This is a multicenter, safety and pharmacokinetic trial to determine the MTD and/or select a recommended phase 2 dose (RP2D) of vemurafenib in children with recurrent or refractory gliomas containing the BRAFV600E or BRAF Ins T mutation.
Name: Vemurafenib
Description: To determine if the maximum tolerated dose of vemurafenib established in adults is safe and tolerable in pediatric patients with BRAFV600E-mutant gliomas. (Dose is adjusted for pediatric use. Weighted dose extrapolated from FDA approved standard adult dose)
Measure: Maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) Time: Up to 4 weeksDescription: To describe the toxicity profile/dose limiting toxicity (DLT) of vemurafenib in children with recurrent or refractory glioma. DLT will be assessed by monitoring for adverse events, scheduled laboratory assessments, vital sign measurements, ECGs, and physical examinations. The severity of the toxicities will be graded according to the NCI CTCAE v 4.0. Adverse events and clinically significant laboratory abnormalities (meeting Grade 3, 4, or 5 criteria according to CTCAE) will be summarized by maximum intensity and relationship to study drug. Safety will be assessed weekly for the first 4 weeks and then every 4 weeks. Descriptive statistics will be utilized to display the data on toxicity seen. Safety will be assessed weekly for the first 4 weeks and then every 4 weeks. Descriptive statistics will be utilized to display the data on toxicity seen.
Measure: Toxicity Profile (dose limiting toxicities) Time: Up to 4 weeksDescription: Venous blood samples (2 mL) will be collected in sodium heparin to measure concentrations of vemurafenib for each PK blood collection. To characterize the pharmacokinetics of vemurafenib in pediatric patients. Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and graphical form. Mandatory plasma pharmacokinetic studies will be performed in all patients enrolled on the MTD, pre-surgical, and "crushed" pill cohorts of this trial. Because the pharmacokinetics of this agent are unknown in the pediatric population, this information will be essential for evaluating toxicity and disease response and for refining dosing in future clinical trials of vemurafenib.
Measure: Concentrations of vemurafenib in the blood found through pharmacokinetic (PK) samples Time: Up to 4 weeksDescription: To document antitumor activity of treatment with vemurafenib, as measured by objective responses.Objective response will be assessed using the RECIST Response criteria. The response will be collected on case report forms (CRFs). The study team will include complete responses (CR's), partial responses (PR's) and sustained stable disease (SSD- defined as stable disease on two successive scans). The target response rate is 20%. The number and percent of subjects with each type of response will be summarized and presented in data listings.
Measure: Objective Response Time: Up to 4 weeksDescription: Subsequent to the safety cohort, the study team will begin enrollment into a presurgical study. Patients who are candidates for surgical resection at the time of relapse, would be eligible for this component of the trial. The aim will be to measure drug levels (based on the dose chosen in the safety cohort) in tumor, with an additional aim to describe target modulation, with vemurafenib treated tumor compared with corresponding archived tissue from prior surgery. Tumor phospho-extracellular signal-regulated kinase (ERK) levels will be used as a molecular readout for agent activity. Drug levels will be measured by liquid chromatography/Mass spec. The statistical analysis will be descriptive and will be limited to frequency tables and summary statistics.
Measure: Intra-tumoral drug concentration Comparison Time: Up to 4 weeksDescription: Progression-free survival at 6 months (PFS6) is defined as the proportion of patients alive and progression-free 180 days after Study Day 1. Duration of PFS is defined as the time from Study Day 1 to the earlier of disease progression or death due to any cause. All patients included in the study must be assessed for PFS6, even if there are major protocol treatment deviations or if they are ineligible.
Measure: Progression-free survival Time: Up to 6 monthsDescription: To examine the levels of Phospho-ERK in patient tumor tissue during vemurafenib therapy then compare those to archived tissue on the same patient.
Measure: Levels of Phospho-ERK Comparison Time: Up to 4 weeksAllocation: N/A
Single Group Assignment
There is one SNP
Vemurafenib in Children With Recurrent/Refractory BRAF Gene V600E (BRAFV600E)-Mutant Gliomas This is a multicenter, safety and pharmacokinetic trial to determine the MTD and/or select a recommended phase 2 dose (RP2D) of vemurafenib in children with recurrent or refractory gliomas containing the BRAFV600E or BRAF Ins T mutation. --- V600E ---