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
Conditions
Brief summary
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
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.
Interventions
DRUGcilengitide
Given IV
OTHERlaboratory biomarker analysis
Correlative studies
OTHERpharmacological study
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response to Cilengitide | Up to 16 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Treatment Failure (TTF) | 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 | The distribution of TTF will be analyzed separately using PL estimate. |
| Time to Death (TTD) | Time from study enrollment to death from any cause, assessed up to 5 years | The distribution of TTD will be analyzed separately using PL estimate. |
| Rate of Toxicity, Especially That of Symptomatic Intratumoral Hemorrhage (ITH) Assessed by Common Terminology Criteria for Adverse Events Version 4.0 | Up to 5 years | Rate of individual toxicity including that of symptomatic ITH will be summarized in each course of treatment using standard descriptive statistical methods. |
| Pharmacokinetic Parameter of Cilengitide in Plasma: Volume of Central Compartment (Vc) | At baseline and 1, 3, and 6 hours after the first dose of cilengitide | 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. |
| Pharmacokinetic Parameter of Cilengitide in Plasma: Elimination Rate Constant (Ke) | At baseline and 1, 3, and 6 hours after the first dose of cilengitide | 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. |
| Time to Tumor Progression (TTP) | Time from study enrollment to radiographically determined tumor progression or recurrence, assessed up to 5 years | The distribution of TTP will be analyzed separately using product limit (PL) estimate. |
| Pharmacokinetic Parameter of Cilengitide in Plasma: Systemic Clearance (Cl) | At baseline and 1, 3, and 6 hours after the first dose of cilengitide | 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. |
| Pharmacogenetic Polymorphism in Drug Transporter Gene ABCB1 and Relate to Cilengitide Disposition as Measured by AUC | At baseline | 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. |
| Pharmacogenetic Polymorphism in Drug Transporter Gene ABCB1 and Relate to Cilengitide Disposition as Measured by Systemic Clearance | At Baseline | 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. |
| Pharmacogenetic Polymorphism in Drug Transporter Gene ABCG2 and Relate to Cilengitide Disposition as Measured by AUC | At baseline | 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. |
| Pharmacogenetic Polymorphism in Drug Transporter Gene ABCG2 and Relate to Cilengitide Disposition as Measured by Systemic Clearance | At baseline | 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. |
| Pharmacokinetic Parameter of Cilengitide in Plasma: Half-life (t1/2) | At baseline and 1, 3, and 6 hours after the first dose of cilengitide | 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. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Cilengitide) Patients receive cilengitide IV over 1 hour (1800 mg/m2/dose, maximum 75mg/kg) 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.
cilengitide: Given IV
laboratory biomarker analysis: Correlative studies
pharmacological study: Correlative studies | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 3 |
| Overall Study | Ineligible | 1 |
| Overall Study | Lack of Efficacy | 22 |
| Overall Study | Physician Decision | 4 |
Baseline characteristics
| Characteristic | Treatment (Cilengitide) |
|---|---|
| Age, Continuous | 13 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment Australia | 1 participants |
| Region of Enrollment Canada | 1 participants |
| Region of Enrollment United States | 28 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 8 / 29 |
| serious Total, serious adverse events | 8 / 29 |
Outcome results
Primary
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.
Time frame: Up to 16 weeks
Population: Six patients are considered inevaluable for objective response (including one ineligible patient) and excluded from analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Cilengitide) | Objective Response to Cilengitide | With Objective Response | 1 participants |
| Treatment (Cilengitide) | Objective Response to Cilengitide | Without Objective Response | 23 participants |
Secondary
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.
Time frame: At baseline
Population: The analysis includes 12 eligible patients with both AUC data and ABCB1 Exon 26 data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Cilengitide) | Pharmacogenetic Polymorphism in Drug Transporter Gene ABCB1 and Relate to Cilengitide Disposition as Measured by AUC | 0.00 Spearman's correlation |
p-value: 1Spearman's Correlation
Secondary
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.
Time frame: At Baseline
Population: The analysis includes 12 eligible patients with both systemic clearance data and ABCB1 Exon 26 data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Cilengitide) | Pharmacogenetic Polymorphism in Drug Transporter Gene ABCB1 and Relate to Cilengitide Disposition as Measured by Systemic Clearance | 0.56 Spearman's Correlation |
p-value: 0.057Spearman's Correlation
Secondary
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.
Time frame: At baseline
Population: The analysis includes 12 eligible patients with both AUC data and ABCG2 Exon 5 data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Cilengitide) | Pharmacogenetic Polymorphism in Drug Transporter Gene ABCG2 and Relate to Cilengitide Disposition as Measured by AUC | -0.22 Spearman's Correlation |
p-value: 0.495Spearman's Correlation
Secondary
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.
Time frame: At baseline
Population: The analysis includes 12 eligible patients with both systemic clearance data and ABCG2 Exon 5 data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Cilengitide) | Pharmacogenetic Polymorphism in Drug Transporter Gene ABCG2 and Relate to Cilengitide Disposition as Measured by Systemic Clearance | -0.48 Spearman's Correlation |
p-value: 0.114Spearman's Correlation
Secondary
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.
Time frame: At baseline and 1, 3, and 6 hours after the first dose of cilengitide
Population: All 18 patients consenting for pharmacokinetic study are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Cilengitide) | Pharmacokinetic Parameter of Cilengitide in Plasma: Elimination Rate Constant (Ke) | 0.58 hr^(-1) |
Secondary
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.
Time frame: At baseline and 1, 3, and 6 hours after the first dose of cilengitide
Population: All 18 patients consenting for pharmacokinetic study are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Cilengitide) | Pharmacokinetic Parameter of Cilengitide in Plasma: Half-life (t1/2) | 1.26 hours |
Secondary
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.
Time frame: At baseline and 1, 3, and 6 hours after the first dose of cilengitide
Population: All 18 patients consenting for pharmacokinetic study are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Cilengitide) | Pharmacokinetic Parameter of Cilengitide in Plasma: Systemic Clearance (Cl) | 3.84 L/hr/m^2 |
Secondary
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.
Time frame: At baseline and 1, 3, and 6 hours after the first dose of cilengitide
Population: All 18 patients consenting for pharmacokinetic study are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Cilengitide) | Pharmacokinetic Parameter of Cilengitide in Plasma: Volume of Central Compartment (Vc) | 6.20 L/m^2 |
Secondary
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.
Time frame: Up to 5 years
Population: Twenty-nine eligible patients are included in the analysis. One patient was excluded due to ineligibility.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Cilengitide) | Rate of Toxicity, Especially That of Symptomatic Intratumoral Hemorrhage (ITH) Assessed by Common Terminology Criteria for Adverse Events Version 4.0 | 6.9 percent of pts with symptomatic ITH |
Secondary
Time to Death (TTD)
The distribution of TTD will be analyzed separately using PL estimate.
Time frame: Time from study enrollment to death from any cause, assessed up to 5 years
Population: Twenty-nine eligible patients are included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Cilengitide) | Time to Death (TTD) | 172 Days |
Secondary
Time to Treatment Failure (TTF)
The distribution of TTF will be analyzed separately using PL estimate.
Time frame: 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
Population: Twenty-nine eligible patients are included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Cilengitide) | Time to Treatment Failure (TTF) | 28 Days |
Secondary
Time to Tumor Progression (TTP)
The distribution of TTP will be analyzed separately using product limit (PL) estimate.
Time frame: Time from study enrollment to radiographically determined tumor progression or recurrence, assessed up to 5 years
Population: 29 eligible patients are included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Cilengitide) | Time to Tumor Progression (TTP) | 28 Days |