Vemurafenib for Pediatric Brain Cancer

Recruiting at 20 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of California, San Francisco

Must not be taking: Anticancer drugs, BRAF inhibitors

Disqualifiers: Neurofibromatosis Type 1, Uncontrolled seizures, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking any other anticancer or investigational drug therapy before participating. If you are on medications that can prolong the QT interval (a heart rhythm measure), you will also need to stop those. It's best to discuss your current medications with the study team to see if any need to be adjusted.

What data supports the effectiveness of the drug Vemurafenib for pediatric brain cancer?

Research shows that Vemurafenib, a drug targeting the BRAFV600E mutation, has shown promising results in treating pediatric brain tumors. In studies, some children experienced tumor shrinkage or stabilization, and the drug was generally well-tolerated, although some side effects like skin rashes were noted. ^{1 2 3 4 5}

What safety data exists for Vemurafenib in pediatric brain cancer treatment?

Vemurafenib has been studied in children with brain tumors and is generally well-tolerated, though some patients experienced skin issues like rashes and other side effects such as fever. In one study, serious skin growths were reported in a small number of patients, but overall, the treatment showed manageable toxicity. ^{1 2 3 4 6}

How is the drug Vemurafenib unique in treating pediatric brain cancer?

Vemurafenib is unique because it specifically targets the BRAFV600E mutation, which is a key driver in certain pediatric brain tumors, and it is administered orally, making it more accessible for children. Unlike some other treatments, it can be given in crushed tablet form for young children who cannot swallow pills, and it has shown promising anti-tumor activity with manageable side effects. ^{1 2 3 4 7}

What is the purpose of this trial?

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.

Research Team

Sabine Mueller, MD, PhD, MAS

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for children with recurrent or refractory gliomas that have a specific BRAFV600E mutation. They must be able to swallow tablets, not have had certain treatments recently, and their organs need to function well. Kids under 18 are eligible for the safety study, while those up to 25 can join other parts of the trial if they meet additional criteria.

Inclusion Criteria

Cardiac: Corrected QT (QTc) interval <450 msec on EKG

I have had all suspicious skin lesions removed.

Signed informed consent according to institutional guidelines must be obtained

Exclusion Criteria

History of allergic reactions attributed to compounds of similar chemical or biologic composition to vemurafenib

I am not on any other cancer treatments or experimental drugs.

I do not have uncontrolled seizures.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety and Pharmacokinetic Assessment

Determine the maximum tolerated dose (MTD) and/or select a recommended phase 2 dose (RP2D) of vemurafenib in children with recurrent or refractory gliomas

4 weeks

Weekly visits for the first 4 weeks

Phase 0 Study

Conduct a Phase 0 study in a pre-surgical cohort to measure intra-tumoral drug concentrations and target inhibition

4 weeks

Expansion Cohort

Enroll an expansion cohort to preliminarily estimate efficacy of vemurafenib

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Vemurafenib

Trial Overview The trial is testing Vemurafenib's safety and proper dosing in kids with brain tumors that came back or didn't respond to treatment. It aims to find the maximum tolerable dose (MTD) and/or recommend a phase 2 dose (RP2D). The drug concentration in tumor tissue will also guide eligibility for later phases.

Participant Groups

Group I: Vemurafenib Experimental Treatment 1 Intervention

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 already approved in United States, European Union, Canada for the following indications:

Approved in United States as Zelboraf for:

• Unresectable or metastatic melanoma with BRAF V600E mutation
• Erdheim-Chester Disease (ECD) with BRAF V600 mutation

Approved in European Union as Zelboraf for:

• Adults with BRAF V600E mutation positive unresectable or metastatic melanoma

Approved in Canada as Zelboraf for:

• Unresectable or metastatic melanoma with BRAF V600E mutation

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

In a study involving 19 children with recurrent BRAFV600E mutant brain tumors, vemurafenib was found to have promising anti-tumor activity, with 1 complete response and 5 partial responses observed among the patients.

The recommended phase 2 dose (RP2D) was established at 550 mg/m2 twice daily, with manageable side effects including rash and fever, indicating that vemurafenib can be safely administered to pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of vemurafenib in children with recurrent or progressive BRAFV600E mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002). Nicolaides, T., Nazemi, KJ., Crawford, J., et al.[2021]

In a study involving 32 pediatric patients with BRAF V600-mutant low-grade glioma, dabrafenib showed a 44% objective response rate and an impressive 85% one-year progression-free survival rate, indicating its effectiveness in treating this type of brain tumor.

The treatment was generally well-tolerated, with 91% of patients experiencing treatment-related adverse events, primarily fatigue, and only 28% experiencing severe (grade 3/4) side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Dabrafenib in Pediatric Patients with BRAF V600 Mutation-Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study. Hargrave, DR., Bouffet, E., Tabori, U., et al.[2023]

In a phase I/II study involving 139 pediatric patients with relapsed/refractory malignancies, trametinib was found to have a recommended dose of 0.032 mg/kg for children under 6 years and 0.025 mg/kg for those 6 years and older, with manageable safety profiles and no dose-limiting toxicities when combined with dabrafenib.

Among 49 patients with BRAF V600-mutant low-grade gliomas, the combination therapy of dabrafenib and trametinib showed a higher objective response rate of 25% compared to 15% for trametinib alone, indicating improved efficacy with the combination treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600-Mutant Low-Grade Glioma. Bouffet, E., Geoerger, B., Moertel, C., et al.[2023]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

BRAF V600E Inhibitor (Vemurafenib) for BRAF V600E Mutated Low Grade Gliomas. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Phase I study of vemurafenib in children with recurrent or progressive BRAFV600E mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002). [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Vemurafenib in pediatric patients with BRAFV600E mutated high-grade gliomas. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Vemurafenib in Children With Recurrent/Refractory BRAF Gene V600E-Mutant Astrocytomas. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Dabrafenib in Pediatric Patients with BRAF V600 Mutation-Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600-Mutant Low-Grade Glioma. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Early molecular diagnosis of BRAF status drives the neurosurgical management in BRAF V600E-mutant pediatric low-grade gliomas: a case report. [2022]