Dabrafenib + Trametinib + Hydroxychloroquine for Brain Tumor

Not currently recruiting at 15 trial locations

Overseen By Nina Butingan, MBS

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Pediatric Brain Tumor Consortium

Must be taking: RAF/MEK inhibitors

Must not be taking: Anti-cancer drugs

Disqualifiers: Breastfeeding, Significant illness, Retinopathy, 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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for children with certain brain tumors, particularly when previous treatments were ineffective or the tumors returned. Researchers aim to determine if adding hydroxychloroquine, a drug that may inhibit tumor growth, to dabrafenib and trametinib, drugs that block tumor growth enzymes, makes a difference. The trial seeks children with specific genetic mutations in their tumors, such as BRAF V600 or those related to neurofibromatosis type 1, a genetic condition causing tumors on nerves. Participants should have brain tumors that either did not respond well to past similar treatments or have recurred despite treatment. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you must stop all current medications, but you must discontinue any prohibited medications or herbal preparations within 7 days of enrollment and 14 days before starting the study therapy. If you are on anti-cancer or investigational drug therapy, you cannot participate.

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 continue any prohibited medications or herbal preparations within 7 days of enrollment and 14 days of starting the study therapy. It's best to discuss your current medications with the study team to see if they are allowed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that dabrafenib and trametinib, often used together, have been approved for certain cancers, indicating their safety is well understood. One study found these drugs effective for pediatric brain tumors with specific mutations, with generally manageable side effects.

Hydroxychloroquine has been studied alongside these drugs to assess its potential in stopping tumor growth. Current research indicates that this combination is usually well-tolerated. However, like any treatment, side effects can occur. Some patients experienced mild to moderate side effects, such as fever or skin rash, but these were usually not severe.

For those considering joining a clinical trial, it's important to understand that while these treatments show promise, individual reactions can differ. Always consult a healthcare professional about the potential risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Dabrafenib, Trametinib, and Hydroxychloroquine for treating brain tumors because it targets the BRAF V600 mutations, which are common in certain types of brain tumors but not specifically addressed by current standard treatments. Unlike traditional therapies like surgery, radiation, or chemotherapy, this combination works by inhibiting the BRAF and MEK pathways, which are crucial for the growth of cancer cells. Additionally, Hydroxychloroquine is thought to interfere with autophagy, a process that cancer cells use to survive, offering a unique approach that could enhance the effectiveness of the treatment. This multi-targeted method provides a promising new strategy that could potentially improve outcomes for patients with these specific genetic mutations.

What evidence suggests that this trial's treatments could be effective for brain tumors?

Research has shown that dabrafenib combined with trametinib can help treat certain brain tumors with BRAF V600 mutations. This combination is approved for children with low-grade gliomas and has effectively stopped tumor growth. In this trial, some participants will receive dabrafenib, trametinib, and hydroxychloroquine, which might enhance the treatment by attacking tumor cells in a new way. Hydroxychloroquine blocks a process called autophagy, which cancer cells use to survive. Researchers are testing this approach in various treatment arms to determine if it can stop brain tumor growth more effectively than previous treatments. ^{1 2 3 4 6}

Who Is on the Research Team?

Lindsey Hoffman, DO

Principal Investigator

Phoenix Children's Hospital

Are You a Good Fit for This Trial?

This trial is for children with low or high grade brain tumors that have specific genetic mutations (BRAF V600, BRAF fusion/duplication) and may include those with neurofibromatosis type 1. Participants must have tried similar treatments without success, be in good health otherwise, not pregnant or breastfeeding, able to use contraception if applicable, and understand the study.

Inclusion Criteria

I weigh at least 9 kg.

I meet the weight requirements for my treatment phase.

I am a sexually active male and will use a condom to prevent fathering a child.

Exclusion Criteria

You have a serious unrelated illness.

Patients unable to discontinue prohibited medications or herbal preparations within specified time frames

I do not have another cancer that could affect this treatment's safety or results.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Estimate the maximum tolerated doses (MTD) and recommended Phase II doses (RP2D) of D+T+HCQ and T+HCQ in children and young adults with recurrent or progressive glioma

28 days per course, up to 2 years

Continuous monitoring with regular visits

Phase II Treatment

Patients continue to receive either the D+T+HCQ or T+HCQ combination at the RP2D defined in Phase I

28 days per course, up to 2 years

Continuous monitoring with regular visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Dabrafenib
• Hydroxychloroquine
• Trametinib

Trial Overview The trial tests combining hydroxychloroquine with dabrafenib and/or trametinib to see if it's more effective at stopping tumor growth than current treatments. It's a phase I/II trial which means they're looking for the safest dose that works best against these types of brain tumors.

How Is the Trial Designed?

Group I: Phase 2 Stratum 6 LGG with NF Type 1 Experimental Treatment 2 Interventions

LGG with Neurofibromatosis Type 1 will receive Trametinib and Hydroxychloroquine. All medications are administered orally with Trametinib given once per day and HCQ give twice per day at the recommended Phase 2 dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria.

Group II: Phase 2 Stratum 5 LGG with BRAF aberration Experimental Treatment 2 Interventions

LGG with BRAF duplication or fusion with any partner will receive Trametinib and Hydroxychloroquine. All medications are administered orally with Trametinib given once per day and HCQ give twice per day at the recommended Phase 2 dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria.

Group III: Phase 2 Stratum 4 HGG with BRAF V600 mutation Experimental Treatment 3 Interventions

HGG with BRAF V600E/D/K mutation will receive Dabrafenib, Trametinib and Hydroxychloroquine. All medications are administered orally with Dabrafenib and HCQ given twice a day and Trametinib given once per day at the recommended Phase 2 dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria

Group IV: Phase 2 Stratum 3 LGG with BRAF V600 mutation Experimental Treatment 3 Interventions

LGG with BRAF V600E/D/K mutation will receive Dabrafenib, Trametinib and Hydroxychloroquine. All medications are administered orally with Dabrafenib and HCQ given twice a day and Trametinib given once per day at the recommended Phase 2 dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria.

Group V: Phase 1 Stratum 2 BRAF aberration or LGG with NF1 Experimental Treatment 2 Interventions

LGG with BRAF duplication or fusion with any partner or LGG with NF1 will received Trametinib and Hydroxychloroquine. All medications are administered orally with Trametinib given once per day and HCQ give twice per day at the assigned dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria.

Group VI: Phase 1 Stratum 1 BRAF V600E LGG or HGG Experimental Treatment 3 Interventions

LGG or HGG with BRAF V600E/D/K mutation will receive Dabrafenib, Trametinib and Hydroxychloroquine. All medications are administered orally with Dabrafenib and HCQ given twice a day and Trametinib given once per day at the assigned dose for a 28 day course. Courses may repeat until the patient meets an off treatment criteria.

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

Approved in European Union as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation
• Adjuvant treatment of melanoma with a BRAF V600 mutation

Approved in United States as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600E mutation
• Adjuvant treatment of melanoma with a BRAF V600E or V600K mutation
• Metastatic non-small cell lung cancer with a BRAF V600E mutation

Approved in Canada as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation
• Adjuvant treatment of melanoma with a BRAF V600 mutation

Approved in Japan as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Who Is Running the Clinical Trial?

Pediatric Brain Tumor Consortium

Lead Sponsor

Trials

38

Recruited

1,600+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

American Lebanese Syrian Associated Charities (ALSAC)

Collaborator

Trials

9

Recruited

670+

American Lebanese Syrian Associated Charities

Collaborator

Trials

9

Recruited

670+

Published Research Related to This Trial

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]

In a phase 2 study with a minimum of 5-year follow-up, the combination of dabrafenib and trametinib showed a high overall response rate of 68.4% in pretreated patients and 63.9% in treatment-naive patients with BRAF V600E-mutant metastatic NSCLC, indicating strong efficacy.

The therapy demonstrated a manageable safety profile, with pyrexia being the most common side effect (56%), and provided substantial overall survival benefits, with median overall survival of 18.2 months for pretreated patients and 17.3 months for treatment-naive patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis. Planchard, D., Besse, B., Groen, HJM., et al.[2022]

Combination therapy with the BRAF V600E inhibitor dabrafenib and the MEK inhibitor trametinib significantly improves progression-free survival in patients with BRAF V600-positive metastatic melanoma, but it is associated with serious side effects, including an increased risk of hemorrhagic events.

This case report highlights the occurrence of intracranial hemorrhage in a patient undergoing this combination therapy, emphasizing the need for vigilance in monitoring neurological symptoms in patients receiving these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of intracranial hemorrhage caused by combined dabrafenib and trametinib therapy for metastatic melanoma. Lee, le M., Feun, L., Tan, Y.[2022]

Dabrafenib plus trametinib demonstrated significant efficacy in treating BRAFV600E mutation-positive high-grade glioma, with a 33% objective response rate in 45 patients, including complete and partial responses.

In the low-grade glioma cohort, the treatment showed even higher efficacy, with a 69% objective response rate in 13 patients, indicating that this combination therapy could be a promising option for patients with these types of tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Wen, PY., Stein, A., van den Bent, M., et al.[2022]

A 61-year-old man with BRAF V600E-mutated lung adenocarcinoma experienced cerebral infarction after treatment with dabrafenib and trametinib, highlighting a potential risk associated with this therapy.

Despite being considered safe in previous trials, this case suggests that clinicians should monitor for signs of cerebral infarction during treatment, especially in patients with complications like disseminated intravascular coagulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cerebral infarction after treatment with dabrafenib plus trametinib for BRAF-V600E-positive non-small cell lung cancer: A case report. Taniguchi, Y., Tamiya, A., Yanagisawa, A., et al.[2023]

Trametinib, when combined with dabrafenib, significantly prolongs median survival by about 8 months compared to vemurafenib alone in patients with metastatic or inoperable melanoma, based on a study of 704 patients.

While trametinib can enhance treatment efficacy, it also carries serious adverse effects, including life-threatening conditions like heart failure and gastrointestinal perforation, making it essential for patients to weigh the benefits against the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trametinib (MEKINIST°) Metastatic or inoperable BRAF V600-positive melanoma: a few extra months of life. [2019]

In a compassionate-use setting involving 271 patients with BRAF V600-mutant unresectable or metastatic melanoma, the combination of dabrafenib and trametinib demonstrated a high overall response rate of 67.3% and a median overall survival of 20.0 months for BRAFi-naive patients.

The treatment was well tolerated with no new safety concerns, showing significant clinical activity even in patients with brain metastases, indicating its effectiveness across different treatment lines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib is effective in the treatment of BRAF V600-mutated metastatic melanoma patients: analysis of patients from the dabrafenib plus trametinib Named Patient Program (DESCRIBE II). Atkinson, V., Sandhu, S., Hospers, G., et al.[2023]

The combination of dabrafenib and trametinib significantly improves progression-free survival and overall survival in patients with unresectable or metastatic melanoma with a BRAF (V600E/K) mutation, compared to monotherapy with dabrafenib or vemurafenib, based on results from two large phase III studies.

This combination therapy is well-tolerated, showing no increase in overall toxicity compared to monotherapy, and results in fewer skin-related adverse events, likely due to reduced activation of the MAPK pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF (V600) Mutation. Dhillon, S.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04201457

NCT04201457 | A Trial of Dabrafenib, Trametinib and ... This phase I/II trial is designed to study the side effects, best dose and efficacy of adding hydroxychloroquine to dabrafenib and/or trametinib in children ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11695311/

The role of MEK inhibition in pediatric low-grade gliomas - PMC A follow-up phase II trial, NCT02684058, studied the use of combination trametinib + dabrafenib (T+D) as first-line treatment for BRAF V600- ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03754179

Dabrafenib/Trametinib/Hydroxychloroquine for Advanced ... This phase 1/2 trial addresses the efficacy and safety of the combination of dabrafenib, trametinib and the oral autophagy inhibitor hydroxychloroquine in ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12109687/

Precision Medicine for Pediatric Glioma and NF1-Associated ... A phase I prospective trial demonstrated a 15% response rate for trametinib alone and 25% for combination therapy in recurrent BRAF p.V600E ...

5. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-dabrafenib-trametinib-pediatric-patients-low-grade-glioma-braf-v600e-mutation

FDA approves dabrafenib with trametinib for pediatric ... FDA approves dabrafenib with trametinib for pediatric patients with low-grade glioma with a BRAF V600E mutation ... Additional efficacy outcome ...

6. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dabrafenib-combination-trametinib-unresectable-or-metastatic-solid

FDA grants accelerated approval to dabrafenib in ... FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E