Dabrafenib + Trametinib + Hydroxychloroquine for Brain Tumor

Recruiting at 14 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

57 Participants Needed

Trial Summary

What is the purpose of this trial?

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 with low grade or high grade brain tumors previously treated with similar drugs that did not respond completely (progressive) or tumors that came back while receiving a similar agent (recurrent). Patients must also have specific genetic mutations including BRAF V600 mutations or BRAF fusion/duplication, with or without neurofibromatosis type 1. Neurofibromatosis type 1 is an inherited genetic condition that causes tumors to grow on nerve tissue. Hydroxychloroquine, works in different ways to stop the growth of tumor cells by killing the cells or stopping them from dividing. Trametinib and dabrafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving hydroxychloroquine with trametinib and/or dabrafenib may lower the chance of brain tumors growing or spreading compared to usual treatments.

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.

What data supports the idea that Dabrafenib + Trametinib + Hydroxychloroquine for Brain Tumor is an effective treatment?

The available research shows that the combination of Dabrafenib and Trametinib has been effective in treating brain tumors with a specific mutation called BRAF V600E. In a case series, patients with this mutation in their brain tumors showed significant improvement when treated with these drugs. Additionally, in a trial involving patients with brain tumors, the combination of Dabrafenib and Trametinib was found to be active and safe. While there is no direct mention of Hydroxychloroquine in the context of brain tumors, the combination of Dabrafenib and Trametinib has shown promise in treating similar conditions, suggesting potential effectiveness when Hydroxychloroquine is added. ^{1 2 3 4 5}

What data supports the effectiveness of the drug combination Dabrafenib, Trametinib, and Hydroxychloroquine for brain tumors?

Research shows that the combination of Dabrafenib and Trametinib has been effective in treating brain tumors with a specific mutation (BRAF V600E), leading to significant clinical responses. This combination has also been successful in treating other cancers like melanoma, suggesting potential benefits for brain tumors. ^{1 2 3 4 5}

What safety data is available for the treatment of Dabrafenib, Trametinib, and Hydroxychloroquine for brain tumors?

The combination of Dabrafenib and Trametinib has been studied extensively in patients with BRAF V600-mutated conditions, such as metastatic melanoma and glioma. These studies indicate that the combination is generally well-tolerated, with most adverse events being mild or moderate and manageable. Common side effects include fever, skin-related issues, and gastrointestinal symptoms. Serious adverse events like heart failure, deep vein thrombosis, and cerebral infarction have been reported but are less common. Hydroxychloroquine's safety profile is not detailed in these studies, but it is generally known to be well-tolerated with long-term use in other conditions. Overall, the combination of Dabrafenib and Trametinib is considered to have a manageable safety profile, but close monitoring for serious side effects is recommended. ^{1 3 6 7 8}

Is the combination of Dabrafenib, Trametinib, and Hydroxychloroquine generally safe for humans?

Dabrafenib and Trametinib have been used together in treating certain types of melanoma and other cancers, showing a manageable safety profile with most side effects being mild or moderate. However, serious side effects like heart problems and bleeding have been reported with Trametinib, and a case of cerebral infarction (a type of stroke) was noted with the combination. Hydroxychloroquine is generally safe but can cause side effects like vision changes and heart issues. ^{1 3 6 7 8}

Is the drug Dabrafenib and Trametinib a promising treatment for brain tumors?

Yes, Dabrafenib and Trametinib show promise as a treatment for brain tumors, especially those with a specific mutation called BRAF V600E. Studies have shown that this drug combination can lead to significant improvements in patients with brain tumors, including better survival rates and reduced side effects. ^{1 2 3 4 6}

What makes the drug combination of Dabrafenib, Trametinib, and Hydroxychloroquine unique for treating brain tumors?

This drug combination is unique because it targets the BRAF V600E mutation, which is a common driver in certain brain tumors, using a dual inhibitor approach with Dabrafenib and Trametinib, and it is being explored for its potential to improve outcomes in brain tumors where effective treatments are limited. ^{1 2 3 4 6}

Research Team

Lindsey Hoffman, DO

Principal Investigator

Phoenix Children's Hospital

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

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]

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]

References

1. England 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. [2022]

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. England 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). [2023]

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

A case of intracranial hemorrhage caused by combined dabrafenib and trametinib therapy for metastatic melanoma. [2022]

5. United States 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. [2022]

6. Singapore 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. [2023]

7. France pubmed.ncbi.nlm.nih.gov

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

8. France pubmed.ncbi.nlm.nih.gov

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