Dabrafenib + Trametinib + IMRT for Thyroid Cancer

Recruiting at3 trial locations

Overseen by Sasan Fazeli, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Manisha Shah

Must be taking: Dabrafenib, Trametinib

Must not be taking: Antiepileptics, Antiretrovirals

Disqualifiers: Other malignancy, Brain metastases, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial studies how well dabrafenib, trametinib, and intensity modulated radiation therapy (IMRT) work together in treating patients with BRAF mutated anaplastic thyroid cancer. 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 kill tumor cells and shrink tumors. Giving dabrafenib, trametinib, and IMRT together may kill more tumor cells.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it mentions that patients currently taking any prohibitive medication are excluded. It's best to discuss your current medications with the trial team to see if they are allowed.

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 BRAF mutations, as it can stop cancer cell growth in these cases. However, in some studies, the combination did not show superior results compared to Dabrafenib alone for certain types of thyroid cancer. ^{1 2 3 4 5}

Is the combination of Dabrafenib and Trametinib safe for humans?

The combination of Dabrafenib and Trametinib has been studied in various cancers, including thyroid and melanoma, and is generally considered safe for humans. Common side effects include fever, fatigue, and nausea, but these are usually mild or moderate and manageable. No new safety concerns have been identified in recent studies. ^{1 4 6 7 8}

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

The combination of Dabrafenib and Trametinib is unique for treating thyroid cancer with BRAF mutations because it targets specific genetic changes in the cancer cells, potentially allowing for more effective treatment in cases where traditional therapies like radioactive iodine are ineffective. This combination has shown promise in improving survival rates in aggressive forms of thyroid cancer, such as anaplastic thyroid cancer, by inhibiting key pathways that promote cancer cell growth. ^{1 4 5 9 10}

Research Team

Sasan Fazeli, MD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for adults with anaplastic thyroid cancer that has a specific BRAF mutation. They should be in good physical condition (ECOG < 2), have certain blood cell counts within range, and not be pregnant or breastfeeding. Participants must agree to use contraception and cannot have had certain recent treatments or have overlapping radiation therapy fields from past treatments.

Inclusion Criteria

Females are required to use an effective method of contraception

I can do all my daily activities without help.

My tumor has a BRAF mutation (V600E or V600K).

Exclusion Criteria

I am HIV-positive and/or on antiretroviral therapy.

Receiving any other investigational agent

I do not have any unmanaged ongoing illnesses.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive dabrafenib and trametinib for 7-28 days to assess safety and tolerability

1-4 weeks

Concurrent Radiation

Patients receive dabrafenib, trametinib, and undergo IMRT over 6.5 weeks

6.5 weeks

Post-Radiation

Patients continue dabrafenib and trametinib for 4 weeks post-radiation

4 weeks

Maintenance

Patients with residual disease continue treatment until progression or unacceptable toxicity; those with complete response stop treatment after 8 weeks

8 weeks

Follow-up

Participants are monitored every 2 months for 1 year after completion of study treatment

12 months

Treatment Details

Interventions

• Dabrafenib (Kinase Inhibitor)
• Intensity-Modulated Radiation Therapy (Radiation)
• Trametinib (Kinase Inhibitor)

Trial Overview The study tests the combination of two drugs, Dabrafenib and Trametinib, with intensity-modulated radiation therapy (IMRT) on patients with BRAF mutated anaplastic thyroid cancer. The goal is to see if this trio is more effective at stopping tumor growth than current methods.

Participant Groups

Group I: Treatment (dabrafenib, trametinib, IMRT) Experimental Treatment 3 Interventions

See Detailed Description

Dabrafenib is already approved in Canada, Japan for the following indications:

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?

Manisha Shah

Lead Sponsor

Trials

3

Recruited

80+

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

Robert Stone

City of Hope Medical Center

Chief Executive Officer since 2014

Juris Doctorate from the University of Chicago, Bachelor's degree in Political Science from the University of Redlands

Sumanta (Monty) Pal

City of Hope Medical Center

Chief Medical Officer since 2023

MD

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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]

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]

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 trametinib showed promising antitumor activity in Japanese patients with BRAF V600E/K mutant melanoma, with an overall response rate of 83% in both phase 1 and phase 2 of the study involving 12 patients.

The treatment was generally well-tolerated, with common adverse events including fever (75%) and increased liver enzymes (67%), indicating that while effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced cutaneous melanoma. Yamazaki, N., Tsutsumida, A., Takahashi, A., et al.[2018]

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]

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

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

6. France pubmed.ncbi.nlm.nih.gov

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

7. 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]

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

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced cutaneous melanoma. [2018]

9. England pubmed.ncbi.nlm.nih.gov

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

10. England pubmed.ncbi.nlm.nih.gov

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