Encorafenib + Binimetinib +/- Nivolumab for Thyroid Cancer

Overseen By George Morris, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Providence Health & Services

Must not be taking: BRAF/MEK inhibitors, Immunotherapy

Disqualifiers: Autoimmune disease, Cardiovascular diseases, 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

Compensation: Varies

Number of Visits: 1

Duration: Up to 2 years

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial studies how well encorafenib and binimetinib, with or without nivolumab, work in treating a specific type of thyroid cancer that has spread and doesn't respond to usual treatments. The drugs aim to stop cancer growth and help the immune system fight the cancer. Encorafenib and binimetinib are used in combination to treat BRAF V600 mutation-positive melanoma, showing improved response rates and survival.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot use certain prohibited medications, including some herbal supplements, within one week before starting the study treatment.

Is the combination of Encorafenib, Binimetinib, and Nivolumab safe for humans?

The combination of Encorafenib and Binimetinib has been shown to have an acceptable safety profile in patients with certain types of cancer, such as melanoma and lung cancer, although some patients may experience visual side effects. Nivolumab, another drug that might be added, is generally considered safe but can have side effects like fatigue and skin reactions. ^{1 2 3 4 5}

How is the drug combination of Encorafenib, Binimetinib, and Nivolumab unique for treating thyroid cancer?

This drug combination is unique because it targets specific genetic mutations (BRAF mutations) in cancer cells, which is a novel approach for thyroid cancer treatment. Encorafenib and Binimetinib have shown effectiveness in treating other cancers with BRAF mutations, like melanoma, and adding Nivolumab, an immune system booster, may enhance the treatment's effectiveness. ^{1 4 5 6 7}

What data supports the effectiveness of the drug combination Encorafenib, Binimetinib, and Nivolumab for thyroid cancer?

Research shows that the combination of Encorafenib and Binimetinib is effective in treating BRAF-mutant melanoma, improving survival and quality of life. While this is not specific to thyroid cancer, it suggests potential benefits for similar mutations in thyroid cancer. ^{1 2 4 8 9}

Who Is on the Research Team?

Matthew H Taylor

Principal Investigator

Providence Health & Services

Are You a Good Fit for This Trial?

This trial is for adults with metastatic, radioiodine-refractory thyroid cancer that has a BRAF V600 mutation. Participants must have measurable disease, be in good physical condition (ECOG status <=1), and not be pregnant or nursing. They should not have had certain prior treatments or conditions that could affect the study's safety.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document

Your heart's QT interval is not longer than 480 milliseconds after being adjusted for your baseline heart rate.

Your heart's pumping ability is good, with a left ventricular ejection fraction (LVEF) of 50% or higher.

Exclusion Criteria

I haven't taken any prohibited medications in the last week.

I had major surgery less than 3 weeks ago or am still dealing with its side effects.

I have heart problems or significant heart disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive encorafenib and binimetinib orally. In Arm II, participants also receive nivolumab intravenously. Cycles repeat every 28 days.

Up to 2 years

Monthly visits

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

12 months

1 visit at 30 days, then every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Binimetinib
• Encorafenib
• Nivolumab

Trial Overview The effectiveness of encorafenib and binimetinib, with or without nivolumab, is being tested on patients with specific thyroid cancer. The goal is to see if these drugs can stop tumor growth by blocking enzymes needed for cell growth and boosting the immune system's ability to fight cancer.

How Is the Trial Designed?

Group I: Arm II (encorafenib, binimetinib, nivolumab) - CLOSED Experimental Treatment 3 Interventions

Patients receive encorafenib PO QD and binimetinib PO BID as in arm I. Patients also receive nivolumab IV over 30 minutes on day 1. Cycles with nivolumab repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (encorafenib, binimetinib) Experimental Treatment 2 Interventions

Patients receive encorafenib PO QD and binimetinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Binimetinib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation

Approved in European Union as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Approved in Canada as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation

Approved in Japan as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Who Is Running the Clinical Trial?

Providence Health & Services

Lead Sponsor

Trials

131

Recruited

827,000+

Providence Cancer Center, Earle A. Chiles Research Institute

Collaborator

Trials

21

Recruited

500+

Published Research Related to This Trial

Binimetinib, an uncompetitive inhibitor of MEK1/2, has shown significant efficacy in treating metastatic melanoma, particularly in combination with encorafenib, resulting in a progression-free survival (PFS) of 14.9 months compared to 7.3 months with vemurafenib alone in Phase 3 trials.

While binimetinib has a tolerable safety profile, there is currently no long-term data on durable responses or overall survival benefits compared to other treatments, highlighting the need for individualized treatment plans for patients with BRAF-mutated metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The discovery and development of binimetinib for the treatment of melanoma. Tran, B., Cohen, MS.[2021]

In a phase II study involving 98 patients with BRAFV600E-mutant metastatic non-small-cell lung cancer (NSCLC), the combination of encorafenib and binimetinib achieved a confirmed objective response rate of 75% in treatment-naïve patients and 46% in previously treated patients, indicating significant efficacy.

The treatment was generally well-tolerated, with common side effects including nausea (50%) and diarrhea (43%), but it also led to dose reductions in 24% of patients and one serious adverse event of intracranial hemorrhage, highlighting the importance of monitoring safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAFV600-Mutant Metastatic Non-Small-Cell Lung Cancer. Riely, GJ., Smit, EF., Ahn, MJ., et al.[2023]

In the COLUMBUS study involving 577 patients with advanced BRAF-mutant melanoma, the combination treatment of encorafenib plus binimetinib significantly improved health-related quality of life (HRQoL) scores compared to vemurafenib, indicating a meaningful enhancement in patients' perceived health status.

Patients receiving the combination therapy also experienced a delay in deterioration of quality of life, suggesting that this treatment not only improves survival but also helps maintain a better quality of life during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of life in patients with BRAF-mutant melanoma receiving the combination encorafenib plus binimetinib: Results from a multicentre, open-label, randomised, phase III study (COLUMBUS). Gogas, H., Dummer, R., Ascierto, PA., et al.[2021]

In a Phase 3 study involving 392 patients with radioiodine-refractory differentiated thyroid cancer, lenvatinib treatment resulted in a median tumor size reduction of 42.9%, with responders experiencing an even greater reduction of 51.9%.

The initial assessment at 8 weeks showed a rapid tumor size decline of 24.7%, followed by a slower continuous shrinkage, indicating that early tumor response may be a predictor of longer progression-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of Tumor Size Changes Over Time From the Phase 3 Study of Lenvatinib in Thyroid Cancer. Robinson, B., Schlumberger, M., Wirth, LJ., et al.[2019]

A 56-year-old woman experienced transient visual symptoms, including blurry vision and colored halos, after starting Encorafenib/Binimetinib for metastatic melanoma, indicating potential retinal side effects of the treatment.

Despite the initial symptoms being linked to subretinal fluid (SRF), the patient later experienced similar visual disturbances without any detectable SRF, suggesting that Binimetinib may cause intermittent visual symptoms even after fluid resolution.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Visual symptoms in a patient treated with MEK inhibitors. Tibaldi, T., Roccuzzo, G., Fazio, A., et al.[2022]

Encorafenib and binimetinib, a combination of a BRAF inhibitor and a MEK inhibitor, received FDA approval in June 2018 for treating patients with unresectable or metastatic melanoma that has specific BRAF mutations (V600E or V600K).

The combination therapy is also being explored in ongoing phase III clinical trials for metastatic colorectal cancer, indicating its potential broader application beyond melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib and Binimetinib: First Global Approvals. Shirley, M.[2019]

In a study of melanoma patients treated with encorafenib and binimetinib, the most common skin-related side effects were palmoplantar hyperkeratosis (54%) and palmoplantar erythrodysesthesia (58%) when using encorafenib alone.

Encouragingly, the combination therapy of encorafenib and binimetinib was found to be well tolerated, with fewer cutaneous adverse events compared to established BRAF inhibitors, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The spectrum of cutaneous adverse events during encorafenib and binimetinib treatment in B-rapidly accelerated fibrosarcoma-mutated advanced melanoma. Graf, NP., Koelblinger, P., Galliker, N., et al.[2019]

In a 5-year study of patients with advanced BRAF V600-mutant melanoma, those treated with the combination of encorafenib and binimetinib (COMBO group) had a longer duration of survival without disease progression compared to those receiving either encorafenib alone or vemurafenib.

The combination treatment also resulted in fewer patients needing additional anticancer therapies after treatment, and while side effects were similar across all groups, they decreased over time for the COMBO group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

COLUMBUS 5-year update: a randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF. Dummer, R., Flaherty, KT., Robert, C., et al.[2023]

Citations

1. England pubmed.ncbi.nlm.nih.gov

The discovery and development of binimetinib for the treatment of melanoma. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAFV600-Mutant Metastatic Non-Small-Cell Lung Cancer. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Quality of life in patients with BRAF-mutant melanoma receiving the combination encorafenib plus binimetinib: Results from a multicentre, open-label, randomised, phase III study (COLUMBUS). [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Characterization of Tumor Size Changes Over Time From the Phase 3 Study of Lenvatinib in Thyroid Cancer. [2019]

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

Kinase inhibitors in thyroid cancers. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Visual symptoms in a patient treated with MEK inhibitors. [2022]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Encorafenib and Binimetinib: First Global Approvals. [2019]

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

The spectrum of cutaneous adverse events during encorafenib and binimetinib treatment in B-rapidly accelerated fibrosarcoma-mutated advanced melanoma. [2019]

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

COLUMBUS 5-year update: a randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF. [2023]