Vemurafenib + Cobimetinib for Thyroid Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must not be taking: Anti-BRAF, Anti-MEK

Disqualifiers: Prior RAI treatment, Low risk DTC, Major surgery, Active infection, 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: 4

Duration: 6 weeks

21 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on certain cancer treatments like anti-BRAF or anti-MEK drugs, you may not be eligible to participate.

What data supports the effectiveness of the drug Vemurafenib + Cobimetinib for thyroid cancer?

Vemurafenib, a BRAF inhibitor, has shown promising results in patients with papillary thyroid cancer that have the BRAF(V600E) mutation, leading to partial responses and stable disease. Additionally, the combination of vemurafenib and cobimetinib has improved survival in patients with BRAF V600-mutated melanoma, suggesting potential benefits for similar mutations in thyroid cancer. ^{1 2 3 4 5}

Is the combination of Vemurafenib and Cobimetinib safe for humans?

The combination of Vemurafenib and Cobimetinib has been studied in patients with melanoma and is generally well tolerated, with common side effects including diarrhea, rash, fatigue, swelling, nausea, and vomiting. In a study involving patients with advanced solid tumors, dose-limiting side effects included severe rash and blurred vision, but the treatment was considered manageable. ^{1 2 6 7 8}

How is the drug combination of Vemurafenib and Cobimetinib unique for thyroid cancer?

The combination of Vemurafenib and Cobimetinib is unique for thyroid cancer because it targets specific genetic mutations (BRAF V600) that are common in this cancer type, offering a personalized treatment approach. This combination is used off-label, meaning it's not the standard treatment for thyroid cancer, but it has shown promise in improving outcomes for patients with these mutations. ^{1 2 3 4 9}

What is the purpose of this trial?

This phase II trial tests how well vemurafenib and cobimetinib work in treating patients with high risk differentiated thyroid carcinoma with BRAFV600E mutation, in preparation for radioactive iodine therapy. Vemurafenib and cobimetinib are used in patients whose cancer has a mutated (changed) form of a gene called BRAF. They are in a class of medications called kinase inhibitors. They work by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Giving vemurafenib and cobimetinib may work better to treat patients with high risk differentiated thyroid carcinoma with BRAFV600E mutation, in preparation for radioactive iodine therapy.

Research Team

Sasan Fazeli, MD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for patients with high-risk differentiated thyroid carcinoma that has a specific BRAFV600E gene mutation. It's aimed at those preparing for radioactive iodine therapy.

Inclusion Criteria

Documented informed consent of the participant and/or legally authorized representative

High risk for recurrence according to the American Thyroid Association (ATA) guideline defined as having one or more of the features below: Gross extrathyroidal extension, FTC with extensive vascular invasion (> 4), PTC with vascular invasion, Advanced nodal disease of (any node >3 cm, > 4 nodes, or extra-nodal extension), BRAF+TERT promoter mutation, Post op thyroglobulin (TG) suggestive of distant metastasis, Distant metastatic sites (only for exploratory arm), Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, Blood pressure (BP) ≤ 140/90 mm Hg at screening with or without antihypertensive medications and no change in antihypertensive medications within 1 week prior to treatment start, Creatinine clearance ≥ 50 mL/min according to the Cockcroft and Gault formula, Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, Hemoglobin ≥ 9.0 g/dL, Platelet count ≥ 100 x 109/L, Normal blood coagulation function as evidenced by an International Normalized Ratio (INR) ≤ 1.5, Bilirubin ≤ 1.5 × upper limit of normal (ULN) except for unconjugated hyperbilirubinemia or Gilbert's syndrome, Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN if subject has liver metastases), Women of childbearing potential must have a negative urine or serum β-HCG pregnancy test within 7 days prior to the administration of the first study treatment, Agreement by women of childbearing potential (WOCBP) and males of childbearing potential* to use an effective** method of birth control** for at least 3 months prior to screening through 1 year of study follow-up, Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only), Effective birth control defined as hormonal and/or barrier contraception, Non-English speaking persons and adults lacking capacity to consent are not excluded from participation

My thyroid cancer is of follicular origin.

Exclusion Criteria

My urine protein levels are below 1 g/24 h.

I cannot undergo radioactive iodine treatment.

I have had serious heart issues or uncontrolled high blood pressure recently.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive vemurafenib orally twice per day for 6 weeks and cobimetinib once per day for 3 weeks, followed by 1 week off, and then continuing for 2 weeks. This is followed by iodine 131 therapy and additional days of vemurafenib and cobimetinib.

6 weeks

Multiple visits (in-person) for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including imaging and blood sample collection.

12 months

Every 3 months (in-person)

Treatment Details

Interventions

• Cobimetinib
• Vemurafenib

Trial Overview The effectiveness of vemurafenib and cobimetinib, both kinase inhibitors, is being tested to see if they can better prepare patients with the BRAFV600E mutation for radioactive iodine treatment by slowing cancer growth.

Participant Groups

Group I: Treatment (vemurafenib and cobimetinib) Experimental Treatment 11 Interventions

Patients receive vemurafenib PO BID for 6 weeks and cobimetinib PO QD for 3 weeks, followed by 1 week off, and then continuing for 2 weeks. Patients then receive iodine 131 PO followed by 3 additional days of vemurafenib PO BID and cobimetinib PO QD. Patients receive thyrogen IM daily for 2 days followed by I-123 diagnostic scan during screening and on study. Patients also undergo MRI during screening, PET scan or CT scan and blood sample collection throughout the study and ultrasound imaging and I-131 whole body scan during follow up.

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

Approved in European Union as Cotellic for:

• Melanoma

Approved in United States as Cotellic for:

• Melanoma

Approved in Canada as Cotellic for:

• Melanoma

Approved in Switzerland as Cotellic for:

• Melanoma

Approved in Japan as Cotellic for:

• Melanoma

Who Is Running the Clinical Trial?

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+

Findings from Research

Vemurafenib and cobimetinib treatment showed effectiveness in two patients with BRAF V600-mutated thyroid carcinoma, resulting in a partial response even when administered via a feeding tube.

Despite the treatment's efficacy, both patients experienced significant toxicity, indicating that while the feeding tube method is feasible, careful monitoring for side effects is essential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and toxicity of vemurafenib and cobimetinib in relation to plasma concentrations, after administration via feeding tube in patients with BRAF-mutated thyroid cancer: a case series and review of literature. van Berge Henegouwen, JM., van der Wijngaart, H., Zeverijn, LJ., et al.[2022]

Sorafenib has been FDA approved for treating well-differentiated radioactive iodine-resistant metastatic thyroid cancer, marking it as the second drug approved for this condition in 40 years, based on Phase III data presented at the ASCO 2013 conference.

While sorafenib shows a modest ability to induce partial remission, it is particularly effective at halting disease progression, suggesting that combining it with other targeted therapies could enhance treatment outcomes given the presence of activating mutations in thyroid cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sorafenib in radioactive iodine-refractory well-differentiated metastatic thyroid cancer. McFarland, DC., Misiukiewicz, KJ.[2021]

In a retrospective study of 17 patients with advanced papillary thyroid cancer (PTC) and the BRAF(V600E) mutation, vemurafenib showed a partial response in 47% of patients and stable disease in 53%, indicating its potential efficacy as a treatment.

Despite some adverse events, including fatigue and weight loss, vemurafenib was generally well-tolerated, with a durable response rate of 67% and a median time to treatment failure of 13 months, supporting its use in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and tolerability of vemurafenib in patients with BRAF(V600E) -positive papillary thyroid cancer: M.D. Anderson Cancer Center off label experience. Dadu, R., Shah, K., Busaidy, NL., et al.[2022]

Vemurafenib, a BRAF inhibitor, has shown the potential to induce partial responses and maintain stable disease in patients with papillary thyroid cancer that no longer responds to radioactive iodine treatment.

However, the treatment is associated with significant safety concerns, as approximately 65% of patients experienced serious adverse events, including the development of squamous cell carcinomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vemurafenib Active in Iodine-Refractory Thyroid Cancer. [2019]

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]

Multi-kinase inhibitors (MKIs) significantly improve progression-free survival (PFS) and overall survival (OS) in patients with radioiodine-refractory differentiated thyroid cancer (RAI-rDTC), with a median PFS hazard ratio of 0.30 and OS hazard ratio of 0.70 based on a meta-analysis of randomized controlled trials.

While MKIs are effective, they are associated with a higher incidence of adverse events compared to control treatments, highlighting the need for careful patient evaluation to balance treatment benefits against potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of multi-kinase inhibitors in patients with radioiodine-refractory differentiated thyroid cancer: a systematic review and meta-analysis of clinical trials. Su, J., Wang, M., Fu, Y., et al.[2022]

In the coBRIM trial, patients with BRAF (V600) mutation-positive unresectable or metastatic melanoma who received cobimetinib in combination with vemurafenib experienced significantly longer progression-free survival compared to those treated with vemurafenib alone.

The combination treatment also resulted in a higher overall response rate and prolonged overall survival, while maintaining a manageable safety profile, making it a valuable treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cobimetinib Plus Vemurafenib: A Review in BRAF (V600) Mutation-Positive Unresectable or Metastatic Melanoma. Keating, GM.[2019]

Cobimetinib, a MEK1/2 inhibitor, was found to be generally well tolerated in a study involving 97 patients with advanced solid tumors, with the maximum tolerated doses established at 60 mg on a 21/7 schedule and 100 mg on a 14/14 schedule.

The treatment showed promising anti-tumor activity, particularly in melanoma patients with the BRAF(V600E) mutation, resulting in one unconfirmed complete response and six confirmed partial responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors. Rosen, LS., LoRusso, P., Ma, WW., et al.[2019]

Vemurafenib demonstrated antitumor activity in patients with BRAF(V600E)-positive papillary thyroid cancer, showing a partial response in 38.5% of patients who had not previously received multikinase inhibitors, based on a phase 2 trial involving 51 participants.

While the treatment was effective, it was associated with significant adverse events, with 65% of patients experiencing grade 3 or 4 side effects, including serious conditions like squamous cell carcinoma of the skin and lymphopenia, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. Brose, MS., Cabanillas, ME., Cohen, EE., et al.[2022]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Efficacy and toxicity of vemurafenib and cobimetinib in relation to plasma concentrations, after administration via feeding tube in patients with BRAF-mutated thyroid cancer: a case series and review of literature. [2022]

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

Sorafenib in radioactive iodine-refractory well-differentiated metastatic thyroid cancer. [2021]

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

Efficacy and tolerability of vemurafenib in patients with BRAF(V600E) -positive papillary thyroid cancer: M.D. Anderson Cancer Center off label experience. [2022]

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

Vemurafenib Active in Iodine-Refractory Thyroid Cancer. [2019]

5. 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]

6. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of multi-kinase inhibitors in patients with radioiodine-refractory differentiated thyroid cancer: a systematic review and meta-analysis of clinical trials. [2022]

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

Cobimetinib Plus Vemurafenib: A Review in BRAF (V600) Mutation-Positive Unresectable or Metastatic Melanoma. [2019]

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

A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors. [2019]

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

Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. [2022]