Dabrafenib + Trametinib + IMRT for Thyroid Cancer

Recruiting at 3 trial locations

Overseen By Sasan Fazeli, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Manisha Shah

Must be taking: Dabrafenib, Trametinib

Must not be taking: Antiepileptics, Antiretrovirals

Disqualifiers: Other malignancy, Brain metastases, others

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

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

Compensation: Varies

Number of Visits: Unknown

6 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of combining two drugs, dabrafenib (a BRAF inhibitor) and trametinib, with a specific type of radiation therapy (intensity modulated radiation therapy or IMRT) to treat BRAF-mutated anaplastic thyroid cancer. The goal is to determine if this combination can more effectively halt tumor growth by blocking enzymes that aid cancer cell growth and using radiation to shrink tumors. Individuals diagnosed with this specific type of thyroid cancer, whose tumors have the BRAF V600E or V600K mutation, may be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

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.

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

Research shows that dabrafenib and trametinib have treated patients with BRAF-mutant anaplastic thyroid cancer, yielding promising safety results. Studies indicate these medications can increase survival rates for patients with this cancer type.

Most patients have tolerated dabrafenib and trametinib well, though some have reported side effects like fever, tiredness, and skin problems, which are usually manageable. Combined with intensity modulated radiation therapy (IMRT), which uses high-energy beams to target tumors, the aim is to improve treatment outcomes.

This combination of treatments is still under study. Researchers are actively evaluating its safety and effectiveness when used together. Trial participants will be closely monitored to ensure any side effects are promptly addressed. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Dabrafenib and Trametinib for thyroid cancer because it targets the disease in a novel way. Unlike standard treatments, which often involve surgery or radioactive iodine, this combo specifically blocks the activity of proteins that promote cancer cell growth. Dabrafenib targets the BRAF protein, while Trametinib inhibits MEK, both crucial parts of a signaling pathway that is often overactive in thyroid cancer. This targeted approach not only addresses the root cause of the cancer’s growth but also has the potential to be more effective with fewer side effects than traditional treatments.

What evidence suggests that dabrafenib, trametinib, and IMRT might be an effective treatment for thyroid cancer?

Research has shown that the drugs dabrafenib and trametinib can treat BRAF-mutated anaplastic thyroid cancer. One study found that using these drugs together can extend patients' lives. They work by inhibiting the enzymes that promote cancer cell growth. In this trial, participants will receive a combination of dabrafenib, trametinib, and radiation therapy, specifically IMRT, which uses strong energy beams to kill cancer cells and shrink tumors. Combining these treatments in this trial may enhance their effectiveness, potentially leading to improved patient outcomes. ^{1 2 3 4 6}

Who Is on the Research Team?

Sasan Fazeli, MD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Dabrafenib
• Intensity-Modulated Radiation Therapy
• Trametinib

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.

How Is the Trial Designed?

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

See Detailed Description

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?

Manisha Shah

Lead Sponsor

Trials

3

Recruited

80+

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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 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 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]

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 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]

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 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 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. clinicaltrials.gov clinicaltrials.gov/study/NCT03975231

Dabrafenib, Trametinib, and IMRT in Treating Patients With ... This trial studies how well dabrafenib, trametinib, and intensity modulated radiation therapy (IMRT) work together in treating patients with BRAF mutated ...

2. 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].

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2019-02745

Dabrafenib, Trametinib, and IMRT in Treating Patients with ... Radiation therapy uses high energy beams to kill tumor cells and shrink tumors. Giving dabrafenib, trametinib, and IMRT together may kill more tumor cells.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S093665552200512X

Dabrafenib and Trametinib Therapy for Advanced ... Dabrafenib and trametinib increase survival of BRAF-mutant anaplastic thyroid cancer. · Real-world data plug gaps in evidence in rare disease group. · Largest ...

5. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2023-0125.html

A phase I trial of concurrent intensity Modulated Radiation ... 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 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11898454/

Modern Therapeutic Approaches in Anaplastic Thyroid Cancer Dabrafenib/trametinib (DT), with or without pembrolizumab and lenvatinib plus pembrolizumab (LP), demonstrated superior ORR, PFS and overall ...