Dabrafenib + Trametinib for Thyroid Cancer

Not currently recruiting at 52 trial locations

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Novartis Pharmaceuticals

Must not be taking: BRAF inhibitors, MEK inhibitors

Disqualifiers: Anaplastic carcinoma, Medullary carcinoma, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 5

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial evaluates whether dabrafenib (a BRAF inhibitor) and trametinib are effective and safe for treating Differentiated Thyroid Cancer (DTC) that does not respond to standard radioactive iodine therapy. It targets patients whose cancer has worsened after one or two treatments aimed at the VEGFR protein. Ideal candidates for this trial have advanced DTC, a specific BRAF V600E gene mutation, and have not found success with other treatments. Participants will receive either the new drug combination or a placebo to compare outcomes. As a Phase 3 trial, this study serves as the final step before potential FDA approval, offering patients early access to promising treatments.

Will I have to stop taking my current medications?

The trial requires that you stop taking any small molecule kinase inhibitors at least 2 weeks before joining, and any cancer antibody or systemic chemotherapy at least 4 weeks before joining. If you are on these medications, you will need to stop them before participating.

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

Studies have shown that the combination of dabrafenib and trametinib is generally well-tolerated in patients with certain types of cancer, including thyroid cancer. Research indicates that this treatment is safe for most patients, as they did not experience severe side effects.

In previous studies with patients who have the BRAFV600E mutation, dabrafenib and trametinib together effectively treated the cancer and were safe to use. The most common side effects were mild, such as fatigue, fever, or nausea. While these side effects were common, they were usually easy to manage and not serious.

This combination treatment has also been used successfully in other types of cancer, which supports confidence in its safety. Patients should discuss possible side effects and any concerns with their doctor before joining a clinical trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for thyroid cancer?

Researchers are excited about Dabrafenib and Trametinib for thyroid cancer because these drugs specifically target the BRAF gene mutation, which is often involved in the growth of cancer cells. Unlike standard treatments like surgery or radioactive iodine, which are more generalized, Dabrafenib and Trametinib work by inhibiting specific cancer-driving pathways. This targeted approach has the potential to be more effective for patients with this specific genetic mutation, offering a more personalized therapy option.

What evidence suggests that dabrafenib and trametinib could be effective for thyroid cancer?

This trial will compare the combination of dabrafenib and trametinib with a placebo in treating thyroid cancer with the BRAFV600E mutation. Research has shown that this combination may help treat this type of thyroid cancer. In one study, 69% of patients with this mutation experienced significant tumor shrinkage. Another study found strong positive effects in a similar type of thyroid cancer. This combination blocks enzymes that cancer cells need to grow. These early results suggest it could be effective for patients whose cancer did not respond to other treatments. ^{2 3 6 7 8}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

Adults over 18 with advanced thyroid cancer that's not responding to radioactive iodine and has a specific mutation (BRAFV600E) can join. They must have tried at least one but no more than two prior therapies targeting VEGFR, be in decent physical condition, and have at least one tumor that can be measured. People who've had certain other cancers or treatments recently, or those with eye disease risks, cannot participate.

Inclusion Criteria

My tumor has the BRAFV600E mutation.

Signed informed consent must be obtained prior to performing any specific pre-screening and screening procedure

My thyroid cancer does not respond to radioactive iodine treatment.

Exclusion Criteria

I have been treated with BRAF or MEK inhibitors before.

My thyroid cancer is RET fusion positive.

I haven't had cancer treatment with antibodies or chemotherapy in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive dabrafenib plus trametinib or placebo until disease progression or other criteria are met

Up to 2 years

Visits at week 4, week 8, week 12, week 20, and every 12 weeks thereafter

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Open-label extension

Participants in the placebo arm may cross over to receive dabrafenib plus trametinib if progression is confirmed

What Are the Treatments Tested in This Trial?

Interventions

• Dabrafenib
• Trametinib

Trial Overview

The trial is testing the effectiveness of combining Dabrafenib and Trametinib against placebos in patients whose thyroid cancer has worsened despite previous treatment. Participants will be randomly assigned to either the drug combo or placebo group in a 2:1 ratio based on their past treatments.

How Is the Trial Designed?

Group I: Dabrafenib plus Trametinib Experimental Treatment 2 Interventions

Eligible participants will receive Dabrafenib 150 mg twice a day (BID) and Trametinib 2 mg once a day (QD) until disease progression as per RECIST 1.1 as confirmed by blinded independent review committee (BIRC), unacceptable toxicity, pregnancy, loss of clinical benefit as determined by the investigator, withdrawal of consent, lost to follow-up, death, or study termination by the sponsor.

Group II: Dabrafenib Placebo plus Trametinib Placebo Placebo Group 2 Interventions

Eligible participants will receive matching placebo for Dabrafenib 150 mg twice a day (BID) and matching placebo for Trametinib 2 mg once a day (QD) until disease progression as per RECIST 1.1 as confirmed by blinded independent review committee (BIRC), unacceptable toxicity, pregnancy, loss of clinical benefit as determined by the investigator, withdrawal of consent, lost to follow-up, death, or study termination by the sponsor.

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?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

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]

The combination of dabrafenib and erlotinib significantly enhances the inhibition of cell proliferation, colony formation, and migration in BRAF-mutated anaplastic thyroid carcinoma (ATC) cells, compared to using either drug alone.

This combination treatment also effectively suppresses tumor growth and induces apoptosis in an in vivo xenograft model, suggesting it could be a promising strategy to overcome resistance to dabrafenib in patients with BRAF-mutated ATC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of dabrafenib and erlotinib combination treatment on anaplastic thyroid carcinoma. Choi, YS., Kwon, H., You, MH., et al.[2022]

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]

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 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]

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 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 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]

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Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy beams to ...

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ascopubs.org/doi/10.1200/JCO.2017.73.6785

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Dabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E–mutated anaplastic thyroid cancer and was well ...

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This study reported promising efficacy against BRAF V600-mutant tumours. Dabrafenib and trametinib would offer a new therapeutic option for rare cancers.