Triple Drug Therapy for Thyroid Cancer

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—pembrolizumab, dabrafenib (a BRAF inhibitor), and trametinib—to determine their effectiveness in treating BRAF V600E-mutated anaplastic thyroid cancer. The aim is to shrink tumors before surgery by halting their growth and aiding the immune system in attacking cancer cells. Individuals with this type of thyroid cancer and a BRAF V600E mutation may be suitable candidates for the trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Studies have shown that the combination of pembrolizumab, dabrafenib, and trametinib holds promise for treating thyroid cancer with the BRAF V600E mutation. Research suggests that this treatment can control tumor growth and improve surgical outcomes.

The safety data is encouraging. Previous research has not reported any treatment-related deaths. These drugs have been used in other studies and are generally well-tolerated. Most side effects, if they occur, are usually manageable and not life-threatening.

This treatment is currently in a Phase 2 trial, indicating it has passed initial safety tests in humans. Researchers are still gathering more information to confirm its safety and effectiveness. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of dabrafenib, trametinib, and pembrolizumab for thyroid cancer because it targets the disease in a way current treatments don't. Most existing options focus on traditional chemotherapy or radioactive iodine treatment, but this triple therapy combines targeted therapy and immunotherapy. Dabrafenib and trametinib specifically target the BRAF mutation and MEK pathway, which are often involved in thyroid cancer growth, while pembrolizumab stimulates the immune system to attack cancer cells. This multi-faceted approach could potentially offer more effective treatment, especially for patients whose cancers are resistant to standard therapies.

What evidence suggests that this trial's treatments could be effective for BRAF V600E-mutated anaplastic thyroid cancer?

Research has shown that combining the drugs dabrafenib, trametinib, and pembrolizumab may effectively treat BRAF V600E-mutated anaplastic thyroid cancer. This trial will evaluate the effectiveness of this combination. Studies have found that dabrafenib and trametinib work well together against this cancer. Adding pembrolizumab, an immune therapy, might enhance the treatment by strengthening the immune system to fight cancer cells. In earlier trials, patients taking dabrafenib and trametinib lived without cancer progression for an average of 6.7 months and had an overall survival time of 13.5 months. With pembrolizumab added, researchers hope for even better results. ^{1 2 3 4 6}

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 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 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]

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]

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 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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S0305737225001641

Effectiveness of immune checkpoint inhibitor therapy in ... A phase II trial (NCT04675710) aims to assess its response in combination with dabrafenib and trametinib in BRAFV600E-mutated ATC, while a ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12432571/

Clinical outcomes of dabrafenib plus trametinib in locally ... Subbiah et al. reported that this combination showed strong clinical activity in anaplastic thyroid cancer (ATC) with the BRAF V600E mutation [18,21]. An open- ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6008

Neoadjuvant pembrolizumab in combination with ... Median PFS and OS of DT without pembrolizumab were 6.7 and 13.5 months, respectively, in the ROAR trial. Neoadjuvant DTP achieved locoregional ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04675710

NCT04675710 | Pembrolizumab, Dabrafenib, and ... Pembrolizumab, dabrafenib, and trametinib may help to control BRAF V600E-mutated anaplastic thyroid cancer when given before surgery. Detailed Description.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7341904/

Targeted Therapy for Advanced Thyroid Cancer: Kinase ... Updated efficacy and safety data of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E–mutated anaplastic thyroid cancer (ATC) [abstract].

6. merck.com merck.com/news/new-data-for-keytruda-pembrolizumab-in-combination-with-talimogene-laherparepvec-dabrafenib-plus-trametinib-or-low-dose-ipilimumab-in-advanced-melanoma-presented-at-2016-asco-annual-meeting/

New Data for KEYTRUDA® (pembrolizumab) in ... There were no treatment-related deaths. The phase 2 part of the study is ongoing and will further evaluate the safety and efficacy of the KEYTRUDA combination ...