Dabrafenib + Trametinib + Hydroxychloroquine for Brain Tumor
Recruiting in Palo Alto (17 mi)
+14 other locations
Age: < 65
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Waitlist Available
Sponsor: Pediatric Brain Tumor Consortium
No Placebo Group
Breakthrough Therapy
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.
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.
14578What 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.
23578What 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.
14567Do 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.
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 am a sexually active male and will use a condom to prevent fathering a child.
My neurological condition is stable and any seizures are under control.
My blood, liver, kidney, and heart functions meet the required levels.
I can do most activities but may need help.
My cancer has returned or worsened and has a specific genetic makeup.
Exclusion Criteria
I am not on any other cancer treatment or experimental drugs.
I have certain eye conditions or active stomach/intestine issues.
Participant Groups
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.
6Treatment groups
Experimental Treatment
Group I: Phase 2 Stratum 6 LGG with NF Type 1Experimental Treatment2 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 aberrationExperimental Treatment2 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 mutationExperimental Treatment3 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 mutationExperimental Treatment3 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 NF1Experimental Treatment2 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 HGGExperimental Treatment3 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
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Lurie Children's Hospital-ChicagoChicago, IL
Memorial Sloan Kettering Cancer CenterNew York, NY
Children's Healthcare of AtlantaAtlanta, GA
St. Jude Children Research HospitalMemphis, TN
More Trial Locations
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Who is running the clinical trial?
Pediatric Brain Tumor ConsortiumLead Sponsor
National Cancer Institute (NCI)Collaborator
American Lebanese Syrian Associated Charities (ALSAC)Collaborator
American Lebanese Syrian Associated CharitiesCollaborator
References
A case of intracranial hemorrhage caused by combined dabrafenib and trametinib therapy for metastatic melanoma. [2022]Combination therapy with BRAF V600E inhibitor dabrafenib and MEK inhibitor trametinib significantly improves progression-free survival of patients with BRAF V600-positive metastatic melanoma, but their use can be associated with life-threatening toxicities. We report the case of a patient receiving dabrafenib and trametinib for metastatic melanoma who developed intracranial hemorrhage while on therapy. Combination therapy with dabrafenib and trametinib improves progression-free survival of patients with BRAF V600-positive metastatic melanoma. Nevertheless, it is associated with an increased incidence and severity of any hemorrhagic event. To the best of our knowledge, this is the first report of intracranial hemorrhage with pathological confirmation.
Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF (V600) Mutation. [2022]The BRAF inhibitor dabrafenib (Tafinlar(®)) and the MEK inhibitor trametinib (Mekinist(®)) are indicated, as monotherapy or in combination with each other, for the treatment of patients with unresectable or metastatic melanoma with a BRAF (V600) mutation. This article reviews the therapeutic efficacy and tolerability of combination treatment with dabrafenib and trametinib in this indication and summarizes relevant pharmacological data. Dabrafenib plus trametinib significantly prolonged progression-free survival (PFS) and overall survival (OS), improved objective response rates (ORRs) and preserved health-related quality of life (HR-QOL) to a greater extent than dabrafenib (in the double-blind COMBI-d study) and vemurafenib (in the open-label COMBI-v study) in two large, randomized, phase III studies in treatment-naïve patients with unresectable or metastatic melanoma with BRAF (V600E/K) mutation. Limited treatment benefit with the combination was also seen in patients who had progressed on prior BRAF inhibitor therapy, as indicated by ORRs of ≤ 15 % and stable disease in ≤ 50 % of patients in small phase I and II studies. Combination therapy did not increase overall toxicity relative to dabrafenib or vemurafenib monotherapy, with most adverse events (AEs) mild or moderate in severity and generally manageable. Fewer skin-related AEs (e.g. cutaneous malignancies, hyperkeratinosis and hand-foot syndrome) were reported with combination therapy than with dabrafenib or vemurafenib, probably because of reduced paradoxical activation of the MAPK pathway. Thus, dabrafenib plus trametinib provides an important treatment option for patients with BRAF (V600) mutation-positive unresectable or metastatic melanoma.
Trametinib (MEKINIST°) Metastatic or inoperable BRAF V600-positive melanoma: a few extra months of life. [2019]About 50% of patients with meta- static or inoperable melanoma carry a tumour with BRAF V600 mutation.The drug of first choice for these patients is vemurafenib, a BRAF inhibitor, which appears to prolong survival by a few months. Dabrafenib is a vemurafenib me-too with a slightly different known profile of adverse effects. Trametinib, a MEK inhibitor, is now authorised in the European Union for use in this setting, either as monotherapy or in combination with dabrafenib (marketed by the same company). Trametinib monotherapy has not been compared to BRAF inhibitor monotherapy. In a randomised, unblinded trial versus cytotoxic drugs in 322 patients, the median survival time did not differ statistically between the groups (15.6 versus 11.3 months; p = 0.09), but 65% of patients in the chemotherapy group received trametinib after disease pro- gression, making it more difficult to detect a difference between the groups. In an unblinded randomised controlled trial in 704 patients who had never received treatment for metastatic or inoperable disease, the trametinib + dabrafenib combination prolonged median survival by about 8 months more than vemurafenib. In another double-blind randomised controlled trial in 423 patients, median survival was about 6 months longer with trametinib + dabrafenib than with placebo + dabrafenib. The trametinib+ dabrafenibcombination was poorly effective after BRAF inhibitor failure in non-comparative trials including a few dozen patients in which the only endpoint was tumour response. Trametinib has many adverse effects, some of which can be life-threatening, such as heart failure, deep vein thrombosis, bleeding (including intracranial haemorrhage), neutropenia, and gastrointestinal perforation. Trametinib also causes retinal disorders and pneumonitis. Combining trametinib with dabrafenib reduces the risk of hyperkeratosis and skin cancer associated with dabrafenib, but increases the frequency of fever (including very high fever). Trametinib interactions mainly involve additive effects or antagonism. In practice, when a patient with metastatic or inoperable BRAF V600-positive melanoma is willing to accept the significant toxicity of trametinib in the hope of gaining several extra months of life, the trametinib + dabrafenib combination is a first-line option.
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]BRAF V600E is a common oncogenic driver in a variety of primary brain tumors. Dual inhibitor therapy using dabrafenib (a selective oral inhibitor of several mutated forms of BRAF kinase) and trametinib (a reversible inhibitor of MEK1 and MEK2) has been used successfully for treatment of metastatic melanoma, anaplastic thyroid cancer, and other tumor types, but has been reported in only a few patients with primary brain tumors and none with pleomorphic xanthoastrocytoma. Here, the authors report on the substantial clinical response and reduction in cutaneous toxicity in a case series of BRAF V600E primary brain cancers treated with dual BRAF/MEK inhibitor therapy.
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]In clinical trials, dabrafenib plus trametinib improved overall survival (OS) compared with single-agent BRAF inhibitors (BRAFi) in patients with BRAF V600-mutant unresectable or metastatic melanoma. We investigated dabrafenib plus trametinib therapy in a compassionate-use setting [Named Patient Program (NPP); DESCRIBE II]. A retrospective chart review of patients with BRAF V600-mutated unresectable stage III/IV melanoma receiving dabrafenib plus trametinib as compassionate use was conducted. Treatment patterns and duration, clinical outcomes, and tolerability were evaluated. Of 271 patients, 92.6% had stage IV melanoma, including 36.5% with brain metastases. Overall, 162 patients (59.8%) were BRAFi naive and 171 (63.1%) received first-line dabrafenib plus trametinib. Among BRAFi-naive patients, the overall response rate (ORR) was 67.3%, median OS (mOS) was 20.0 months, and median progression-free survival (mPFS) was 7.5 months. In BRAFi-naive patients with known brain metastases (n = 62), ORR was 61.3%, mOS was 15.5 months, and mPFS was 6.2 months. Eighty-four patients received BRAFi monotherapy for >30 days and switched to dabrafenib plus trametinib prior to progression. Of these 84 patients, 63 had known disease status at the time of switch, and 22 improved with the combination therapy. No new safety signals were identified, and dabrafenib plus trametinib was well tolerated. Dabrafenib plus trametinib showed substantial clinical activity in NPP patients with BRAF V600-mutated unresectable or metastatic melanoma. Analysis of treatment patterns demonstrated the effectiveness of the combination in patients with brain metastases and across lines of therapy with a well tolerated and manageable safety profile.
Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis. [2022]Dabrafenib plus trametinib was found to have robust antitumor activity in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). We report updated survival analysis of a phase 2 study (NCT01336634) with a minimum of 5-year follow-up and updated genomic data.
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]Label="BACKGROUND">Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAFV600E mutation-positive high-grade glioma and low-grade glioma.
Cerebral infarction after treatment with dabrafenib plus trametinib for BRAF-V600E-positive non-small cell lung cancer: A case report. [2023]Dabrafenib plus trametinib is the standard treatment for BRAF V600E-mutated non-small cell lung cancer. No treatment-related cerebral infarction (CI) has been reported in previous clinical trials. Here, we described a 61-year-old Japanese man with BRAF V600E-mutated lung adenocarcinoma treated with dabrafenib plus trametinib as a third-line treatment. On the 10th day of dabrafenib plus trametinib treatment, the patient developed fever and was urgently hospitalized on the 18th day owing to impaired consciousness. The patient had disseminated intravascular coagulation because of infection, was treated with thrombomodulin and ceftriaxone, and subsequently improved. On the 44th day, dabrafenib plus trametinib was resumed with a one-step dose reduction. Three hours after the first oral administration, the patient developed chills, fever, and hypotension. He received intravenous fluids. On the 64th day, 20 mg prednisolone was administered from the previous day, and dabrafenib plus trametinib was resumed with a further one-step reduction in dose. Five hours after the first oral administration, the patient developed fever, hypotension, paralysis of the right upper and lower limbs, and dysarthria appeared. Head magnetic resonance imaging revealed multiple cerebral infarcts. Hemoconcentration because of intravascular dehydration may have caused CI. In conclusion, CI should be taken into consideration during treatment with dabrafenib plus trametinib.