Vemurafenib in Children With Recurrent/Refractory BRAF Gene V600E (BRAFV600E)-Mutant Gliomas

NCT01748149 | Completed Early Phase 1 DMC FDA Drug

• 2 other identifiers: 120819NCI-2014-00387
• Study Type: interventional
• Target: 40
• Locations: 2 countries
• Sites: 21

Brief Summary

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.

Conditions

Pediatric Recurrent/Refractory BRAFV600E-mutant Gliomas

Keywords

recurrent/refractory BRAFV600E-mutant gliomas; pediatrics; children; neo-adjuvant vemurafenib

Outcome Measures

Primary Outcomes (4)

• Maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D)

  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)

  Up to 4 weeks

• Proportion of participants with dose limiting toxicities

  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.

  Up to 4 weeks

• Median concentrations of vemurafenib in the blood found through pharmacokinetic (PK) samples

  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.

  Up to 4 weeks

• Objective Response Rate

  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.

  Up to 4 weeks

Secondary Outcomes (2)

• Median Intra-tumoral drug level concentration

  Up to 4 weeks

• Progression-free survival

  Up to 6 months

Study Arms (1)

Vemurafenib

EXPERIMENTAL

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.

Drug: Vemurafenib

Interventions

Vemurafenib DRUG

Vemurafenib is supplied in 120-mg and 240-mg film-coated tablets packed in bottles for oral administration. Dosing is based on the body surface area (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 twice a day (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.

Also known as: RO5185426, PLX4032

Vemurafenib

Eligibility Criteria

• Age: Up to 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patients with histologically confirmed diagnosis of glioma (WHO Grades I-IV) will be eligible. Patient tumors must test positive for the BRAFV600E mutation at University of California, San Francisco (UCSF) Molecular Pathology central laboratory. If mutation cannot be confirmed from a prior test and archival tumor is not available to confirm presence of BRAFV600E mutation, patients must have tumor biopsy to collect tumor sample for mutation confirmation.
• Patient must be less than 18 years of age at registration for the safety study. Patients must be \< 25 years of age for Phase 0 and Efficacy Cohorts.
• Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration.
• Patients must be able to swallow tablets (or applesauce, if part of bioavailability "crushed" six patient cohort).
• Patient must have magnetic resonance (MR) imaging performed within two weeks of first dose of drug.
• Karnofsky Performance Scale (KPS for \> 16 yrs of age) or Lansky Performance Score(LPS for ≤ 16 years of age) ≥ 60 assessed within two weeks prior to registration.
• The patient must have failed at least one prior therapy besides surgery- radiation or chemotherapy (either cytotoxic or biologic agent)- prior to study registration. Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
• Myelosuppressive chemotherapy: Patients must have received their last dose of known myelosuppressive anticancer chemotherapy at least three weeks prior to study registration or at least six weeks if nitrosourea.
• Biologic agent: Patient must have recovered from any toxicity potentially related to the agent and received their last dose of the biologic agent ≥ 7 days prior to study registration.
• For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval should be discussed with the study chair.
• For biologic agents that have a prolonged half-life, the appropriate interval since last treatment should be discussed with the study chair prior to registration.
• Monoclonal antibody treatment: At least three half-lives must have elapsed prior to registration. Such patients should be discussed with the study chair prior to registration.
• Radiation: Patients must have:
• Had their last fraction of local irradiation to primary tumor ≥12 weeks prior to registration; investigators are reminded to review potentially eligible cases to avoid confusion with pseudo-progression.
• Had their last fraction of craniospinal irradiation or total body irradiation \> 12 weeks prior to registration

You may not qualify if:

• Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction) that will likely interfere with the study procedures or results.
• All patients with known clinical diagnosis of Neurofibromatosis Type 1 are excluded.
• Patients receiving any other anticancer or investigational drug therapy.
• Patients with uncontrolled seizures are not eligible for the study.
• Previous BRAF inhibitor use such as vemurafenib, GSK2118436 or sorafenib.
• Patients with QTc interval \>450 msecs or other factors that increase the risk of QTprolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) including heart failure that meets New York Heart Association(NYHA) class III and IV definitions are excluded.
• Required use of a concomitant medication that can prolong the QT interval. A comprehensive list of agents with the potential to cause QTc prolongation can be found at http://www.azcert.org/medical-pros/drug-lists/browse-drug-list.cfm?alpha=A
• Patients with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to vemurafenib.
• Negative result of BRAFV600E screening test performed at UCSF.

Sponsors & Collaborators

• University of California, San Francisco: lead
• Genentech, Inc.: collaborator

Study Sites (21)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Mattel Children's Hospital UCLA

Los Angeles, California, 90095, United States

Location

Children's Hospital and Research Center at Oakland

Oakland, California, 94609-1809, United States

Location

Rady Children's Hospital - San Diego

San Diego, California, 92123, United States

Location

UCSF Medical Center-Mount Zion

San Francisco, California, 94115, United States

Location

UCSF Medical Center-Parnassus

San Francisco, California, 94143, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

University of Florida Health Science Center - Gainesville

Gainesville, Florida, 32610, United States

Location

Lurie Children's Hospital-Chicago

Chicago, Illinois, 60611, United States

Location

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, 21287, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

University of Minnesota/Masonic Children's Hospital

Minneapolis, Minnesota, 55454, United States

Location

Saint Louis Children's Hospital

St Louis, Missouri, 63110, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, 84112, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Related Publications (1)

• Nicolaides T, Nazemi KJ, Crawford J, Kilburn L, Minturn J, Gajjar A, Gauvain K, Leary S, Dhall G, Aboian M, Robinson G, Long-Boyle J, Wang H, Molinaro AM, Mueller S, Prados M. Phase I study of vemurafenib in children with recurrent or progressive BRAFV600E mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002). Oncotarget. 2020 May 26;11(21):1942-1952. doi: 10.18632/oncotarget.27600. eCollection 2020 May 26.

  PMID: 32523649 DERIVED

MeSH Terms

Conditions

Recurrence

Interventions

Vemurafenib

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Sabine Mueller, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 7, 2012
• First Posted: December 12, 2012
• Study Start: April 29, 2014
• Primary Completion: December 5, 2018
• Study Completion: July 31, 2025
• Last Updated: August 3, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1); US (20)