Clinical Trials

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.

PRIMARY OBJECTIVES: I. Determine if treatment of pediatric patients with newly diagnosed supratentorial primitive neuroectodermal CNS tumors or high-risk medulloblastoma with intensive induction chemotherapy comprising vincristine, etoposide, cyclophosphamide, and cisplatin in combination with high-dose methotrexate and leucovorin calcium followed by consolidation chemotherapy comprising carboplatin and thiotepa and peripheral blood stem cell rescue results in a higher complete response rate then in patients treated with the same regimen without high-dose methotrexate and leucovorin calcium. SECONDARY OBJECTIVES: I. Determine whether biologic characterization of these tumors will refine therapeutic stratification separating atypical teratoid rhabdoid tumors from primitive neuroectodermal tumors (PNETs) and possibly identifying other markers of value for stratification within the group of PNETs. II. Compare event-free survival and patterns of failure in patients treated with these regimens. III. Compare the acute, chronic, and late effects of these regimens, particularly in terms of tolerance to the same consolidation regimen after treatment with 2 different induction regimens, in these patients. IV. Compare the gastrointestinal and nutritional toxicities of these regimens in these patients. V. Compare the quality of life outcomes in patients treated with these regimens. VI. Compare the neuropsychological effects of these regimens in these patients. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to diagnosis* (M0 medulloblastoma with ≥ 1.5 cm² residual tumor vs M1 medulloblastoma [positive lumbar CSF cytology] vs M2, M3, or M4 medulloblastoma vs supratentorial PNET [any M-stage] vs M0 medulloblastoma < 8 months without residual disease or with < 1.5 cm² radiographic measurable residual tumor vs anaplastic M0 medulloblastoma without residual disease or with < 1.5 cm² radiographic measurable residual vs classic M0 (nondesmoplastic) medulloblastoma with < 1.5 cm² radiographic measurable residual tumor). NOTE: *All diagnoses are for children < 36 months unless otherwise noted. INDUCTION THERAPY: Patients are randomized to 1 of 2 induction treatment arms. ARM I: Patients receive vincristine IV on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3; and filgrastim (G-CSF) IV or subcutaneously (SC) beginning on day 4 and continuing until blood counts recover. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive vincristine IV on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or orally every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Once methotrexate levels are in a safe range, patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Patients also receive G-CSF IV or SC beginning 24 hours after the completion of chemotherapy and continuing until blood counts recover. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. In both arms, patients with stable disease or partial response after induction therapy proceed to second-look surgery followed by consolidation therapy. Patients with a complete response after induction therapy proceed directly to consolidation therapy. CONSOLIDATION THERAPY: Beginning no more than 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 54 and continuing until blood counts recover. Patients also receive autologous peripheral blood stem cells (PBSC) IV on day 4. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Blood and tissue samples are collected at baseline for correlative studies, including gene expression profiling, biological marker analysis (i.e., cMyc, ErbB2/ErbB4), comparative genome analysis, and mutation analysis. After completion of study therapy, patients are followed up periodically for 4 years and then annually thereafter.

OBJECTIVES:

     Primary

       -  Determine the safety and toxicity of intratumoral and/or resection cavity administration of a recombinant, attenuated Edmonston B vaccine strain derivative of measles virus genetically engineered to produce human carcinoembryonic antigen (CEA) in patients with recurrent glioblastoma multiforme.

       -  Determine the maximum tolerated dose of this oncolytic virus in these patients.

       -  Determine viral gene expression at each dose level as manifested by CEA titers in patients treated with this oncolytic virus.

       -  Assess viremia, viral replication, and measles virus shedding/persistence after intratumoral administration of this oncolytic virus.

       -  Assess humoral and cellular immune response to the injected virus in these patients.

     Secondary

       -  Determine, preliminarily, the antitumor efficacy of this vaccine in these patients.

     OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 sequential treatment groups.

       -  Group 1 (resection cavity administration): Patients undergo en block resection of their tumor (after confirming diagnosis) on day 1, followed by recombinant measles virus encoding human carcinoembryonic antigen (MV-CEA) administered into the resection cavity over 10 minutes.

       -  Group 2 (intratumoral and resection cavity administration): Patients undergo placement of a catheter within the tumor, followed by MV-CEA administration into the tumor through the catheter over 10 minutes on day 1. Patients undergo en block resection of their tumor with computer-assisted stereotactic techniques on day 5, followed by MV-CEA administered around the tumor bed.

     In both groups, cohorts of 1-6 patients receive escalating doses of MV-CEA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD in group 1 has been determined, patients are assigned to group 2. The MTD in group 1 is used to determine the starting dose in group 2. At least 10 patients are treated at the MTD determined in group 2.

     Biopsy specimen, resected tumor, normal tissue, and peripheral blood are collected during study for immunologic and biomarker correlative studies, including analysis of CD46 receptor levels (by immunohistochemistry [IHC]), measles virus N protein (by IHC), measles and viral gene expression and replication (by in situ hybridization), CEA monitoring (by immunoassay), measles virus N mRNA (by reverse transcriptase-polymerase chain reaction), and measles virus immunity. Assessments of immune competence and peripheral response to viral administration are also performed.

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

     PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

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.

PRIMARY OBJECTIVES:

     l. To compare the overall survival (OS) of subjects receiving the combination of temozolomide and irinotecan with that of subjects receiving temozolomide, irinotecan, and bevacizumab for recurrent medulloblastoma (MB)/PNET of childhood.

     SECONDARY OBJECTIVES:

     I. To assess the response rate for each treatment arm. II. To determine event-free survival (EFS) for each patient compared across regimens.

     OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms.

     ARM I: Patients receive oral temozolomide and irinotecan hydrochloride IV over 90 minutes on days 1-5.

     ARM II: Patients receive oral temozolomide and irinotecan hydrochloride IV as in arm I and bevacizumab IV over 30-90 minutes on days 1 and 15.

     In both arms, treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

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

OBJECTIVES: - To evaluate the diagnostic and prognostic relevance of various molecular, cytogenetic, and other tumor markers in high-grade glioma in paraffin-embedded tissue collected from patients enrolled in the Mayo Clinic or North Central Cancer Treatment Group (NCCTG) high-grade glioma trials conducted since 1979. - To evaluate alterations of specific chromosomes and chromosomal regions including 7, 9p, 10p, 10q, 13q, 17p, 17q, 19q, 22q, X, and Y using PCR analysis of microsatellite repeats and FISH. - To determine DNA ploidy by flow cytometric analysis. - To examine various markers of cellular proliferation and cellular function including flow cytometric determination of %S-phase, %G2M, and immunohistochemical evaluation of PCNA, Ki-67, and p53. - To evaluate additional markers identified by the Glioma Markers Network. - To compare the incidence of markers in the major histologic subtypes (anaplastic astrocytoma [AA], anaplastic oligoastrocytoma [AOA], glioblastoma multiforme [GBM]) and to assess their correlation in the total group, as well as within each of these subtypes. - To compare the ploidy determinations by FISH and flow cytometry. OUTLINE: Paraffin-embedded tissue and peripheral blood samples, previously or currently collected from clinical trials participants at the time she/he enrolled in the trial, are evaluated for as many markers as possible, changes in cytogenic and molecular genetic tumor markers, frequency distributions of all tumor markers and histological and clinical variables by polymerase chain reaction, IHC, flow cytometry, and FISH analysis.

OBJECTIVES: Primary - To ascertain in patients with one to four brain metastases whether there is improved overall survival in patients who receive stereotactic radiosurgery (SRS) to the surgical bed compared to patients who receive whole-brain radiotherapy (WBRT). - To ascertain in patients with one to four brain metastases whether there is less neurocognitive progression at 6 months post-radiation in patients who receive SRS to the surgical bed compared to patients who receive WBRT. Secondary - To ascertain in patients with resected brain metastases whether there is improved quality-of-life (QOL) in patients who receive SRS to the surgical bed compared to patients who receive WBRT. - To ascertain in patients with one to four brain metastases whether there is equal longer time to central nervous system (CNS) failure (brain) in patients who receive SRS to the surgical bed compared to patients who receive WBRT. - To ascertain in patients with one to four brain metastases whether there is longer duration of functional independence in patients who receive SRS to the surgical bed compared to patients who receive WBRT. - To ascertain in patients with one to four brain metastases whether there is better long-term neurocognitive status in patients who receive SRS to the surgical bed compared to patients who receive WBRT. - To tabulate and descriptively compare the post-treatment adverse events associated with the interventions. - To evaluate local tumor bed recurrence at 6 months with post-surgical SRS to the surgical bed in comparison to WBRT. - To evaluate time to local recurrence with post-surgical SRS to the surgical bed in comparison to WBRT. - To evaluate if there is any difference in CNS failure patterns (local, distant, leptomeningeal) in patients who receive SRS to the surgical bed compared to patients who receive WBRT. Exploratory - To evaluate radiation changes in the limbic system that may correlate with neurotoxicity using brain MRI scans. - To determine whether Apo E (i.e., Apo E2, Apo E3, and Apo E4) genotyping may prove to be a predictor of radiation-induced neurocognitive decline (or neuroprotection). - To determine whether inflammatory markers (i.e., IL-1, IL-6, and TNF-α) may prove to be predictors of radiation-induced neurocognitive decline. - To determine whether oxidative stress biomarkers (i.e., protein carbonyl content, lipid hydroperoxides, and isoprostane levels) may prove to be predictors of radiation-induced neurocognitive decline. - To determine whether hormone and growth factors [i.e., glucocorticoids (e.g., cortisol), gonadal steroids (e.g., estradiol, testosterone, progesterone), growth hormone, human chorionic gonadotropin (hCG), insulin-like growth factor-1 (IGF-1), and neuronal growth factor (NGF)] may prove to be a predictor of radiation-induced neurocognitive decline. OUTLINE: This is a multicenter study. Patients are stratified according to age in years (< 60 vs ≥ 60), extracranial disease controlled (≤ 3 months vs > 3 months), number of pre-operative brain metastases (1 vs 2-4), histology (lung vs radioresistant [brain metastases from a sarcoma, melanoma, or renal cell carcinoma histology] vs other), and resection cavity maximal diameter (≤ 3 cm vs > 3 cm). Patients are randomized to 1 of 2 treatment arms. - Arm I: Patients undergo whole-brain radiotherapy (WBRT) once a day, 5 days a week, for approximately 3 weeks. - Arm II: Patients undergo stereotactic radiosurgery (SRS) using a gamma knife or a linear accelerator procedure. Serum, whole blood, and urine samples are collected at baseline and periodically during study for genetic markers, inflammatory markers, oxidative stress biomarkers, and hormone and growth factor studies by ELISA and other assays. Patients complete the Functional Assessment of Cancer Therapy-Brain (FACT-BR), the activities of daily living (ADLs), the Fatigue/Uniscale Assessment, and the Linear Analog Self Assessment (LASA) quality-of-life questionnaires at baseline and periodically during study. Neurocognitive functions, such as memory, verbal fluency, visual attention, executive function, and delayed memory, are also assessed. After completion of study therapy, patients are followed up periodically for 5 years.