Avutometinib + Defactinib for Thyroid Cancer

Recruiting at 7 trial locations

Overseen By David G. Pfister, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Warfarin, Strong CYP3A4, others

Disqualifiers: Brain metastases, Glaucoma, Hypertension, 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: Unknown

Duration: up to 2 years

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether the combination of two drugs, avutometinib (VS-6766) and defactinib (VS-6063), can effectively treat certain types of thyroid cancer that do not respond well to standard treatments like radioiodine. Researchers aim to determine if this combination can benefit individuals with RAF dimer-driven differentiated thyroid cancer or anaplastic thyroid cancer while minimizing side effects. The trial seeks participants diagnosed with these specific types of thyroid cancer, particularly if their cancer has certain genetic mutations or has spread and is unsuitable for surgery. Participants should have experienced cancer progression despite previous treatments. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does mention that you cannot use certain medications that strongly affect specific enzymes (CYP3A4, CYP2C9, and P-glycoprotein). It's best to discuss your current medications with the trial team to see if any adjustments are needed.

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

Research has shown that the combination of avutometinib and defactinib has been tested for safety in people with solid tumors. In these studies, patients generally tolerated the treatments well. Nearly half of the patients experienced a positive effect on their tumors, with an objective response rate of 42.3%.

Although the studies primarily focused on the treatments' effectiveness, they found only a few or mild side effects. This suggests that the combination may be safe for patients to try. However, as with any treatment, side effects may occur, so discussing these with a doctor is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Avutometinib and Defactinib for thyroid cancer because they offer a novel combination approach targeting specific cancer pathways. Unlike the standard treatments like chemotherapy or radioactive iodine, which broadly attack cancer cells, Avutometinib and Defactinib work by inhibiting the MAPK and FAK pathways. This targeted action could potentially lead to more effective treatments with fewer side effects. Additionally, the combination regimen of three weeks on and one week off provides a structured treatment cycle that may enhance patient quality of life.

What evidence suggests that the combination of avutometinib and defactinib might be an effective treatment for thyroid cancer?

Research suggests that combining the drugs avutometinib and defactinib may treat thyroid cancer by blocking proteins that promote cancer cell growth. In studies with patients who have solid tumors, this combination led to tumor shrinkage in 42.3% of patients. Additionally, patients experienced an average of 20.1 months before their cancer worsened, indicating the treatment might control the disease for a significant time. This trial will evaluate the effectiveness of this combination specifically for thyroid cancer, including anaplastic thyroid cancer (ATC) and radioiodine-refractory (RAIR), recurrent and/or metastatic differentiated thyroid cancer (DTC). While these results are encouraging, more research is needed to understand how well this treatment works specifically for thyroid cancer. ^{1 2 5 6 7}

Who Is on the Research Team?

Alan L Ho, MD, PhD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with thyroid cancer that's not responding to radioiodine. Participants must have specific genetic changes in their tumors, measurable disease progression, and be able to take oral medication. They should have recovered from previous treatments and can't join if they've had certain recent surgeries or therapies, are pregnant/breastfeeding, or have severe heart issues, uncontrolled hypertension, active infections like COVID-19 within the last month.

Inclusion Criteria

I have tissue samples from my cancer available for study.

My disease has worsened within the last 14 months.

Patients must have a measurable disease according to RECIST v1.1 guidelines.

Exclusion Criteria

Patients who are pregnant or breastfeeding

You have HIV or active Hepatitis C.

I have symptoms from cancer that has spread to my brain or its coverings.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive avutometinib and defactinib for thyroid cancer treatment, 3 weeks on/1 week off

up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Avutometinib
• Defactinib

Trial Overview The study tests a combination of two drugs: Avutometinib and Defactinib on patients with RAF dimer-driven thyroid cancer who haven't responded well to radioiodine treatment. It aims to see if this drug combo is effective and safe with tolerable side effects.

How Is the Trial Designed?

Group I: Radioiodine-refractory (RAIR), recurrent and/or metastatic differentiated thyroid cancer (DTC) Experimental Treatment 2 Interventions

Patients will be treated with avutometinib 3.2 mg twice weekly and defactinib 200 mg twice daily, both 3 weeks on/1 week off.

Group II: Anaplastic thyroid cancer (ATC) Experimental Treatment 2 Interventions

Patients will be treated with avutometinib 3.2 mg twice weekly and defactinib 200 mg twice daily, both 3 weeks on/1 week off.

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Verastem, Inc.

Industry Sponsor

Trials

42

Recruited

2,800+

Published Research Related to This Trial

Combining vemurafenib, a BRAFV600E inhibitor, with metformin or rapamycin significantly reduced cell viability and increased apoptosis in thyroid cancer cell lines, including those resistant to vemurafenib.

This combination therapy not only showed effectiveness in reducing cancer cell survival but also altered key signaling pathways, suggesting a potential new treatment strategy for advanced metastatic thyroid cancer that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

mTOR inhibitors sensitize thyroid cancer cells to cytotoxic effect of vemurafenib. Hanly, EK., Bednarczyk, RB., Tuli, NY., et al.[2021]

In a study of 20 patients with papillary thyroid carcinoma (PTC) and matched lymph node metastases, 80% showed consistent BRAFV600E mutation status between the primary tumor and metastasis.

The findings indicate that a wild-type BRAFV600E status in the primary thyroid tumor does not exclude the possibility of a mutation in the lymph node metastasis, highlighting the complexity of genetic mutations in cancer progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigation of BRAF mutation in a series of papillary thyroid carcinoma and matched-lymph node metastasis with ARMS PCR. Zhang, J., Yang, Y., Zhao, J., et al.[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]

New multitargeted kinase inhibitors have been found to significantly improve overall survival and progression-free survival in patients with metastatic differentiated and medullary thyroid cancers.

These findings suggest that these newer treatments may offer a more effective option for managing advanced thyroid cancers compared to previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Treatment Options for Metastatic Thyroid Cancer. Kunadharaju, R., Goyal, G., Rudraraju, A., et al.[2020]

PLX4032, a BRAFV600E-specific inhibitor, effectively reduces the growth of BRAFV600E-positive papillary thyroid cancer cells while having the opposite effect on normal BRAF-wild-type thyroid cells, indicating its targeted efficacy.

The anti-proliferative effects of PLX4032 in BRAF-mutated cells are linked to its ability to inhibit key signaling molecules in the MAPK pathway, suggesting a potential for combination therapies in treating thyroid cancer with this mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disruption of mutated BRAF signaling modulates thyroid cancer phenotype. Hanly, EK., Rajoria, S., Darzynkiewicz, Z., et al.[2021]

In a phase II trial involving 27 patients with advanced thyroid cancer, gefitinib did not produce any objective tumor responses, but 32% of patients experienced stable disease with some reductions in tumor volume.

Despite the lack of significant tumor response, gefitinib showed potential biological activity, as evidenced by falling thyroglobulin levels in some patients and a median progression-free survival of 3.7 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of gefitinib in patients with advanced thyroid cancer. Pennell, NA., Daniels, GH., Haddad, RI., et al.[2018]

Tyrosine kinase inhibitors have been approved for treating various types of thyroid cancer, showing favorable short-term efficacy and manageable toxicity based on clinical trials.

Long-term real-world studies involving 27 studies provide valuable insights into survival rates and rare but serious side effects, highlighting the importance of these treatments in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world insights into the efficacy and safety of tyrosine kinase inhibitors against thyroid cancers. Li, L., Cheng, L., Sa, R., et al.[2022]

Vemurafenib-resistant papillary thyroid carcinoma (PTC) cells show resistance to apoptosis and accumulate in the G2-M phase, indicating a mechanism of drug resistance linked to genetic changes, including chromosome 5 amplification and mutations in RNA-binding motifs.

Combining vemurafenib with palbociclib, a CDK4/6 inhibitor, enhances apoptosis in resistant PTC cells, suggesting that this dual therapy could be an effective strategy against both vemurafenib-resistant and naive BRAFWT/V600E-positive PTC, potentially preventing the growth of aggressive cancer cell sub-clones.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vemurafenib-resistance via de novo RBM genes mutations and chromosome 5 aberrations is overcome by combined therapy with palbociclib in thyroid carcinoma with BRAFV600E. Antonello, ZA., Hsu, N., Bhasin, M., et al.[2023]

Tyrosine kinase inhibitors (TKIs) like vandetanib and cabozantinib have been shown to significantly prolong progression-free survival in patients with advanced medullary thyroid cancer (MTC), while sorafenib is effective for late-stage differentiated thyroid cancer (DTC), based on Phase III studies.

Common side effects of these TKIs include hypertension, gastrointestinal issues, and fatigue, with a notable increase in thyroid-stimulating hormone levels due to their mechanism of action, highlighting the need for careful management of treatment-related toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel therapies for thyroid cancer. Krajewska, J., Jarzab, B.[2022]

Thyroid carcinoma, particularly differentiated types, can often be treated effectively with surgery and radioactive iodine, but some aggressive forms like anaplastic and medullary thyroid carcinomas are resistant to current treatments, highlighting the need for new therapies.

Targeting specific genetic mutations, such as those in the RET proto-oncogene and B-RAF, offers promising avenues for new treatments, with drugs like ZD 6474 showing potential in preclinical models and ongoing trials for B-RAF inhibitors planned in thyroid cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New molecular targeted therapies in thyroid cancer. Milano, A., Chiofalo, MG., Basile, M., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06007924

NCT06007924 | A Study of Avutometinib and Defactinib in ... The researchers are doing this study to find out if the combination of avutometinib and defactinib is an effective treatment for RAF dimer-driven ...

2. mskcc.org mskcc.org/cancer-care/clinical-trials/23-007

A Phase 2 Study of Avutometinib and Defactinib in People ... By blocking proteins called kinases, avutometinib and defactinib may help slow or stop the growth of thyroid cancer. Researchers also want to see if the use of ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12443583/

Defactinib with avutometinib in patients with solid tumors Key findings include an objective response rate of 42.3% (11 of 26; 95% confidence interval 23.4–63.1) and a median progression-free survival of 20.1 months (95 ...

4. withpower.com withpower.com/trial/phase-2-thyroid-neoplasms-7-2023-da7b6

Avutometinib + Defactinib for Thyroid Cancer In a phase II trial involving 27 patients with advanced thyroid cancer, gefitinib did not produce any objective tumor responses, but 32% of patients experienced ...

5. etj.bioscientifica.com etj.bioscientifica.com/view/journals/etj/14/2/ETJ-24-0287.xml

Anticancer drug therapy for anaplastic thyroid cancer in Combination therapy with a BRAF inhibitor and MEK inhibitor has shown encouraging efficacy in patients with BRAF V600E-mutated anaplastic thyroid cancer.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11201408/

Recent Trends and Potential of Radiotherapy in the Treatment ... Anaplastic thyroid cancer (ATC) is a rare but highly aggressive malignancy characterized by advanced disease at diagnosis and a poor ...

7. nature.com nature.com/articles/s41591-025-03763-y

Defactinib with avutometinib in patients with solid tumors Key findings include an objective response rate of 42.3% (11 of 26; 95% confidence interval 23.4–63.1) and a median progression-free survival of ...