Dabrafenib Clinical Trials

What Is Dabrafenib?

Dabrafenib is an FDA-approved medication for melanoma, lung cancer, and glioma. It is a targeted therapy that works by inhibiting the BRAF protein, specifically in cancers with a BRAF V600 gene mutation. This mutation can cause uncontrolled cell growth. By blocking the abnormal BRAF protein, dabrafenib aims to slow or stop the growth of cancer cells.

In clinical trials, dabrafenib is being investigated for a range of conditions, often in combination with other drugs. These include various types of melanoma, such as metastatic, unresectable, malignant, and different stages of cutaneous melanoma. It is also under study for other cancers, including thyroid cancer, and for conditions characterized by a BRAF gene mutation, such as Erdheim-Chester Disease. A total of 147 trials have been conducted or are ongoing, with 27 currently recruiting participants. These studies have enrolled 28,715 participants since the first trial began in 2011.

Uses and Conditions Under Study

Dabrafenib is primarily studied for various forms of cancer, especially those with specific genetic mutations. The majority of research focuses on melanoma, a type of skin cancer.

• Melanoma: Dabrafenib is extensively studied for different stages and types of melanoma, including metastatic, unresectable, and malignant melanoma, as well as specific stages like Stage IIIC and Stage IV cutaneous melanoma. These studies often target melanomas with a BRAF V600 gene mutation, which dabrafenib is designed to inhibit. There are 79 trials specifically investigating dabrafenib for melanoma and its subtypes.
• Other Cancers: Beyond melanoma, dabrafenib is also being investigated for other types of cancer. This includes thyroid cancer, where it is being studied in 5 trials. Additionally, 12 trials are broadly investigating dabrafenib for various forms of cancer, often focusing on advanced cases or those with specific genetic alterations.
• BRAF Gene Mutation-Related Conditions: Dabrafenib's mechanism of action targets the BRAF V600 gene mutation. Therefore, it is also being studied for other rare conditions linked to this mutation, such as Erdheim-Chester Disease (ECD). Six trials specifically focus on the BRAF gene mutation itself, exploring its role across different tumor types.

These studies aim to evaluate the efficacy and safety of dabrafenib, sometimes as a monotherapy but often in combination with other targeted therapies like trametinib, or with immunotherapies and other agents.

Dosing

Dabrafenib is typically administered orally, usually as tablets.

• Adult Dosing: For adult patients (18 years and older), a common dosage studied is 150 mg (often as two 75 mg tablets) taken twice daily. This results in a total daily dose of 300 mg. This regimen is typically continued throughout each 28-day cycle of treatment.
• Pediatric Dosing: For pediatric patients, dosing is adjusted based on age and body weight:
  • Children aged 1 to less than 12 years typically receive dabrafenib as 10 mg dispersible tablets, taken orally twice daily. The specific dose is adjusted according to their body weight.
  • For pediatric patients aged 12-15 years and young adults (TYA patients) aged 16 to less than 18 years, specific dosing schedules are also established, though the exact details are not provided here.

Dabrafenib is often studied in combination with other medications, such as trametinib, and the precise dosage and administration schedule can vary depending on the specific clinical trial design and the condition being treated.

Side Effects

In clinical trials involving over 1600 patients, the most common side effect reported with Dabrafenib was fever (pyrexia). 56.1% of patients taking Dabrafenib experienced fever, compared to 29.3% of patients on placebo. Other common side effects included:

• Fatigue: 36.6% of patients on Dabrafenib experienced fatigue, compared to 29.4% on placebo.
• Nausea: 34.4% of patients on Dabrafenib experienced nausea, compared to 25.0% on placebo.
• Headache: 31.9% of patients on Dabrafenib experienced headaches, compared to 25.5% on placebo.
• Diarrhea: 31.8% of patients on Dabrafenib experienced diarrhea, compared to 18.4% on placebo.
• Chills: 29.8% of patients on Dabrafenib experienced chills, compared to 13.8% on placebo.
• Joint pain (arthralgia): 28.9% of patients on Dabrafenib experienced joint pain, compared to 23.5% on placebo.
• Rash: 28.5% of patients on Dabrafenib experienced a rash, compared to 18.4% on placebo.

Clinical Trial Results

Clinical trials have evaluated Dabrafenib in different cancer types and treatment regimens:

Non-Small Cell Lung Cancer (NSCLC)

A study (NCT01336634) investigated Dabrafenib as a monotherapy and in combination with Trametinib in patients with BRAF V600E mutation-positive metastatic NSCLC. In Cohort A, where Dabrafenib was used as a monotherapy (121 participants):

• The overall response rate (ORR) was 22.3%.
• The median progression-free survival (PFS) was 5.4 months.
• The median overall survival (OS) was 12.7 months.
• The median duration of response (DoR) was 11.8 months.

In Cohort B, patients received the combination of Dabrafenib and Trametinib (92 participants):

• The ORR was 42.4%.
• The median PFS was 10.2 months.
• The median OS was 18.2 months.
• The median DoR was 9.8 months.

Melanoma

A study (NCT01584648) compared Dabrafenib plus placebo to Dabrafenib plus Trametinib in patients with BRAF-mutant melanoma. For patients receiving Dabrafenib plus placebo (285 participants):

• The ORR was 39.6%.
• The median PFS was 8.8 months.
• The median OS was 18.7 months.
• The median DoR was 10.2 months.

For patients receiving Dabrafenib plus Trametinib (303 participants):

• The ORR was 48.2%.
• The median PFS was 10.2 months.
• The median OS was 25.8 months.
• The median DoR was 12.9 months.

Another study (NCT01597908) compared Dabrafenib plus Trametinib to Vemurafenib alone in patients with unresectable or metastatic BRAF V600E/K cutaneous melanoma. Patients treated with Dabrafenib plus Trametinib had an ORR of 68%, a median PFS of 12.1 months, a median OS of 26.0 months, and a median DoR of 13.8 months. In comparison, patients treated with Vemurafenib alone had an ORR of 53%, a median PFS of 7.3 months, a median OS of 17.8 months, and a median DoR of 8.5 months.

In an adjuvant treatment study (NCT01682083) for high-risk BRAF V600 mutation-positive melanoma, Dabrafenib and Trametinib combination therapy showed improved outcomes compared to placebo. The median freedom from relapse (FFR), relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS) were not reached for the combination therapy group, indicating longer survival times. For the placebo group, the median FFR and RFS were 16.6 months, while DMFS and OS medians were not reached.

Pediatric Tumors

A study (NCT01677741) evaluated the safety, tolerability, and pharmacokinetics of oral Dabrafenib in children and adolescents with BRAF V600 mutation-positive tumors. In this study, all 10 participants with high-grade gliomas (HGG) showed a best overall response, and all 24 participants with low-grade gliomas (LGG) also showed a best overall response. Treatment-emergent adverse events were observed across various dose escalation and tumor-specific expansion cohorts.

Currently Recruiting Trials

Where to Participate

• Anchorage, Alaska (7)
• Milwaukee, Wisconsin (7)
• St Louis, Missouri (7)
• Fargo, North Dakota (6)
• Chicago, Illinois (6)
• Miami, Florida (6)
• Pontiac, Michigan (5)
• Flint, Michigan (5)
• San Francisco, California (5)
• Ann Arbor, Michigan (5)

Development Timeline

• Phase II trials account for the largest portion with 68 studies.
• Phase I trials represent 27 studies, exploring initial safety and dosing.
• Combined Phase I/Phase II studies number 17.
• Later-stage development includes 10 Phase III trials and 4 Phase IV studies, indicating progression towards broader use and long-term assessment.