Triple Drug Therapy for Thyroid Cancer

Recruiting at 5 trial locations

Overseen By Mark Zafereo

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Dabrafenib, Trametinib

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Cardiovascular impairment, Untreated brain metastases, Autoimmune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 6

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase II trial studies the effect of pembrolizumab, dabrafenib, and trametinib before surgery in treating patients with BRAF V600E-mutated anaplastic thyroid cancer. BRAF V600E is a specific mutation (change) in the BRAF gene, which makes a protein that is involved in sending signals in cells and in cell growth. It may increase the growth and spread of tumor cells. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Pembrolizumab, dabrafenib, and trametinib may help to control BRAF V600E-mutated anaplastic thyroid cancer when given before surgery.

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

The trial protocol does not specify if you need to stop your current medications. However, if you are on chemotherapy, you must not have received it within 1 week prior to the study. If you are on dabrafenib/trametinib, you may continue according to the standard run-in. Please consult with the trial team for guidance on your specific medications.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on certain treatments like chemotherapy, you may need to wait at least one week before starting the trial. It's best to discuss your specific medications with the trial team.

What safety data exists for triple drug therapy in thyroid cancer?

The safety data for the combination of Dabrafenib, Trametinib, and Pembrolizumab in thyroid cancer shows that common adverse events include skin disorders, fever, hyperglycemia, nausea, chills, and fatigue. No treatment-related deaths were reported. The combination therapy was generally well tolerated, with no new safety signals detected. These findings are based on multiple studies evaluating the efficacy and safety of Dabrafenib and Trametinib in BRAF V600E-mutated thyroid cancers, including differentiated and anaplastic types. ^{1 2 3 4 5}

Is the triple drug therapy for thyroid cancer safe for humans?

The combination of Dabrafenib and Trametinib has been studied in thyroid cancer patients and is generally well tolerated, with common side effects including skin issues, fever, fatigue, and nausea. No treatment-related deaths were reported, and no new safety concerns were identified in the studies. ^{1 2 3 4 5}

Is the drug combination of Dabrafenib, Pembrolizumab, and Trametinib promising for thyroid cancer?

Yes, the combination of Dabrafenib and Trametinib shows promise for treating a specific type of thyroid cancer with a BRAF V600E mutation. It has been effective in improving survival rates and has been well tolerated by patients, representing a significant advancement for this rare and aggressive cancer. ^{2 3 4 5 6}

What makes the triple drug therapy for thyroid cancer unique?

This triple drug therapy combines dabrafenib, pembrolizumab, and trametinib, targeting BRAF V600E mutations in thyroid cancer, which is a novel approach as it combines targeted therapy with immunotherapy, potentially offering a more effective treatment for this aggressive cancer type. ^{2 3 4 5 6}

What data supports the idea that Triple Drug Therapy for Thyroid Cancer is an effective treatment?

The available research shows that the combination of Dabrafenib and Trametinib, which are part of the Triple Drug Therapy, has been effective in treating certain types of thyroid cancer, particularly those with a specific mutation called BRAF V600E. In one study, this combination was shown to have a significant impact on survival in patients with anaplastic thyroid cancer, a very aggressive form of the disease. Another study found that Dabrafenib and Trametinib together had a similar response rate to Dabrafenib alone in treating differentiated thyroid cancer that does not respond to radioactive iodine. This suggests that while the combination is effective, it may not always be superior to using Dabrafenib by itself. Overall, these drugs have shown promise in treating thyroid cancer with specific genetic mutations. ^{1 2 3 5 7}

What data supports the effectiveness of the drug combination Dabrafenib, Trametinib, and Pembrolizumab for thyroid cancer?

Research shows that the combination of Dabrafenib and Trametinib is effective in treating thyroid cancers with specific BRAF mutations, such as anaplastic thyroid cancer, by inhibiting cancer cell growth. Although Pembrolizumab is not specifically mentioned in these studies, it is known to enhance the immune system's ability to fight cancer in other contexts. ^{1 2 3 5 7}

Who Is on the Research Team?

Mark Zafereo

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with anaplastic thyroid cancer that has a specific BRAF V600E gene mutation. Participants must have measurable disease, agree to biopsies and surgery if possible, not be pregnant or breastfeeding, use contraception, and have good organ function and performance status. Exclusions include significant heart issues, untreated brain metastases, active autoimmune diseases requiring treatment within the past 2 years, severe allergies to pembrolizumab or its components.

Inclusion Criteria

Your hemoglobin level is at least 9.0 g/dL or 5.6 mmol/L.

You have a disease that can be measured using specific guidelines.

You have enough infection-fighting white blood cells in your body.

Exclusion Criteria

Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

I am not pregnant or breastfeeding.

I have a history of serious eye conditions like RVO, CSR, or uncontrolled glaucoma.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Phase

Patients receive dabrafenib, trametinib, and pembrolizumab before surgery to assess tumor response and resectability

9-15 weeks

3-5 cycles of treatment, each cycle lasting 21 days

Surgery

Patients undergo surgery if the disease is deemed resectable after neoadjuvant treatment

1 day

Adjuvant Phase

Post-surgery, patients may receive pembrolizumab and undergo IMRT with or without additional chemotherapy

6 weeks

Concurrent treatment with pembrolizumab and IMRT

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 72 months

Every 3 months during years 1-2, every 6 months during years 3-4, then annually

What Are the Treatments Tested in This Trial?

Interventions

• Dabrafenib
• Pembrolizumab
• Trametinib

Trial Overview The study tests the combination of pembrolizumab (an immune system booster), dabrafenib and trametinib (which block enzymes aiding tumor growth) before surgery in patients with a certain type of thyroid cancer. The goal is to see if this pre-surgery treatment can help control the cancer better.

How Is the Trial Designed?

Group I: Treatment (dabrafenib, trametinib, pembrolizumab) Experimental Treatment 6 Interventions

Patients receive 21-day cycles of dabrafenib 150 mg orally (PO) twice daily from Days 1-21, trametinib 2mg PO once daily from Days 1-21, and pembrolizumab 200mg intravenously (IV) on Day 1 of each cycle.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

In a phase II trial involving 24 patients with radioactive iodine refractory metastatic differentiated thyroid cancer, dabrafenib and trametinib treatment led to a partial response in 38% of patients at 6 months, indicating its efficacy in restoring iodine uptake in BRAF p.V600E-mutated cases.

The treatment was associated with a high rate of adverse events (96%), although only 10 patients experienced severe (grade 3-4) adverse effects, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory BRAF p.V600E-Mutated Differentiated Thyroid Cancer. Leboulleux, S., Do Cao, C., Zerdoud, S., et al.[2023]

In a study of 36 patients with BRAF V600E-mutant anaplastic thyroid cancer, the combination of dabrafenib and trametinib showed a significant overall response rate of 56%, with three patients achieving complete responses.

The treatment demonstrated manageable safety, with no new adverse effects identified, and improved median progression-free survival of 6.7 months and overall survival of 14.5 months, indicating it is a promising option for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study. Subbiah, V., Kreitman, RJ., Wainberg, ZA., et al.[2022]

In a phase 2 trial involving 53 patients with BRAF-mutated radioactive iodine refractory differentiated thyroid cancer, both dabrafenib monotherapy and the combination of dabrafenib + trametinib showed similar objective response rates, with 42% and 48% respectively, indicating no significant advantage of the combination therapy.

The most common side effects included skin disorders and fever, but there were no treatment-related deaths, suggesting that both treatment options are relatively safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib Versus Dabrafenib + Trametinib in BRAF-Mutated Radioactive Iodine Refractory Differentiated Thyroid Cancer: Results of a Randomized, Phase 2, Open-Label Multicenter Trial. Busaidy, NL., Konda, B., Wei, L., et al.[2023]

In a study of 27 patients with anaplastic thyroid carcinoma (ATC), those treated with the combination of Dabrafenib and Trametinib (DT) had a median overall survival of 475 days, significantly longer than the 156 days for multimodal therapy and 39 days for compassionate care (P < .001).

The DT group also demonstrated a median progression-free survival of 270 days, compared to less than 32 days for BRAF wild type patients, with no severe adverse events reported, indicating a strong safety and efficacy profile for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Target therapy for BRAF mutated anaplastic thyroid cancer: a clinical and molecular study. da Silva, TN., Rodrigues, R., Saramago, A., et al.[2023]

Dabrafenib, a BRAF inhibitor, effectively reduced the viability of anaplastic thyroid cancer (ATC) cells with BRAF mutations by inducing cell cycle arrest, while trametinib, a MEK inhibitor, showed variable efficacy across different ATC cell lines.

The study revealed that combining both inhibitors had a cytostatic effect on all tested ATC cells, but resistance mechanisms, such as increased SNAI1 expression, were observed, particularly in cells with specific mutations, indicating the need for tailored treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Growth arrest by activated BRAF and MEK inhibition in human anaplastic thyroid cancer cells. Kurata, K., Onoda, N., Noda, S., et al.[2017]

In a phase II trial involving 16 patients with BRAF V600E-mutated anaplastic thyroid cancer, the combination of dabrafenib and trametinib showed a high overall response rate of 69%, indicating significant efficacy in a cancer type with previously limited treatment options.

The treatment was well tolerated, with common side effects including fatigue, fever, and nausea, and no new safety concerns were identified, marking a promising advancement for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer. Subbiah, V., Kreitman, RJ., Wainberg, ZA., et al.[2022]

The use of neoadjuvant therapy with dabrafenib and trametinib in a patient with locally advanced recurrent differentiated thyroid carcinoma (DTC) led to a significant radiographic response, allowing for a less invasive partial laryngectomy instead of a total laryngectomy.

This approach not only preserved the patient's voice and allowed for early resumption of oral feeding but also demonstrated that neoadjuvant treatment can effectively reduce the extent of surgery needed, potentially lowering associated complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant dabrafenib and trametinib for functional organ preservation in recurrent BRAF V600E-mutated papillary thyroid cancer. Farlow, JL., McCrary, HC., Sipos, JA., et al.[2023]

Citations

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

A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory BRAF p.V600E-Mutated Differentiated Thyroid Cancer. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study. [2022]

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

Dabrafenib Versus Dabrafenib + Trametinib in BRAF-Mutated Radioactive Iodine Refractory Differentiated Thyroid Cancer: Results of a Randomized, Phase 2, Open-Label Multicenter Trial. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Target therapy for BRAF mutated anaplastic thyroid cancer: a clinical and molecular study. [2023]

5. Greece pubmed.ncbi.nlm.nih.gov

Growth arrest by activated BRAF and MEK inhibition in human anaplastic thyroid cancer cells. [2017]

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

Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Neoadjuvant dabrafenib and trametinib for functional organ preservation in recurrent BRAF V600E-mutated papillary thyroid cancer. [2023]