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BackgroundActivation 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.MethodsSelumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course. BRAF aberrations in tumor tissue were determined by real-time polymerase chain reaction and fluorescence in situ hybridization.ResultsThirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2-3 rash (n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, the median (range) area under the curve (AUC0-∞) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng × h/mL) and 6.5 L × h-1 × m-2 (3.4 to 14.0 L × h-1 × m-2), respectively. Thirteen of 19 tumors had BRAF abnormalities. Among the 5 (20%) of 25 subjects with sustained partial responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. Subjects received a median of 13 cycles (range: 1-26). Fourteen (37%) completed all protocol treatment (26 cycles [n = 13], 13 cycles [n = 1]) with at least stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 9.8%.ConclusionSelumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.

PurposeTwo 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).Patients and methodsAdult 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 had to be sustained for 8 weeks, was confirmed by central neuroimaging review. Molecular tests to identify patterns of response and insensitivity were performed when tissue was available.ResultsA total of 31 patients were enrolled onto PBTC-025B, and 12 were enrolled onto PBTC-032. Three patients in PBTC-025B and one in PBTC-032, all with SHH-subgroup MB (SHH-MB), exhibited protocol-defined responses. Progression-free survival (PFS) was longer in those with SHH-MB than in those with non-SHH-MB, and prolonged disease stabilization occurred in 41% of patient cases of SHH-MB. Among those with SHH-MB, loss of heterozygosity of PTCH1 was associated with prolonged PFS, and diffuse staining of P53 was associated with reduced PFS. Whole-exome sequencing identified mutations in SHH genes downstream from SMO in four of four tissue samples from nonresponders and upstream of SMO in two of four patients with favorable responses.ConclusionVismodegib exhibits activity against adult recurrent SHH-MB but not against recurrent non-SHH-MB. Inadequate accrual of pediatric patients precluded conclusions in this population. Molecular analyses support the hypothesis that SMO inhibitor activity depends on the genomic aberrations within the tumor. Such inhibitors should be advanced in SHH-MB studies; however, molecular and genomic work remains imperative to identify target populations that will truly benefit.

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 trials offers hope for the future. Given the broad range of possibilities for future trials, the Brain Malignancy Steering Committee convened a clinical trials planning meeting that was held at the Udvar-Hazy Center in Chantilly, Virginia, on September 19 and 20, 2013. This manuscript reports the deliberations leading up to the event from the Targeted Therapies Working Group and the results of the meeting.

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 Study (CCG) CCG-945 have a worse prognosis compared to the entire group. Of 172 children eligible for analysis, 60 had midline tumors primarily localized to the thalamus, hypothalamus and basal ganglia. Time-to-progression and death were determined from the date of initial diagnosis, and survival curves were calculated. Univariate analyses were undertaken for extent of resection, chemotherapy regimen, anatomic location, histology, proliferation index, MGMT status and p53 over-expression. For the entire midline tumor group, 5-year PFS and OS were 18.3 ± 4.8 and 25 ± 5.4 %, respectively. Many patients only had a biopsy (43.3 %). The sub-groups with near/total resection and hypothalamic location appeared to have better PFS and OS. However, the effect of tumor histology on OS was significant for children with discordant diagnoses on central pathology review of LGG compared to HGG. Proliferative index (MIB-1 > 36 %), MGMT and p53 over-expression correlated with poor outcomes. Children treated on CCG-945 with midline HGG have a worse prognosis when compared to the entire group. The midline location may directly influence the extent of resection. Central pathology review and entry of patients on clinical trials continue to be priorities to improve outcomes for children with HGG.

A study was conducted to evaluate whether cranial irradiation could be excluded as a form of treatment among children with acute lymphoblastic leukemia (ALL). Results indicated that stopping such a form of treatment could be safely omitted with effective risk-adjusted chemotherapy.

Children with gliomas that contain high levels of p53 protein have a poor prognosis. Gliomas are a type of brain tumor. In a study of 231 children, survival rates were 44% in those with low levels of p53 protein and 17% in those with high levels.

Tailoring chemotherapy to a child's metabolic rate may improve prognosis in children with certain types of acute lymphoblastic leukemia. Children metabolize drugs differently and those who metabolize drugs quickly may not benefit as well from chemotherapy. Researchers randomly assigned 182 children with acute lymphoblastic leukemia to receive chemotherapy based on their body surface area or on their metabolic rate. Tailoring the drug dosage to the metabolic rate improved prognosis, but only in children with leukemia of the B cell line.

Granulocyte colony-stimulating factor (G-CSF) may reduce the incidence of infection in children with neutropenia but it appears to have few other benefits. Neutropenia is a drop in white blood cells called neutrophils often caused by chemotherapy. Researchers gave daily injections of G-CSF or placebo to 148 children with chemotherapy-induced neutropenia. Children receiving G-CSF had a lower rate of infections, but G-CSF did not reduce hospitalization rates, prolong survival or reduce medical care costs.

Black children and white, Hispanic, and Asian children with cancer who have equal access to contemporary therapy appear to have similar survival rates. Researchers compared the survival rates in 798 black children with various forms of cancer with the rates in 4,507 white, Hispanic, and Asian children with various cancers. The patients were treated between January, 1962 and June, 1992 regardless of their families' ability to pay. Among the children who received care before the advent of major treatment advances, the overall 10-year cancer survival rate was 37% in black children and 50% in the other children. Among the children who were treated after the advent of major therapeutic advances, the 10-year survival rate was 67% in blacks and 66% in the others. The improved treatment outcome observed in black children is largely due to a higher survival rate in those with acute lymphoblastic leukemia., Objective.--To determine whether there is a racial difference in prognosis among childhood cancers. Design.--An overall (30-year) survival analysis by race was followed by separate studies for "early" and "recent" treatment eras, defined by time points at which significantly improved outcome was demonstrated for specific tumor types. Stratified analyses were performed to adjust for recognized prognostic features. Setting.--Pediatric oncology research and treatment center. Patients.--The study included 798 black and 4507 white children with newly diagnosed malignancies treated from January 1962 through June 1992. These patients were accepted for treatment regardless of their financial status and were enrolled on disease-specific protocols. Results.--Across the 30-year study period, black children had a significantly poorer rate of survival than white children (P