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

Trial Summary

What is the purpose of this trial?

Evaluating the sensitivity and feasibility of using ctDNA assays optimized for detecting very low ctDNA counts from cerebrospinal fluid (CSF) and plasma. The investigators will evaluate the sensitivity of ctDNA from plasma and CSF at baseline (defined as Cycle1 Day1 (C1D1) pre-treatment) and over time in response to treatment with plixorafenib co-administered with cobicistat in BRAF-V600E mutant glioma refractory to prior therapies.

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.

How is the drug Plixorafenib different from other treatments for brain tumors?

Plixorafenib is unique because it targets the BRAF V600E mutation, which is a common driver in certain brain tumors, and may offer a new option for patients who do not respond well to traditional chemotherapy. This approach is similar to other BRAF inhibitors like vemurafenib and dabrafenib, which have shown effectiveness in treating brain tumors with this mutation. ^{1 2 3 4 5}

Research Team

Karisa Schreck, MD

Principal Investigator

Johns Hopkins University

Eligibility Criteria

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.

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

Side effects from my previous treatments have mostly gone away.

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

References

1. United States 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. [2023]

2. United States 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. [2023]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Oral Targeted Therapies and Central Nervous System (CNS) Metastases. [2022]

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

Long-term Efficacy of Single-agent Vemurafenib for Pleomorphic Xanthoastrocytoma. [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]