Vemurafenib for Pediatric Brain Cancer

No longer recruiting at 22 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safest and most effective dose of vemurafenib, a medication tested for treating certain types of brain cancer in children. Researchers focus on children with gliomas, a type of brain tumor, that have specific genetic mutations called BRAFV600E or BRAF Ins T. Participants should be under 18 years old and have recurring or treatment-resistant gliomas. They must have stable neurological symptoms and be able to swallow pills or mix them with applesauce.

As an Early Phase 1 trial, participants will be among the first to help researchers understand how this new treatment works in children.

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.

Is there any evidence suggesting that vemurafenib is likely to be safe for children with brain cancer?

Research has shown that vemurafenib has been tested in children with brain tumors featuring a specific genetic change called BRAF-V600E. These studies found the drug generally safe for these children, with no new safety issues identified. Vemurafenib is also approved for treating some adults with melanoma, a type of skin cancer, who have the same genetic change. Although not all aspects of its safety in children are known, these earlier studies provide some reassurance. Overall, vemurafenib appears well-tolerated, but ongoing research is crucial to determine the best and safest dose for children. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for brain cancer?

Vemurafenib is unique because it specifically targets the BRAF V600E mutation, a genetic alteration found in some pediatric brain cancers. Unlike traditional chemotherapy, which attacks all rapidly dividing cells, vemurafenib is designed to precisely inhibit the mutated BRAF protein, potentially leading to fewer side effects and more effective tumor control. Researchers are excited about vemurafenib because it offers a targeted approach that could improve outcomes for young patients with this specific genetic profile, providing a more personalized and potentially less toxic treatment option.

What evidence suggests that vemurafenib might be an effective treatment for pediatric brain cancer?

Research shows that vemurafenib, the treatment under study in this trial, may help treat certain brain cancers in children. In earlier studies, children with recurring low-grade gliomas that have the BRAFV600E mutation responded well to vemurafenib. One study found that about 49.6% of patients treated with BRAF inhibitors, like vemurafenib, did not experience cancer progression over three years. This indicates that the cancer remained stable in nearly half of the patients during that period. Vemurafenib is generally considered tolerable, meaning most children can take it without serious side effects. While more research is needed, early results are promising for this targeted treatment. ^{4 6 7 8 9}

Who Is on the Research Team?

Sabine Mueller, MD, PhD, MAS

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

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

I have had all suspicious skin lesions removed.

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

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7260122/

Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002) In summary, we report that vemurafenib is tolerable and efficacious in children with recurrent low grade gliomas with BRAFV600E mutations. The ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7446502/

Outcomes of BRAF V600E Pediatric Gliomas Treated With ... In contrast, patients treated with BRAF inhibition had significantly better PFS of 49.6% at 3 years (95% CI, 35.3% to 69.5%), with a potential plateau afterward ...

3. academic.oup.com academic.oup.com/oncolo/article/29/8/723/7693279

Phase II study of vemurafenib in children and young adults ... This trial aimed to determine response rate in pediatric patients harboring BRAF V600 mutations, excluding low-grade glioma patients with BRAF ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT01748149?term=AREA%5BBasicSearch%5D(AREA%5BConditionSearch%5D(%22Glioma%22)%20AND%20AREA%5BInterventionSearch%5D(%22Benzocaine%22))&rank=5

Vemurafenib in Children With Recurrent/Refractory BRAF ... 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 ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT01748149

Vemurafenib in Children With Recurrent/Refractory BRAF ... To describe the toxicity profile/dose limiting toxicity (DLT) of vemurafenib in children with recurrent or refractory glioma. DLT will be assessed by ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6477532/

A SAFETY STUDY OF VEMURAFENIB, AN ORAL ... We have previously presented favorable radiographic response and safety data for vemurafenib in children with BRAF-V600E mutated brain tumors and report here an ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5692489/

PDCT-19. A SAFETY STUDY OF VEMURAFENIB, AN ... This study was designed to determine the recommended phase 2 dose (RP2D) in patients < 18yrs with BRAF-V600E mutant brain tumors. METHODS. Vemurafenib was given ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2017/202429s012lbl.pdf

ZELBORAF (vemurafenib) tablet for oral use ZELBORAF is not used to treat melanoma with a normal BRAF gene. It is not known if ZELBORAF is safe and effective in children under 18 years of age. What ...

9. ema.europa.eu ema.europa.eu/en/documents/product-information/zelboraf-epar-product-information_en.pdf

Zelboraf, INN-vemurafenib - European Medicines Agency Paediatric population. The safety of vemurafenib in children and adolescents has not been established. No new safety signals were observed in a clinical ...