Vemurafenib in Children With Recurrent/Refractory BRAFV600E-mutant Gliomas
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|ClinicalTrials.gov Identifier: NCT01748149|
Recruitment Status : Recruiting
First Posted : December 12, 2012
Last Update Posted : May 9, 2018
|Condition or disease||Intervention/treatment||Phase|
|Pediatric Recurrent/Refractory BRAFV600E-mutant Gliomas||Drug: Vemurafenib||Early Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||54 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||PNOC-002: Safety, Phase 0, and Pilot Efficacy Study of Vemurafenib, an Oral Inhibitor of BRAFV600E, in Children and Young Adults With Recurrent/Refractory BRAFV600E- or BRAF Ins T Mutant Brain Tumors|
|Study Start Date :||February 2014|
|Estimated Primary Completion Date :||January 2019|
|Estimated Study Completion Date :||June 2020|
Vemurafenib should be swallowed whole with 8 oz (1 cup) of water. Pharmacokinetic studies will determine if vemurafenib can be "crushed". If patients receiving "crushed" tablets are felt to receive adequate exposure, then they will be allowed to participate in the expansion cohort. [Patients approved to take "crushed" tablets should use a pill crusher and mix pill with 3-5 ml apple sauce]. If not, then only patients able to swallow whole pills will be eligible.
The patient will be requested to maintain a medication diary of each dose of medication. The medication diary will be returned to clinic staff at the end of each cycle.
Vemurafenib is supplied in 120-mg and 240-mg film-coated tablets packed in bottles for oral administration. Dosing is based on the BSA calculated at the beginning of each course of therapy. The dose prescribed should be rounded to the nearest deliverable dose based on the BSA adjustment and the available pill sizes. Dosing will not exceed the adult MTD of 960 mg BID. Patients will be provided with a Medication Diary for vemurafenib, instructed in its use, and asked to bring the diary with them to each appointment.
Treatment will be administered on an outpatient basis. Dosing is based on the BSA calculated at the beginning of each course of therapy. The dose prescribed should be rounded to the nearest deliverable dose based on the BSA adjustment and the available pill sizes. Regardless of cohort, patients will self-administer vemurafenib BID at the assigned dose level. Patients will be instructed to hold their dose of vemurafenib for PK or surgery.
- Maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) [ Time Frame: Up to 4 weeks ]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)
- Toxicity Profile (dose limiting toxicities) [ Time Frame: Up to 4 weeks ]
To describe the toxicity profile/dose limiting toxicity 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.
- Concentrations of vemurafenib in the blood found through pharmacokinetic samples [ Time Frame: Up to 4 weeks ]
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.
- Objective Response [ Time Frame: Up to 4 weeks ]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 CRFs. The study team will include CR's, 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.
- Intra-tumoral drug concentration Comparison [ Time Frame: Up to 4 weeks ]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-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.
- Progression-free survival [ Time Frame: Up to 6 months ]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.
- Levels of Phospho-ERK Comparison [ Time Frame: Up to 4 weeks ]To examine the levels of Phospho-ERK in patient tumor tissue during vemurafenib therapy then compare those to archived tissue on the same patient.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01748149
|Contact: Theodore Nicolaides, MDemail@example.com|
|Contact: Jenna Weightfirstname.lastname@example.org|
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|Principal Investigator:||Theodore Nicolaides, MD||University of California, San Francisco|