Clinical Trials

OBJECTIVES:

       -  Collect brain tumor tissue and an accompanying blood sample from pediatric patients with brain tumors treated at Children's Oncology Group institutions.

       -  Provide a repository for long-term storage of specimens from these patients.

       -  Make these specimens available to qualified researchers to understand the biology of pediatric brain tumors.

     OUTLINE: This is a multicenter study

     Brain tumor tissue and blood specimens are collected from patients and banked for future study.

     PROJECTED ACCRUAL: An unlimited number of specimens will be collected.

OBJECTIVES:

       -  To establish a maximum-tolerated dose of dasatinib combined with radiation and temozolomide in patients with newly diagnosed glioblastoma multiforme. (Phase I) (Phase I study closed to patient accrual on April 29, 2011 and has been completed)

       -  To determine the efficacy of dasatinib in combination with radiotherapy and concomitant adjuvant temozolomide, and compare it with the standard of care approach, consisting of radiotherapy and temozolomide, followed by adjuvant temozolomide in these patients. (Phase II) (Phase II study opened to patient accrualon August 5, 2011)

       -  To determine the relationship between tumor biomarkers and clinical outcome of patients treated with the dasatinib/radiotherapy/temozolomide combination. (Phase II)

       -  To evaluate potential mechanisms of therapy resistance in recurrent tumor samples obtained at the time of surgery for recurrent disease.

       -  To assess the impact of the addition of dasatinib to radiotherapy and temozolomide on the quality of life (QOL) of these patients, as assessed by FACT-Br, EORTC QLQ-C15-PAL, and EORTC QLQ-BN20. (Phase II)

       -  To compare the results of the two most commonly used QOL tools, FACT-Br and EORTC QLQ C15-PAL plus BN20 and validate the use of EORTC QLQ-C15-PAL plus BN20 in these patients.(Phase II)

     OUTLINE: This is a multicenter, phase I dose-escalation study of dasatinib (Phase I study closed to patient accrual on April 29, 2011 and has been completed) followed by a randomized phase II study (Phase II study opened to patient accrual on August 5, 2011).

       -  Phase I:

            -  Course 1: Patients receive oral dasatinib once daily and oral temozolomide once daily on days 1-42. Patients undergo external-beam radiotherapy (EBRT), including intensity-modulated radiotherapy, 5 days a week for 6 weeks.

            -  Courses 2-7: Beginning 28-42 days after course 1, patients receive oral dasatinib once daily on days 1-28 and oral temozolomide once daily on days 1-5. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

       -  Phase II: Patients are stratified according to age (> 70 years vs ≤ 70 years). Patients are randomized to 1 of 2 treatment arms.

            -  Arm I:

                 -  Course 1: Patients receive oral dasatinib once daily and oral temozolomide once daily on days 1-42. Patients undergo EBRT 5 days a week for 6 weeks.

                 -  Courses 2-7: Beginning 28-42 days after course 1, patients receive oral dasatinib once daily on days 1-28 and oral temozolomide once daily on days 1-5. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

            -  Arm II:

                 -  Course 1: Patients receive oral placebo once daily on days 1-42 and temozolomide as in arm I. Patients also undergo EBRT as in arm I.

                 -  Courses 2-7: Beginning 28-42 days after course 1, patients receive oral placebo once daily on days 1-28 and temozolomide as in arm I. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

     Tissue samples are collected for correlative studies.

     Quality of life is assessed periodically using the FACT-Br, EORTC QLQ-C15-PAL v.1, and EORTC BN-20 questionnaires.

     After completion of study therapy, patients are followed up every 6 months for 5 years.

Different treatments exist for children with progressive or recurrent low-grade glioma. Each has variable efficacy at slowing or reversing growth, and exploration continues into finding better-tolerated, more effective treatments. Vinorelbine has recently generated interest in stabilizing some pediatric low-grade gliomas. It has been fairly well tolerated in both adult and pediatric studies that have examined its use in other tumors. In addition, the quality of life for children with low-grade gliomas is important and requires further study. This trial will incorporate an optional assessment using validated neuropsychological testing throughout treatment to evaluate the quality of life of the child being treated. Objective: To test the efficacy of Vinorelbine in a larger number of children with pediatric low-grade glioma that has returned or continues to grow. In this trial, Vinorelbine will be given intravenously once a week for 6 weeks followed by a 2 week rest. This cycle can then be repeated for up to 1-2 years if providing clinical benefit.

OBJECTIVES:

     Primary

       -  Determine the maximum-tolerated dose of dasatinib in combination with bevacizumab in patients with recurrent or progressive high-grade glioma or glioblastoma multiforme. (Phase I*)

       -  Assess the safety and adverse events of this regimen in these patients. (Phase I*)

       -  Estimate and compare the efficacy of these regimens in these patients as measured by progression-free survival at six months. (Phase II)

     Secondary

       -  Describe any preliminary evidence of antitumor activity. (Phase I*)

       -  Describe the overall toxicity associated with this regimen in these patients. (Phase I*)

       -  Estimate and compare the efficacy of these regimens in these patients as measured by overall survival (Phase II)

       -  Assess the impact of these regimens on the patient's quality of life using FACT-Br (no longer assessed as of 5/18/2009) (newly added as of 2/2/2010). (Phase II)

       -  Assess the time to disease progression. (Phase II)

       -  Assess the safety and toxicity of these regimens in this patient population. (Phase II)

       -  Determine the relationship between tumor biomarkers and clinical outcome of patients treated with these regimens. (Phase II) (exploratory)

       -  Assess the utility of dynamic contrast-enhanced MRI as a predictor of response to these regimens. (Phase II) (exploratory)

       -  To assess the utility of MRI diffusion-weighted images (DWI), and specifically the apparent diffusion coefficient (ADC), as a predictor of response and survival in patients treated with bevacizumab/dasatinib combination treatment. (Phase II) (exploratory)

       -  Bank leftover tissue for future NCCTG studies. (Phase II) (exploratory) NOTE: *Phase I completed.

     OUTLINE: This is a multicenter, phase I, dose-escalation study (Phase I completed) of dasatinib followed by a phase II randomized study. Patients are grouped according to study (1 vs 2). Patients in the phase II portion are stratified according to age (> 70 years of age vs ≤ 70 years of age), and ECOG performance status (0 vs 1 or 2).

     Phase I: Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oral dasatinib once or twice daily on days 1-14 until the maximum-tolerated dose (MTD) is determined. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. (Phase I completed)

     Phase II (patients are randomized to 1 of 2 treatment arms):

       -  Arm I: Patients receive bevacizumab as in phase I and dasatinib at the MTD as determined in phase I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

       -  Arm II: Patients receive bevacizumab as in phase I and oral placebo once or twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

     Quality of life is assessed by FACT-Br questionnaire at baseline and prior to every other course (no longer assessed as of 5/18/2009)(newly added as of 2/2/2010). Tissue samples are collected at baseline for biomarker studies and assessed by IHC, RT-PCR, and FISH. Patients undergo dynamic contrast-enhanced MRI at baseline, day 3 of course 1, and day 1 of course 2.

     After completion of study therapy, patients are followed up periodically for up to 3 years.

PRIMARY OBJECTIVES: I. To establish a maximum tolerated dose (MTD) of TRC105 (anti-endoglin monoclonal antibody TRC105) combined with bevacizumab in this patient population. (Phase I) II. To assess the safety and adverse events of TRC105 in combination with bevacizumab in this patient population. (Phase II) III. To determine the efficacy of TRC105 in combination with bevacizumab in recurrent glioblastoma as measured by progression-free survival and compare it with the efficacy of bevacizumab alone in this patient population. (Phase II) SECONDARY OBJECTIVES: I. To assess the proportion of patients who are progression free at 6 months, treated with TRC105 in combination with bevacizumab as compared to bevacizumab alone. (Phase II) II. To assess the overall survival of patients treated with TRC105 in combination with bevacizumab compared to bevacizumab alone. (Phase II) III. To compare the impact of the treatment on the patients quality of life (QOL) using the EORTC Quality of Life QLQ-C15-PAL and QLQ-BN20 Patient Questionnaires. (Phase II) IV. To estimate patient recommendations for study participation to others using the Was It Worth It (WIWI) Questionnaire. (Phase II) TERTIARY OBJECTIVES: I. To evaluate the pharmacokinetics of TRC105. (Phase I) II. To evaluate the immunogenicity of TRC105. (Phase I) III. To determine the relationship between tumor biomarkers, circulating biomarkers of vascular response and vascular endothelial growth factor (VEGF)/VEGFR single-nucleotide polymorphism (SNPs) in predicting efficacy and/or toxicity of treatment. (Phase II) IV. To assess the utility of magnetic resonance imaging (MRI) imaging including apparent diffusion coefficient (ADC) as a predictor of response and survival. (Phase II) V. To assess the utility of dynamic contrast enhanced (DCE) MRI as a predictor of response to bevacizumab with or without TRC105. (Phase II) OUTLINE: This is a multicenter, dose-escalation, phase I study of anti-endoglin monoclonal antibody TRC105 followed by a randomized phase II study. Phase I: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of course 2 and all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Phase II: Patients are stratified according to age (> 70 vs =< 70) and resection at recurrence (yes vs no). Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive bevacizumab IV over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of course 2 and all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months.

PRIMARY OBJECTIVES: I. To assess the anti-tumor activity (in terms of the tumor response rate using the Response Evaluation Criteria in Solid Tumors [RECIST] criteria) of pazopanib (pazopanib hydrochloride) (GW786034) in patients with advanced malignant pheochromocytomas and paragangliomas. SECONDARY OBJEC TIVES: I. To assess safety profile of pazopanib. II. To assess duration of tumor response. III. To assess time to treatment failure. IV. To assess progression-free survival time. V. To assess overall survival time. TERTIARY OBJECTIVES: I. For patients with secretory tumors, to examine changes in urinary catecholamine and/or metanephrine levels. II. For patients with secretory tumors, to examine whether pazopanib-induced changes in urinary catecholamine and/or metanephrine levels during the first cycle of treatment may be associated with objective tumor response. III. To examine associations between tumor response and somatic mutational status in archived tumors, or germline mutational status in patient's peripheral blood mononuclear cells, (presence of succinate dehydrogenase complex subunit D [SDHD], succinate dehydrogenase complex subunit B [SDHB], ret proto-oncogene [RET], von Hippel-Lindau tumor suppressor [VHL], neurofibromatosis type-1). IV. To examine associations between tumor response and tumor expression levels of angiogenic and vascular markers including hypoxia inducible factor 1, alpha (HIF-1a), vascular endothelial growth factor receptor (VEGF-R) (total and phospho-) and microvessel density in archival tumor tissue. IV. To examine whether the extent of tumor response/regression may be correlated with plasma pazopanib (GW786034) concentration achieved after the third cycle (first cycle after run-in cycles) of pazopanib (GW786034) therapy. OUTLINE: This is a multicenter study. Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo urine and blood sample collection at baseline and periodically during study for correlative studies. After completion of study therapy, patients are followed up every 3-6 months for a maximum of 3 years.

PRIMARY OBJECTIVES:

     I. To determine correlation between 18F-FDOPA PET activity, MRI contrast enhancement, and high- or low-grade glioma biopsies.

     II. To compare radiotherapy target volume delineation with and without 18F- FDOPA-PET metabolic imaging information to determine role of metabolic imaging in radiotherapy treatment planning.

     SECONDARY OBJECTIVES:

     I. To determine correlation between concordance of 18F-FDOPA PET activity, MRI contrast enhancement, and high- or low-grade glioma biopsies and patient outcomes including overall survival and progression free survival.

     OUTLINE:

     Beginning at no more than 1 week before biopsy and resection, patients undergo fluorine F 18 fluorodopa-labeled PET/CT scan and pre-operative MRI. Patients then undergo stereotactic craniotomy. Some patients may also undergo radiation therapy.

     After completion of study treatment, patients are followed up every year for 5 years.

PRIMARY OBJECTIVES: I. To determine the objective response rate in children with recurrent, refractory, or progressive juvenile pilocytic astrocytomas and optic pathway gliomas who are treated with Regimen A low-dose (20 mg/m²/dose) or Regimen B high-dose (115 mg/m²/dose) lenalidomide. SECONDARY OBJECTIVES: I. To estimate the event-free survival (EFS) (based on standard two-dimensional tumor measurements, determined by each institution) of children with recurrent, refractory, or progressive juvenile pilocytic astrocytomas and optic pathway gliomas who are treated with lenalidomide. II. To compare response categories and EFS across the 3 magnetic resonance (MR) sequences (T2-weighted, fluid attenuated inversion recovery [FLAIR], T1-weighted post-contrast). III. To correlate steady-state pharmacokinetics of lenalidomide (1 sample obtained between Days 5-21) with objective response and EFS. IV. To evaluate toxicities of long-term lenalidomide use. OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms. ARM I (regimen A): Patients receive low-dose lenalidomide orally (PO) once daily (QD) on days 1-21. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity. ARM II (regimen B): Patients receive high-dose lenalidomide PO QD on days 1-21. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection between days 5-21 during course 1 for pharmacokinetic studies. After completion of study treatment, patients are followed up for up to 5 years.

OBJECTIVES:

     Primary

       -  Determine whether there is a survival advantage for patients with newly diagnosed 1p/19q codeleted anaplastic glioma who receive concurrent temozolomide and radiotherapy (RT) followed by adjuvant temozolomide over that observed in patients treated with RT alone (control).

     Secondary

       -  Determine whether there is a neurocognitive advantage in patients who receive temozolomide alone (Arm III) vs temozolomide with concurrent RT (Arm II) over that observed in patients treated with RT alone (Arm I).

       -  Determine whether there is a difference in survival based on t(1;19)(q10,p10) translocation status and MGMT promoter hypermethylation status in these patients.

       -  Perform descriptive comparisons of additional secondary outcome endpoints, including time to progression, progression free survival, and the proportion of patients free of progression at 6, 12, and 24 months.

       -  Determine the toxicity of RT and concurrent/adjuvant temozolomide in these patients.

       -  Determine descriptively whether it is reasonable to delay RT by documenting the time to progression and progression-free survival of patients receiving temozolomide alone.

       -  Determine the quality of life and neurocognitive effects in patients treated on this protocol and correlate these results with outcome endpoints.

       -  Bank blood products (i.e., plasma, DNA, and buffy coat) and tumor tissue for future scientific investigations.

     OUTLINE: This is a multicenter study. Patients are stratified according to cooperative group (EORTC vs North American groups [NCCTG, RTOG, CTSU, and NCIC CTG]), age (≤ 50 years vs > 50 years), and ECOG performance status (0-1 vs 2). Patients are randomized to 1 of 3 treatment arms.

       -  Arm I: Patients undergo radiotherapy (RT) 5 days a week for 6 weeks in the absence of disease progression or unacceptable toxicity.

       -  Arm II: Patients undergo RT as in arm I and receive oral temozolomide once daily on days 1-7 for 6 weeks. Beginning 4 weeks after completion of concurrent chemoradiotherapy, patients receive adjuvant oral temozolomide once daily days 1-5. Treatment with adjuvant temozolomide repeats every 28 days for 6-12 courses in the absence of disease progression and unacceptable toxicity.

       -  Arm III: Patients receive oral temozolomide once daily on days 1-5. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

     Patients complete neurocognitive questionnaires (i.e., the Hopkins Verbal Learning test, the Controlled Oral Word Association test from the Multilingual Aphasia Examination, General Mental Ability: Trail Making tests A and B, and the Recall and Recognition of Word List encoded from the HVLT-R test) and quality of life questionnaires (i.e., EORTC QOL-C30 and QOL-BN20) at baseline and periodically during study therapy.

     Tumor tissue samples are collected during surgery and analyzed by FISH to detect t(1:19), and for MGMT gene promoter hypermethylation status and additional known prognostic markers, including but not limited to PTEN, EGFR, EGFRvIII, and p53.

     After completion of study therapy, patients are followed periodically.

OBJECTIVES:

     Primary

       -  To determine whether the addition of temozolomide to fractionated radiotherapy improves the progression-free survival (PFS) of patients with symptomatic or progressive low-grade gliomas.

       -  To determine whether the addition of temozolomide to fractionated radiotherapy improves the median overall survival (OS) of these patients.

     Secondary

       -  To determine whether combination therapy with temozolomide and radiotherapy improves or maintains cognition and quality of life compared to radiotherapy alone.

       -  To compare the toxicities (severe or worse [≥ grade 3]) of radiotherapy with vs without temozolomide in these patients.

       -  To assess the impact of the presence or absence of 1p and 19q deletion on PFS and OS.

       -  To determine the impact of 1p and 19q status on PFS and OS of patients treated with temozolomide.

       -  To create a tumor and tissue bank, including plasma and germ line DNA, within the ECOG Pathology Coordinating Office.

     OUTLINE: This is a multicenter study. Patients are stratified according to age (< 40 years vs ≥ 40 years), 1p and 19q status (both deleted vs either/both intact vs undeterminable), pre-operative maximum tumor diameter (< 6 cm vs ≥ 6 cm [based on T2 or FLAIR MRI]), Karnofsky performance status (60-70% vs 80-100%), and contrast enhancement on pre-treatment MRI scan (present vs absent). Patients are randomized to 1 of 2 treatment arms.

       -  Arm I: Patients undergo 3-dimensional conformal or intensity-modulated radiotherapy once daily 5 days a week for 5½ weeks (28 fractions).

       -  Arm II: Patients undergo radiotherapy as in arm I and receive concurrent oral temozolomide once daily for 5½ weeks. Beginning 28 days after completion of chemoradiotherapy, patients receive oral temozolomide alone once daily on days 1-5. Treatment with temozolomide repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

     Some patients undergo quality-of-life and neurocognitive (e.g., visual scanning speed, divided attention, language, memory, and fine motor skills) assessments at baseline, annually until disease progression, and at the time of disease progression.

     Tumor tissue samples are collected at baseline for confirmation of diagnosis and determination of 1p and 19q deletion status. Peripheral blood, serum, and additional tumor tissue samples may be collected for further research studies.

     After completion of study treatment, patients are followed up periodically for up to 15 years.