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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how two drugs, vemurafenib and cobimetinib, work together to treat a specific type of thyroid cancer. These drugs aim to slow or stop cancer cells from spreading by blocking a protein that promotes their growth. The trial seeks participants with thyroid cancer that has a BRAFV600E mutation, a genetic change that can make cancer more aggressive. Ideal participants have high-risk thyroid cancer with this mutation and are preparing for radioactive iodine treatment. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that vemurafenib and cobimetinib are likely to be safe for humans?

Earlier research has shown that the combination of vemurafenib and cobimetinib can cause some side effects, but most people tolerate it well. In a study with 254 patients taking both drugs, common side effects included joint pain, rashes, and tiredness, affecting more than 20% of participants. Most found these side effects manageable.

Vemurafenib and cobimetinib have already received approval for treating other types of cancer, indicating they have been tested for safety in various situations. This provides some reassurance about their safety. However, treatments can affect everyone differently. It is important to discuss potential risks and benefits with a doctor before deciding to join a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for thyroid cancer, which typically involve surgery, radioactive iodine, and hormone therapy, vemurafenib and cobimetinib act on specific genetic mutations. These drugs are designed to target and inhibit the BRAF V600 mutation and MEK pathway, which are often involved in aggressive thyroid cancers. Researchers are excited about these treatments because they offer a more precise approach, potentially improving effectiveness and minimizing side effects compared to traditional therapies. Additionally, the combination of vemurafenib and cobimetinib with radioactive iodine could enhance the overall treatment efficacy by making cancer cells more susceptible to radioactive iodine.

What evidence suggests that vemurafenib and cobimetinib might be an effective treatment for thyroid cancer?

This trial will evaluate the combination of vemurafenib and cobimetinib for treating thyroid cancer with the BRAFV600E mutation. Studies have shown that this combination effectively blocks proteins that promote cancer cell growth. In previous research involving patients with similar BRAF mutations, the cancer remained stable for an average of 5.8 months, and the average overall survival time was 15.2 months. These findings suggest that the treatment can slow or halt the spread of cancer cells, making it a promising option for those with this specific mutation. ^{1 2 3 6 7}

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 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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06440850

NCT06440850 | Vemurafenib and Cobimetinib for the ... This phase II trial tests how well vemurafenib and cobimetinib work in treating patients with high risk differentiated thyroid carcinoma with BRAFV600E ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35598186/

Efficacy and toxicity of vemurafenib and cobimetinib in ... Our cases show that vemurafenib/cobimetinib treatment is effective in BRAF V600-mutated thyroid carcinoma, also when administered via a feeding tube.

3. cancernetwork.com cancernetwork.com/view/cobimetinib-plus-vemurafenib-produces-antitumor-activity-in-patients-with-braf-mutations

Cobimetinib Plus Vemurafenib Produces Antitumor Activity ... Among the 31 patients treated, median progression-free survival (PFS) was 5.8 months and median overall survival (OS) was 15.2 months. Grade 3 ...

4. eocco.com eocco.com/-/media/EOCCO/PDFs/Formulary/Cobimetinib_Cotellic_vemurafenib_Zelboraf_Policy.pdf

cobimetinib (Cotellic®), vemurafenib (Zelboraf®) Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06440850?term=AREA%5BConditionSearch%5D(%22Adenocarcinoma,%20Papillary%22)%20AND%20AREA%5BBasicSearch%5D(gene%20therapy)&rank=7

Vemurafenib and Cobimetinib for the Treatment of Patients ... The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure.

6. sciencedirect.com sciencedirect.com/science/article/pii/S2059702923012796

Long term activity of vemurafenib in cancers with BRAF ... Vemurafenib provides durable tumour control and survival in various advanced cancer types. Long-term survival is observed in rare and common histotypes.

7. tecentriq-hcp.com tecentriq-hcp.com/melanoma/dosing-and-administration/dosing.html

COTELLIC ® (cobimetinib) + ZELBORAF ® (vemurafenib ... TECENTRIQ can cause immune-mediated thyroid disorders. · Thyroiditis occurred in 0.2% (4/2616) of patients receiving TECENTRIQ alone, including Grade 2 (<0.1%) ...