central Compartment (Vc) | Cilengitide plasma concentration-time data are fit to a compartmental pharmacokinetic model using MAP-Bayesian estimation as implemented in ADAPT II. For each patient, samples collected at different time points are used to derive one Vc value per patient. | At baseline and 1, 3, and 6 hours after the first dose of cilengitide | 
| Pharmacokinetic Parameter of Cilengitide in Plasma: Elimination Rate Constant (Ke) | Cilengitide plasma concentration-time data are fit to a compartmental pharmacokinetic model using MAP-Bayesian estimation as implemented in ADAPT II. For each patient, samples collected at different time points are used to derive one Ke value per patient. | At baseline and 1, 3, and 6 hours after the first dose of cilengitide | 
| Pharmacokinetic Parameter of Cilengitide in Plasma: Half-life (t1/2) | Cilengitide plasma concentration-time data are fit to a compartmental pharmacokinetic model using MAP-Bayesian estimation as implemented in ADAPT II. For each patient, samples collected at different time points are used to derive one t1/2 value per patient. | At baseline and 1, 3, and 6 hours after the first dose of cilengitide | 
| Pharmacokinetic Parameter of Cilengitide in Plasma: Systemic Clearance (Cl) | Cilengitide plasma concentration-time data are fit to a compartmental pharmacokinetic model using MAP-Bayesian estimation as implemented in ADAPT II. For each patient, samples collected at different time points are used to derive one Cl value per patient. | At baseline and 1, 3, and 6 hours after the first dose of cilengitide | 
| Pharmacogenetic Polymorphism in Drug Transporter Gene ABCB1 and Relate to Cilengitide Disposition as Measured by AUC | Cilengitide systemic exposure as measured by AUC is used in this genotype-phenotype analysis. The ABCB1 (P-glycoprotein; P-gp) Exon 26 genotype is coded as 0/1/2 based on the number of T alleles. | At baseline | 
| Pharmacogenetic Polymorphism in Drug Transporter Gene ABCB1 and Relate to Cilengitide Disposition as Measured by Systemic Clearance | Cilengitide systemic exposure as measured by systemic clearance is used in this genotype-phenotype analysis. The ABCB1 (P-glycoprotein; P-gp) Exon 26 genotype is coded as 0/1/2 based on the number of T alleles. | At Baseline | 
| Pharmacogenetic Polymorphism in Drug Transporter Gene ABCG2 and Relate to Cilengitide Disposition as Measured by AUC | Cilengitide systemic exposure as measured by AUC is used in this genotype-phenotype analysis. The ABCG2 (breast cancer resistance protein; BCRP) Exon 5 genotype is coded as 0/1/2 based on the number of G alleles. | At baseline | 
| Pharmacogenetic Polymorphism in Drug Transporter Gene ABCG2 and Relate to Cilengitide Disposition as Measured by Systemic Clearance | Cilengitide systemic exposure as measured by systemic clearance is used in this genotype-phenotype analysis. The ABCG2 (breast cancer resistance protein; BCRP) Exon 5 genotype is coded as 0/1/2 based on the number of G alleles. | At baseline |