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

NCT ID: NCT01748149

Last Updated: 2025-08-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-04-29
• Study Completion Date: 2025-07-31

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.

Detailed Description

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. Using the RP2D, the study team will then conduct a Phase 0 study in a pre-surgical cohort of 10 patients requiring debulking surgery at the time of recurrence. These patients will receive neo-adjuvant vemurafenib, thus allowing the study team to measure intra-tumoral drug concentrations and target inhibition. An expansion cohort will then be enrolled to allow the study team to preliminarily estimate efficacy. Participants are followed up for adverse events while receiving study treatment until resolution.

Conditions

Pediatric Recurrent/Refractory BRAFV600E-mutant Gliomas

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Vemurafenib

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.

Group Type: EXPERIMENTAL

Vemurafenib

Intervention Type: 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.

Interventions

Vemurafenib

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.

Intervention Type: DRUG

Other Intervention Names

RO5185426; PLX4032

Eligibility Criteria

Inclusion Criteria

• 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
• Bone Marrow Transplant: Patient must be:
• ≥ 6 months since allogeneic bone marrow transplant prior to registration
• ≥ 3 months since autologous bone marrow/stem cell prior to registration
• Corticosteroids: Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to registration.
• Growth factors: Off all colony forming growth factor(s) for at least 1 week prior to registration (filgrastim, sargramostim, erythropoietin) and at least 2 weeks for long- acting formulations.
• Organ Function: Documented within 14 days of registration and within 7 days of the start of treatment.
• Adequate bone marrow function:
• Absolute neutrophil count ≥ 1000/μl (unsupported)
• Platelets ≥ 75,000/μl (unsupported)
• Hemoglobin ≥ 8 g/dL (may be supported)
• Adequate hepatic function:
• Total bilirubin < 1.5 times upper limit of normal for age
• serum glutamate pyruvate transaminase (SGPT)/serum glutamate oxaloacetate transaminase (SGOT) (ALT/AST) ≤ 2.5 times institutional upper limit of normal for age
• Adequate renal function:
• Creatinine clearance or Radioisotope glomerular filtration rate (GFR) ≥ 70 ml/min/1.73m2 or a serum creatinine based on age as follows: Less than or equal to 5 years of age= Maximum Serum Creatinine (mg/dL)of 0.8; Older than 5 but 10 years or younger= Maximum Serum Creatinine (mg/dL)of 1.0; Older than 10 but 15 years or younger= Maximum Serum Creatinine (mg/dL)of 1.2; Older than 15 years= Maximum Serum Creatinine (mg/dL) of 1.5
• Electrolytes:
• Sodium: ≥ 130 and ≤ 145 mmol/L
• Potassium: 3.4- 4.8 mmol/L
• Calcium: ≥ 7 mg/dL
• Magnesium: ≥ 0.7 mmol/L
• Nutrition:
• Albumin ≥ 3 g/dL
• Cardiac:
• Corrected QT (QTc) interval <450 msec on EKG.
• Female patients of childbearing potential must not be pregnant or breast-feeding. Female patients of childbearing potential must have a negative serum or urine pregnancy test. The effects of Vemurafenib on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception: (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for four weeks after dosing with vemurafenib ceases. Women must refrain from donating eggs during this same period. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 weeks after completion of study drug administration.
• All skin lesions suspicious for keratoacanthomas/cutaneous squamous cell carcinoma (cSCC) found at baseline dermatology visit must have been excised.
• Signed informed consent according to institutional guidelines must be obtained.

• Patients under 25 years of age will be eligible for the pre-surgical cohort. Patients between 18-25 years of age will be treated at the adult FDA-approved dose of 960 mg BID and can be enrolled immediately. Patients less than 18 years of age will be enrolled and treated at the pediatric MTD once it is defined in the Safety Cohort.
• Surgical patients must have tumor that needs to be removed/debulked and is accessible for the neurosurgeon. Need for surgery must be such that the patient can take drug for 10 days before surgery.

• Expansion cohort will be open if tissue drug levels in the Pre-Surgical cohort meet criteria (Tumor tissue drug concentration is greater than 50 nM). Patients under 25 years of age will be eligible for the expansion cohort. Patients between 18 and 25 years of age will take adult dose of 960 mg BID. Patients less than 18 years of age will take the MTD defined in the safety cohort.

Exclusion Criteria

• 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.

• Maximum Eligible Age: 25 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genentech, Inc.

INDUSTRY

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sabine Mueller, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Locations

Children's Hospital Los Angeles

Los Angeles, California, United States

Mattel Children's Hospital UCLA

Los Angeles, California, United States

Children's Hospital and Research Center at Oakland

Oakland, California, United States

Rady Children's Hospital - San Diego

San Diego, California, United States

UCSF Medical Center-Mount Zion

San Francisco, California, United States

UCSF Medical Center-Parnassus

San Francisco, California, United States

Children's National Medical Center

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

University of Florida Health Science Center - Gainesville

Gainesville, Florida, United States

Lurie Children's Hospital-Chicago

Chicago, Illinois, United States

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

University of Minnesota/Masonic Children's Hospital

Minneapolis, Minnesota, United States

Saint Louis Children's Hospital

St Louis, Missouri, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

Oregon Health and Science University

Portland, Oregon, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

St. Jude Children's Research Hospital

Memphis, Tennessee, United States

Texas Children's Hospital

Houston, Texas, United States

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, United States

Seattle Children's Hospital

Seattle, Washington, United States

Hospital for Sick Children

Toronto, Ontario, Canada

Countries

United States; Canada

References

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.

Reference Type: DERIVED

PMID: 32523649 (View on PubMed)

Other Identifiers

NCI-2014-00387

Identifier Type: OTHER

Identifier Source: secondary_id

120819

Identifier Type: -

Identifier Source: org_study_id