Plixorafenib for Brain Tumors

Overseen By Study Chair, MD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: Herbal medications, Supplements

Disqualifiers: NF-1, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: 6

Duration: 24 cycles (up to 2 years)

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of a new drug, plixorafenib, for brain tumors with a specific gene change called BRAF-V600E, which makes them difficult to treat. Researchers aim to track the drug's effectiveness by examining tiny bits of tumor DNA in body fluids. This trial suits individuals with BRAF-V600E mutant brain tumors who have not responded to other treatments and can identify if their condition involves this specific mutation. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions that you cannot use any other standard or investigational agents and must avoid prohibited medications, including certain herbal supplements and foods, as described in the trial details.

Is there any evidence suggesting that plixorafenib is likely to be safe for humans?

Research has shown that plixorafenib was safe in earlier studies. Tested on various tumors with BRAF V600 mutations, it was generally well-tolerated. Patients experienced few serious side effects at different doses. This finding reassures potential trial participants, suggesting that plixorafenib is both effective and safe for humans. Although the current trial is in its early stages, existing data provides a positive view of the treatment's safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Plixorafenib is unique because it targets a specific mutation known as BRAF-V600E, which is found in certain brain tumors like gliomas. Unlike standard treatments that might not specifically target this mutation, Plixorafenib offers a more precise approach by directly inhibiting the mutant BRAF protein. Researchers are excited about this treatment because it has the potential to be more effective for patients whose tumors have become resistant to existing BRAF and MEK inhibitors. This targeted action could lead to better outcomes for patients who haven't responded well to current therapies.

What evidence suggests that plixorafenib might be an effective treatment for brain tumors?

Research has shown that plixorafenib, the investigational treatment in this trial, may effectively treat brain tumors with BRAF V600E mutations. In studies involving children with certain brain tumors, those treated with BRAF inhibitors like plixorafenib had a 3-year survival rate without tumor growth of nearly 50%, compared to about 30% for those who did not receive the treatment. This suggests that plixorafenib might help control tumor growth for a longer time. Additionally, patients with BRAF V600-mutated solid tumors typically responded to the treatment in about 3.5 months. These findings highlight the potential benefits of plixorafenib for people with this type of brain tumor. ^{4 6 7 8 9}

Who Is on the Research Team?

Karisa Schreck, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

This trial is for individuals with a BRAF mutation in their brain tumor, specifically glioma that hasn't responded to previous treatments. Participants must be able to provide samples of cerebrospinal fluid and blood for the study.

Inclusion Criteria

My MRI shows my disease can be measured and may include leptomeningeal disease.

I agree to use effective birth control.

Specific intervals from previous treatments should have elapsed prior to cycle 1 day 1.

Exclusion Criteria

My cancer has genetic changes related to NF-1 or RAS that cause drug resistance.

Pregnant women are excluded from this study.

I have a serious heart condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-4 weeks

1 visit (in-person)

Pre-operative

Patients undergo pre-operative MRI and clinically-indicated resection or biopsy for confirmation of progression and characterization of potential acquired resistance alterations

1 week

1 visit (in-person)

Treatment

Patients start the study drug (plixorafenib co-administered with cobicistat) 7-28 days post-operatively, taking the drug daily by mouth under fasting conditions continuously for 28-day cycles until progressive disease or up to 24 cycles

24 cycles (up to 2 years)

Every 2 cycles (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with MRI performed post-operatively and blood and CSF samples obtained on day of surgery, at baseline, pre-C2, then with each MRI

2 years

Every 2 cycles (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Plixorafenib

Trial Overview

The trial is testing how well ctDNA (tiny bits of DNA from cancer cells) can be detected in the spinal fluid and blood when patients are treated with Plixorafenib, a drug aimed at targeting BRAF mutations.

How Is the Trial Designed?

Group I: Recurrent BRAF-V600E mutant gliomas previously received BRAFi* +/- MEKi** , Experimental Treatment 2 Interventions

\*BRAFi (v-raf murine sarcoma viral oncogene homolog B1 inhibitor) \*\*MEKi (Methyl ethyl ketone inhibitor)

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Ivy Brain Tumor Foundation

Collaborator

Trials

1

Recruited

20+

Fore Biotherapeutics

Industry Sponsor

Trials

8

Recruited

500+

Published Research Related to This Trial

A 16-year-old male with pleomorphic xanthoastrocytoma showed an initial positive response to vemurafenib, a BRAF V600E inhibitor, highlighting its potential as a treatment option for this type of brain tumor.

After a brief interruption in treatment, the patient experienced an additional response to vemurafenib, suggesting that the drug may remain effective even after progression, which is important for cases where complete tumor resection is not possible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Efficacy of Single-agent Vemurafenib for Pleomorphic Xanthoastrocytoma. Finch, EA., Elton, SW., Huang, BY., et al.[2021]

The RAMNITA study is a phase II clinical trial evaluating the safety and efficacy of combining docetaxel and ramucirumab in 65 patients with advanced non-small cell lung cancer (NSCLC) and brain metastasis, aiming to improve progression-free survival (PFS).

This study is significant as it explores the potential of ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor-2, in treating brain metastasis, which has not been previously established.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment rationale and design of the RAMNITA study: A phase II study of the efficacy of docetaxel + ramucirumab for non-small cell lung cancer with brain metastasis. Tanimura, K., Uchino, J., Tamiya, N., et al.[2023]

In a case series of 4 patients with BRAF V600E primary brain tumors, dual therapy with dabrafenib and trametinib led to near-complete or complete clinical responses in three patients after 8 weeks, demonstrating significant efficacy.

The combination therapy not only showed greater effectiveness than dabrafenib alone but also helped reduce skin-related side effects, such as keratosis, highlighting its potential to improve patient tolerability during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual BRAF/MEK therapy in BRAF V600E-mutated primary brain tumors: a case series showing dramatic clinical and radiographic responses and a reduction in cutaneous toxicity. Bernstein, A., Mrowczynski, OD., Greene, A., et al.[2023]

Oral targeted agents, including BRAF inhibitors and various receptor inhibitors, show potential in treating brain metastases, but there is a lack of comprehensive data on their effectiveness in this specific area.

Many patients with brain metastases are excluded from clinical trials, leading to a significant gap in research and documentation of the intracranial activity of these therapies, highlighting the need for more focused investigations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Targeted Therapies and Central Nervous System (CNS) Metastases. Gabay, MP., Wirth, SM., Stachnik, JM., et al.[2022]

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]

Citations

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pmc.ncbi.nlm.nih.gov

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

Outcomes of BRAF V600E Pediatric Gliomas Treated With ...

In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition ...

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fore.bio

fore.bio/fore-biotherapeutics-announces-positive-outcome-from-a-planned-interim-efficacy-analysis-for-the-forte-basket-study-evaluating-plixorafenib-as-a-monotherapy-for-recurrent-or-progressive-braf-v600-prim/

Fore Biotherapeutics

BRAF altered recurrent primary CNS tumors represent a high unmet medical need and a large market opportunity for plixorafenib. In the advanced ...

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ascopubs.org

ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS2098

Trial in progress: Feasibility of CSF and plasma ctDNA in ...

This study is a single institution trial of plixorafenib in patients (18+ years of age) with BRAF-V600E mutant glioma following progression on prior BRAF- ...

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targetedonc.com

targetedonc.com/view/plixorafenib-delivers-promising-outcomes-in-cns-tumors

Plixorafenib Delivers Promising Outcomes in CNS Tumors

The median time to response for all patients with BRAF V600-mutated solid tumors was 3.5 months. “The updated data from our phase 1/2a study ...

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clinicaltrials.gov

clinicaltrials.gov/study/NCT05503797

NCT05503797 | A Study to Assess the Efficacy and Safety ...

Participants with advanced, rare, non-CNS solid tumors harboring BRAF V600E mutations will receive plixorafenib, continuously in 3-week cycles until disease ...

6.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS2091

FORTE: A phase 2 master protocol assessing plixorafenib ...

In a phase 1/2a study, plixorafenib demonstrated promising safety and clinical activity across a range of doses tested in tumors with BRAF V600 mutations or ...

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9846085/

Implications of BRAF V600E mutation in gliomas

The focus of this review is to summarize the molecular landscape of BRAF across glioma subtypes and the novel therapeutic strategies for BRAF V600E mutated ...

8.

fore.bio

fore.bio/wp-content/uploads/2024/04/SNO-2023-Presentation-Final-Clean.pdf

Efficacy of BRAF Inhibitor Plixorafenib (FORE8394) in ...

BRAF mutations and primary CNS tumors (PCNSTs). • Targeting BRAF V600 mutation has demonstrated clinical benefit across solid tumor types1.

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cancernetwork.com

cancernetwork.com/view/how-does-plixorafenib-compare-with-other-braf-mutant-thyroid-cancer-agents-

How Does Plixorafenib Compare With Other BRAF-Mutant ...

Data from a phase 1/2a trial showed that plixorafenib-based care achieved a median PFS of 63.9 months in patients with BRAF-altered thyroid ...