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

Trial Summary

What is the purpose of this trial?

The researchers are doing this study to find out if the combination of avutometinib and defactinib is an effective treatment for RAF dimer-driven radioiodine-refractory differentiated thyroid cancer or anaplastic thyroid cancer. The researchers will also test whether avutometinib and defactinib is a safe treatment that causes few or mild side effects.

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.

What data supports the effectiveness of the drugs Avutometinib and Defactinib for thyroid cancer?

Research shows that tyrosine kinase inhibitors, which are a type of drug that blocks certain proteins involved in cancer growth, have been effective in treating various types of thyroid cancer. These drugs have shown to prolong survival and manage disease progression in patients with advanced thyroid cancer. ^{1 2 3 4 5}

How is the drug Avutometinib + Defactinib unique for treating thyroid cancer?

The combination of Avutometinib and Defactinib is unique because it targets specific pathways involved in cancer cell growth and survival, potentially offering a new approach for thyroid cancer treatment where standard options are limited. This combination may help overcome resistance seen with other treatments like vemurafenib, which targets the BRAFV600E mutation commonly found in thyroid cancer. ^{6 7 8 9 10}

Research Team

Alan L Ho, MD, PhD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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-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]

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]

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]

References

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

A phase II study of gefitinib in patients with advanced thyroid cancer. [2018]

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

New Treatment Options for Metastatic Thyroid Cancer. [2020]

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

Novel therapies for thyroid cancer. [2022]

4. England pubmed.ncbi.nlm.nih.gov

New molecular targeted therapies in thyroid cancer. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Real-world insights into the efficacy and safety of tyrosine kinase inhibitors against thyroid cancers. [2022]

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

mTOR inhibitors sensitize thyroid cancer cells to cytotoxic effect of vemurafenib. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

Investigation of BRAF mutation in a series of papillary thyroid carcinoma and matched-lymph node metastasis with ARMS PCR. [2019]

8. United States 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. [2023]

9. 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]

10. England pubmed.ncbi.nlm.nih.gov

Disruption of mutated BRAF signaling modulates thyroid cancer phenotype. [2021]