Dabrafenib + Trametinib for Thyroid Cancer

Recruiting at 41 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

153 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests two drugs, dabrafenib and trametinib, on adults with a specific type of advanced thyroid cancer. These patients have a genetic mutation and have not responded to other treatments. The drugs work by blocking proteins that help cancer cells grow.

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.

What data supports the effectiveness of the drug Dabrafenib + Trametinib for thyroid cancer?

Research shows that the combination of Dabrafenib and Trametinib is effective in treating thyroid cancers with specific genetic mutations (BRAF V600E), as seen in studies where it helped stop cancer cell growth and was approved for use in certain aggressive thyroid cancers. ^{1 2 3 4 5}

Is the combination of Dabrafenib and Trametinib safe for humans?

The combination of Dabrafenib and Trametinib has been generally well tolerated in humans, with common side effects including fatigue, fever, and nausea. No new safety concerns were identified in studies involving thyroid cancer and melanoma patients. ^{1 3 4 6 7}

How is the drug combination of Dabrafenib and Trametinib unique for treating thyroid cancer?

The combination of Dabrafenib and Trametinib is unique for treating thyroid cancer because it specifically targets BRAF V600E mutations, which are common in certain aggressive forms of thyroid cancer like anaplastic thyroid cancer (ATC). This combination has been shown to be effective in patients with these mutations, offering a targeted approach compared to traditional treatments. ^{1 3 4 5 8}

Eligibility Criteria

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

I am 18 years old or older.

My tumor has the BRAFV600E mutation.

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

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

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

Treatment Details

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.

Participant Groups

Group I: Dabrafenib plus trametinib Experimental Treatment 2 Interventions

Participants will be treated with dabrafenib twice daily and trametinib once daily

Group II: Placebo dabrafenib plus placebo trametinib Placebo Group 2 Interventions

Participants will receive placebo dabrafenib twice daily and placebo trametinib once daily

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

Findings from Research

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]

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 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]

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 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 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]

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]

References

1. 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]

2. Greece pubmed.ncbi.nlm.nih.gov

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

3. 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]

4. 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]

5. England pubmed.ncbi.nlm.nih.gov

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

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. France pubmed.ncbi.nlm.nih.gov

Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF (V600) Mutation. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Effects of dabrafenib and erlotinib combination treatment on anaplastic thyroid carcinoma. [2022]