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Publications (312)
BACKGROUND
The study aimed to evaluate whether simplified chemotherapy followed by dose-reduced irradiation was effective for treating patients (ages 3-21 years) with localized germinoma. The primary endpoint was 3-year progression free survival (PFS) rate.
METHODS
Patients with a complete response to chemotherapy with carboplatin and etoposide re...
Intracranial germ cell tumors represent 3-5% of pediatric CNS tumors. Non-germinomatous germ cell tumors (NGGCT) have worse outcomes compared to germinomas, however, improved survivals were achieved on COG ACNS0122 utilizing a combination of chemotherapy and craniospinal irradiation (CSI). Since CSI is associated with significant late effects, a Ph...
Background
We evaluated circulating levels of immunosuppressive regulatory T cells (Tregs) and other lymphocyte subsets in patients with newly diagnosed medulloblastoma (MBL) undergoing surgery compared to a control cohort of patients undergo craniectomy for correction of Chiari malformation (CM) and further determined the impact of standard irradi...
Background:
We conducted a phase II study of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy (RT) to assess progression-free survival (PFS) in children with newly diagnosed diffuse intrinsic pontine gliomas (DIPG).
Patients and methods:
Children 3-17 years with newly diagnosed DIPG were eligible. Capeci...
A greater understanding of the Ras-MAP kinase-signaling pathway in pediatric low-grade glioma (LGG) has led to the ability to target this pathway with therapeutic intent. The PBTC conducted a multi-institutional phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/refractory LG...
Background.:
Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG.
Methods.:
Selumetinib was adm...
Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted an investigator-sponsored molecular biology (MB) and phase II study to estimate inhibition of tumor te...
Background:
The outcomes with high-risk central nervous system (CNS) embryonal tumors remain relatively poor despite aggressive treatment. The purposes of this study using postirradiation myeloablative chemotherapy with autologous hematopoietic stem cell rescue (ASCR) were to document feasibility and describe toxicities of the regimen, establish t...
Sunitinib malate is a small multi-targeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and stem cell factor receptor (KIT), which are highly expressed by some high-grade brain tumors. We conducted a phase II study to estimate the efficacy and further ch...
Table S1. Primary off treatment reasons by stratum Supplemental Table II. Compartmental Pharmacokinetic Parameters for Sunitinib and SU012662.
Table S2. Compartmental Pharmacokinetic Parameters for Sunitinib and SU012662.
Background:
p53 is a promising target in human cancer. p28 is a cell-penetrating peptide that preferentially enters cancer cells and binds to both wild-type and mutant p53 protein, inhibiting COP1-mediated ubiquitination and proteasomal degradation. This results in increased levels of p53, which induces cell cycle arrest at G2/M. We conducted a ph...
OBJECT
The impact of central pathology review on outcome has been described in pediatric patients with high-grade glioma (HGG). The objective of this report was to analyze the impact of the central pathology review on outcome in the subgroup of patients with institutional diagnosis of HGG of the spinal cord enrolled in the Children's Cancer Group 9...
Background:
Diffuse intrinsic pontine glioma (DIPG) is associated with poor survival regardless of therapy. We used volumetric apparent diffusion coefficient (ADC) histogram metrics to determine associations with progression-free survival (PFS) and overall survival (OS) at baseline and after radiation therapy (RT).
Methods:
Baseline and post-RT...
Cediranib (AZD2171), an oral pan-vascular endothelial growth factor (VEGF) inhibitor, was evaluated in this phase I study to determine its toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics in children and adolescents with recurrent or refractory primary central nervous system (CN...
Two phase II studies assessed the efficacy of vismodegib, a sonic hedgehog (SHH) pathway inhibitor that binds smoothened (SMO), in pediatric and adult recurrent medulloblastoma (MB).
Adult patients enrolled onto PBTC-025B and pediatric patients enrolled onto PBTC-032 were treated with vismodegib (150 to 300 mg/d). Protocol-defined response, which h...
Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted an investigator-sponsored molecular biology (MB) and phase II study to estimate inhibition of tumor te...
BACKGROUND: Pre-clinical evaluation of vorinostat and isotretinoin demonstrated cytotoxicity in medulloblastoma (MB) and synergistic activity when combined with cisplatin. This study sought to evaluate the feasibility of combining vorinostat and isotretinoin with cytotoxic chemotherapy in young children with newly diagnosed brain tumors. METHODS: E...
Supratentorial PNETs (sPNET) are uncommon embryonal malignancies of the central nervous system whose prognosis has historically been poor. We evaluated the outcome and prognostic factors of children with sPNET treated prospectively on a Children's Oncology Group trial.
Following surgery, patients received craniospinal radiotherapy with concurrent c...
Aurora Kinase A (AURKA) encodes a protein that regulates the formation and stability of the mitotic spindle and is highly active in atypical teratoid rhabdoid tumors (ATRT) through loss of the INI1 tumor suppressor gene. Alisertib (MLN8237) inhibits AURKA in vitro and in vivo. Given the strong preclinical data supporting the use of alisertib for AT...
Objective:
The purpose of the study (conducted 2010-2013) was to determine the efficacy of two common types of tobacco quitlines in adult cancer survivors who regularly smoked cigarettes.
Method:
Adult onset cancer survivors in Memphis, Tennessee (n=427, 67% female, 60% Caucasian) were randomized either to a Proactive (i.e., counselor-initiated...
Children with high-grade glioma (HGG) have a poor prognosis compared to those with low-grade glioma (LGG). Adjuvant chemotherapy may be beneficial, but its optimal use remains undetermined. Histology and extent of resection are important prognostic factors. We tested the hypothesis that patients with midline HGG treated on Children's Cancer Group S...
We sought to estimate the maximum tolerated or recommended phase 2 dose and describe the pharmacokinetics and toxicities of enzastaurin, an oral inhibitor of protein kinase Cβ, in children with recurrent central nervous system malignancies.
Enzastaurin was administered continuously once daily at 3 dose levels (260, 340, and 440 mg/m(2)) and twice d...
PTC299 is a novel, orally-bioavailable small molecule that selectively inhibits vascular endothelial growth factor receptor protein synthesis at the post-transcriptional level. Based on promising preclinical results, we conducted a pediatric phase I study to estimate the maximum tolerated dose, describe dose-limiting toxicities (DLT) and characteri...
Introduction:
The purpose of this investigation was to determine the efficacy of two evidence-based tobacco quitlines in adult survivors of childhood cancer who regularly smoke cigarettes.
Methods:
A total of 519 adult survivors of childhood cancer were randomized to either Proactive + 4 weeks of medication (Counselor-initiated intervention, n =...
Background
Female survivors of central nervous system (CNS) tumors are at an increased risk for gonadal damage and variations in the timing of puberty following radiotherapy and alkylating agent-based chemotherapy.ProcedureClinical and laboratory data were obtained from 30 evaluable female patients with newly diagnosed embryonal CNS tumors treated...
Glioblastoma is the most common primary brain malignancy and is associated with poor prognosis despite aggressive local and
systemic therapy, which is related to a paucity of viable treatment options in both the newly diagnosed and recurrent settings.
Even so, the rapidly increasing number of targeted therapies being evaluated in oncology clinical...
Unlabelled:
The purpose of this study was to describe (18)F-FDG uptake across a spectrum of pediatric brain tumors and correlate (18)F-FDG PET with MR imaging variables, progression-free survival (PFS), and overall survival (OS).
Methods:
A retrospective analysis was conducted of children enrolled in phase I/II clinical trials through the Pediat...
Background:
A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to (i) estimate the maximum tolerated doses (MTDs) or recommended phase II doses (RP2Ds) of veliparib and TMZ; (ii) describe the toxicities of this regimen; and (iii)...
BACKGROUND: In recurrent neuroectodermal brain tumors leptomeningeal disease manifestation was observed in about 50 to 75%
of patients. The role and efficacy of intrathecal therapy in these patients is unclear. As the systemic administration of
etoposide is efficacious in brain tumors a phase II study was initiated to evaluate the efficacy and safe...
We sought to improve lumbar spine bone mineral density (LS-BMD) in long-term survivors of childhood acute lymphoblastic leukemia (ALL) using calcium and cholecalciferol supplementation.
This double-blind, placebo-controlled trial randomized 275 participants (median age, 17 [9-36.1] years) with age- and gender-specific LS-BMD Z-scores <0 to receive...
Background: Epidermal growth factor receptor is overexpressed in most pediatric high-grade gliomas (HGG). Since erlotinib had shown activity in adults with HGG, we conducted a phase II trial of erlotinib and local radiotherapy (RT) in children with newly diagnosed HGG.
Methods: Following maximum surgical resection, patients between 3 and 21 years w...
Survival rates for children with medulloblastoma have risen over the past decade, in part due to the addition of cisplatin-containing adjuvant chemotherapy. Total dose of cisplatin required for optimal treatment is unknown. The purpose of this study was to evaluate the survival outcomes based on cumulative cisplatin doses (CCD) in children with new...
Background
The randomized controlled Pediatric Oncology Group study 9233 tested the hypothesis that dose-intensive (DI) chemotherapy would improve event-free survival (EFS) for children <3 years of age with newly diagnosed malignant brain tumors.Methods
Of 328 enrolled eligible patients, diagnoses were medulloblastoma (n = 112), ependymoma (n = 82)...
BackgroundA phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent low-grade glioma to measure sustained response and/or stable disease lasting ≥6 months and progression-free survival.Methods
Thirty-five evaluable patients received 2 doses (10 mg/kg each) of single-agent BVZ intravenously 2 weeks apart...
The incidence and spectrum of acute toxicities related to the use of bevacizumab (BVZ)-containing regimens in children are largely unknown. This report describes the adverse events in a recently completed large phase 2 trial of BVZ plus irinotecan (CPT-11) in children with recurrent central nervous system tumors.
Pediatric Brain Tumor Consortium tr...
To investigate the safety, dose-limiting toxicities, and pharmacokinetics of the smoothened inhibitor vismodegib in children with refractory or relapsed medulloblastoma.
Initially, vismodegib was administered daily at 85 mg/m2 and escalated to 170 mg/m2. The study was then revised to investigate a flat-dosing schedule of 150 mg for patients with sm...
High expression of ERBB2 has been reported in medulloblastoma and ependymoma; EGFR is amplified and over-expressed in brainstem glioma suggesting these proteins as potential therapeutic targets. We conducted a molecular biology (MB) and phase II study to estimate inhibition of tumor ERBB signaling and sustained responses by lapatinib in children wi...
2035
Background: Almost 80% of adult medulloblastoma are of the SHH subtype. Second line therapy for adult MB is limited; therefore we tested the efficacy of vismodegib, a small molecule inhibitor of Smoothened (SMO) among patients with this disease. Methods: Adult patients with refractory or recurrent MB and who had measureable disease were enroll...
2036
Background: A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to: 1) estimate the maximum tolerated doses (MTD) or recommended phase II doses (RP2D) of veliparib and TMZ using the Continual Reassessment Method; 2) describe t...
Background
We conducted a phase I study to estimate the maximum tolerated dose and describe the dose-limiting toxicities and pharmacokinetics of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy to children with newly diagnosed brainstem or high-grade gliomas.Methods
Children 3-21 y with newly diagnosed intr...
Purpose:
We performed a phase-1 pharmacokinetic optimal dosing study of intraventricular topotecan (IT), administered daily 5×, to determine whether, the maximum tolerated dose of IT topotecan was also the pharmacokinetic optimal dose.
Patients and methods:
Patients received topotecan administered through an intraventricular access device (0.1 o...
Purpose:
Associations of radiation therapy (RT) deviations and outcomes in medulloblastoma have not been defined well, particularly in the era of reduced-dose craniospinal irradiation and chemotherapy. The aim of this study is to evaluate the quality of RT on Children's Cancer Group/Pediatric Oncology Group 9961 and analyze associations of RT devi...
A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in cases of pediatric recurrent ependymoma (EPN) to estimate sustained objective response rate and progression-free survival (PFS). Eligible patients received 2 doses of single-agent BVZ intravenously (10 mg/kg) 2 weeks apart and then BVZ + CPT-11 every 2 weeks until progr...
A pilot study to investigate the feasibility of the addition of intrathecal (IT) mafosfamide to a regimen of concomitant multi-agent systemic chemotherapy followed by conformal radiation therapy (RT) for children <3 years with newly diagnosed embryonal CNS tumors was performed. Ninety-three newly diagnosed infants and children (<3 years) with embry...
To estimate the sustained (≥8 weeks) objective response rate in pediatric patients with recurrent or progressive high-grade gliomas (HGG, Stratum A) or brainstem gliomas (BSG, Stratum B) treated with the combination of O6-benzylguanine (O6BG) and temozolomide(®) (TMZ). Patients received O6BG 120 mg/m(2)/d IV followed by TMZ 75 mg/m(2)/d orally dail...
To estimate the maximum-tolerated dose (MTD), describe dose-limiting toxicities (DLTs), and characterize pharmacokinetic properties of MK-0752, a gamma secretase inhibitor, in children with refractory or recurrent CNS malignancies.
MK-0752 was administered once daily for 3 consecutive days of every 7 days at escalating dosages starting at 200 mg/m(...
Histopathological grading of ependymoma has been controversial with respect to its reproducibility and clinical significance. In a 3-phase study, we reviewed the pathology of 229 intracranial ependymomas from European trial cohorts of infants (2 trials - SFOP/CNS9204) and older children (2 trials - AIEOP/CNS9904) to assess both diagnostic concordan...
This phase II study was designed to assess the safety and efficacy of gefitinib given with and following radiation therapy in children newly diagnosed with a poor prognosis brainstem glioma. Eligible patients were those with a previously untreated nondisseminated diffuse intrinsic brainstem glioma. Histological confirmation was not required, provid...
We performed a phase II study to assess the efficacy and toxicity of tipifarnib, a farnesyltransferase inhibitor, administered with radiation therapy (RT) in children with newly diagnosed diffuse intrinsic pontine gliomas. Children 3-21 years old with pontine gliomas (BSGs) were treated with concurrent tipifarnib and RT, followed by adjuvant tipifa...
Successfully evaluating pathologists' acumen could be very useful in improving the concordance of their calls on histopathologic variables. We are proposing a new method to estimate the reviewers' acumen based on their histopathologic calls. The previously proposed method includes redundant parameters that are not identifiable and results are incor...
To determine whether shortening the infusion duration of high-dose methotrexate (HDMTX; 1 g/m(2)) affects the in vivo accumulation of active methotrexate polyglutamates (MTXPG(1-7)) in leukemia cells and whether this differs among major acute lymphoblastic leukemia (ALL) subtypes.
From June 2000 through October 2007, 356 children with ALL were rand...
The purpose of this study was to assess (18)F-FDG uptake in children with a newly diagnosed diffuse intrinsic brain stem glioma (BSG) and to investigate associations with progression-free survival (PFS), overall survival (OS), and MRI indices.
Two Pediatric Brain Tumor Consortium (PBTC) therapeutic trials in children with newly diagnosed BSG were d...
We report MRI findings from 2 pediatric clinical trials of diffuse intrinsic brainstem glioma (BSG) incorporating concurrent radiation therapy (RT) with molecularly targeted agents (gefitinib and tipifarnib). We determined associations of MRI variables with progression-free survival and overall survival and investigated effects of treatment on thes...
A phase I trial of lenalidomide was performed in children with recurrent, refractory, or progressive primary CNS tumors to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile and pharmacokinetics.
Lenalidomide was administered by mouth daily for 21 days, repeated every 28 days. The starting dose was 15 mg/m(2)/d orally, a...
To estimate the maximum-tolerated dose (MTD); study the pharmacology of escalating doses of gefitinib combined with radiation therapy in patients ⩽21 years with newly diagnosed intrinsic brainstem gliomas (BSG) and incompletely resected supratentorial malignant gliomas (STMG); and to investigate epidermal growth factor receptor (EGFR) amplification...
To assess changes in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values in brainstem gliomas (BSG) in children and to observe the temporal evolution of changes in the white matter tracts following therapy using diffusion tensor imaging (DTI) analysis.
Serial ADC and FA measurements were obtained in three patients with newly...
To estimate the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetic properties of lapatinib, a selective epidermal growth factor receptor (EGFR) and ERBB2 inhibitor, in children with refractory or recurrent CNS malignancies.
Lapatinib was administered orally twice daily at escalating doses starting at 300 mg/m(2) to patient...
CRA9501
Background:Aberrant signaling in SHH pathway is implicated in causing medulloblastoma in approximately 20% of children with this disease. GDC-0449 is an orally active agent that binds to the SMO receptor and prevents downstream signaling through GLI. Preclinical murine models predict efficacy of an SMO antagonist to treat tumors dependent o...
A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent malignant glioma (MG) and intrinsic brainstem glioma (BSG).
Eligible patients received two doses of BVZ intravenously (10 mg/kg) 2 weeks apart and then BVZ plus CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum o...
