Avutometinib + Defactinib for Endometrial Cancer

Recruiting at 7 trial locations

Overseen By Rachel Grisham, MD

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Warfarin, Strong CYP3A4, others

Disqualifiers: Localized disease, MEK inhibitor, 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: 2 years

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether combining Avutometinib (a Raf/MEK inhibitor) and Defactinib can effectively treat mesonephric cancer, a type of advanced or recurrent gynecologic cancer. The study aims to determine if these medications can control the disease when it does not respond to standard treatments or returns after initial therapy. Women with this specific cancer, especially those whose disease has spread or returned despite treatment, might be suitable for the trial. Participants will take both medications as part of the study's treatment plan. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to benefit from potentially effective therapies.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you must stop all current medications, but you cannot take certain medications that interact with the study drugs. Specifically, you must avoid strong CYP3A4, CYP2C9, and P-glycoprotein inhibitors or inducers, as well as strong breast cancer resistance protein inhibitors or inducers, within 14 days before starting the trial and during the trial. If you are on warfarin, you will need to switch to another anticoagulant.

Will I have to stop taking my current medications?

The trial requires stopping certain medications that interact with the study drugs, such as strong CYP3A4, CYP2C9, and P-glycoprotein inhibitors or inducers, 14 days before starting the trial. If you are on warfarin, you may need to switch to another blood thinner.

Is there any evidence suggesting that Avutometinib (VS-6766) and Defactinib are likely to be safe for humans?

Research has shown that the combination of Avutometinib and Defactinib has been tested for safety in humans. These studies indicate that the treatment is generally well-tolerated. Reports of side effects have occurred, which is common in clinical trials, but the potential benefits are promising. One study showed a positive response in patients with certain types of cancer, suggesting a balance between effectiveness and safety.

However, it is important to note that this trial is still in the early stages. The treatment has demonstrated enough safety in earlier studies to proceed, but it is still being closely evaluated for more detailed safety information. If the treatment were not reasonably safe, it would not have advanced to this phase of testing. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for endometrial cancer?

Researchers are excited about Avutometinib and Defactinib for endometrial cancer because these drugs offer a fresh approach compared to standard treatments like surgery, radiation, and chemotherapy. Avutometinib, also known as VS-6766, is unique because it targets the RAF/MEK pathway, a key player in cancer cell growth, in a way that current therapies don’t. Defactinib complements this by inhibiting FAK, a protein that helps cancer cells survive and spread. Together, they form a powerful duo aimed at blocking cancer growth from two angles, potentially leading to more effective treatment outcomes.

What evidence suggests that Avutometinib and Defactinib might be an effective treatment for endometrial cancer?

Research has shown that the combination of Avutometinib and Defactinib, which all participants in this trial will receive, yields promising results for treating certain cancers. In earlier studies, this combination achieved a 46% overall response rate, with nearly half of the patients experiencing tumor shrinkage or halted growth. Lab and animal studies also found that these drugs can effectively fight tumor cells. These findings suggest that Avutometinib and Defactinib might effectively treat advanced or recurring mesonephric gynecologic cancers, such as endometrial cancer. ^{1 2 5 6 7}

Who Is on the Research Team?

Rachel Grisham, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for women over 18 with advanced or recurrent mesonephric gynecologic cancer. They must have good kidney and liver function, no severe heart issues, and cannot be pregnant or breastfeeding. Prior treatment with certain inhibitors or a history of rhabdomyolysis excludes participation.

Inclusion Criteria

My cancer is confirmed as GMC or has GMC characteristics according to my doctor.

My cancer has spread or returned after treatment.

My heart pumps well, with an ejection fraction of 50% or higher.

Exclusion Criteria

I cannot take pills by mouth or have issues absorbing food due to stomach surgery.

I haven't had major surgery in the last 4 weeks, minor surgery in the last 2 weeks, or palliative radiotherapy in the last week.

I have been treated with a MEK, RAF, or FAK inhibitor before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Avutometinib (VS-6766) and Defactinib for 3 weeks followed by a 1 week rest period in each 4-week cycle

2 years

Visits every 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Avutometinib (VS-6766)
• Defactinib

Trial Overview The study tests the effectiveness of Avutometinib (VS-6766) combined with Defactinib in treating mesonephric gynecologic cancers that are either persistent after first-line therapy or have returned after treatment.

How Is the Trial Designed?

Group I: Avutometinib (VS-6766) and Defactinib Experimental Treatment 2 Interventions

All enrolled patients will be treated with Avutometinib (VS-6766) 3.2 mg PO, twice weekly (e.g. M/Th,Tu/F, or W/Sa) + defactinib 200 mg PO BID for 3 weeks, followed by a 1 week rest period, in each 4-week (28 day) cycle.

Avutometinib (VS-6766) is already approved in United States for the following indications:

Approved in United States as Avutometinib for:

• Recurrent low-grade serous ovarian cancer (Breakthrough Therapy Designation)

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

The study found that the combination of encorafenib and trametinib showed the highest anti-tumor activity, effectively suppressing cell proliferation and inducing apoptosis in both BRAF and NRAS mutant melanoma cells.

Encouragingly, this combination also delayed the development of resistance more effectively than currently approved treatments, suggesting it could lead to better outcomes for patients with melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Head-to-Head Comparison of BRAF/MEK Inhibitor Combinations Proposes Superiority of Encorafenib Plus Trametinib in Melanoma. Schulz, A., Raetz, J., Karitzky, PC., et al.[2022]

Selumetinib, an allosteric MEK1/2 inhibitor, combined with docetaxel has shown improved clinical outcomes in a phase II study for patients with KRAS-mutant non-small-cell lung cancer (NSCLC), leading to its evaluation in the phase III SELECT-1 study.

The SELECT-1 study will assess the efficacy and safety of this combination treatment in approximately 634 patients, with progression-free survival as the primary endpoint, potentially making it the first targeted therapy for KRASm advanced NSCLC in a second-line setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study Design and Rationale for a Randomized, Placebo-Controlled, Double-Blind Study to Assess the Efficacy and Safety of Selumetinib in Combination With Docetaxel as Second-Line Treatment in Patients With KRAS-Mutant Advanced Non-Small Cell Lung Cancer (SELECT-1). Jänne, PA., Mann, H., Ghiorghiu, D.[2018]

A patient with metastatic melanoma developed acute VKH-like syndrome after 2 months of treatment with dabrafenib and trametinib, which are targeted therapies for BRAF mutant melanoma.

This case highlights that VKH-like syndrome, although rare, can occur as a serious complication of these therapies, necessitating careful monitoring for visual disturbances in patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Uveitis and Papillitis in the Setting of Dabrafenib and Trametinib Therapy for Metastatic Melanoma: A Case Report. Lim, J., Lomax, AJ., McNeil, C., et al.[2018]

Vemurafenib is highly effective for treating advanced melanoma with BRAF V600E mutations, achieving an objective response rate of 81% in a Phase I study and significantly improving overall survival compared to dacarbazine in a Phase III study (HR for death 0.37).

Common side effects include arthralgia, rash, and photosensitivity, but overall, vemurafenib is well-tolerated, and combination therapies may help address resistance issues that can arise during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vemurafenib in patients with BRAF V600E mutation-positive advanced melanoma. Ravnan, MC., Matalka, MS.[2018]

In the VEM-PLUS study, combining vemurafenib with other targeted therapies or chemotherapy did not significantly improve overall survival (OS) or progression-free survival (PFS) compared to vemurafenib alone in patients with BRAF V600E-mutant solid tumors, except for a notable inferior OS in the combination with carboplatin and paclitaxel.

Patients who had not previously received BRAF inhibitors showed significantly better outcomes, with a median OS of 12.6 months compared to 10.4 months for those who were refractory to BRAF therapy, highlighting the importance of treatment sequencing in managing resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BRAF v600E-mutant cancers treated with vemurafenib alone or in combination with everolimus, sorafenib, or crizotinib or with paclitaxel and carboplatin (VEM-PLUS) study. Nelson, BE., Roszik, J., Janku, F., et al.[2023]

In a phase 3 trial involving 675 patients with metastatic melanoma and the BRAF V600E mutation, vemurafenib significantly improved overall survival rates (84% at 6 months) compared to dacarbazine (64%).

Vemurafenib also demonstrated a 63% reduction in the risk of death and a 74% reduction in the risk of disease progression compared to dacarbazine, although it was associated with common adverse effects that led to dose modifications in 38% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved survival with vemurafenib in melanoma with BRAF V600E mutation. Chapman, PB., Hauschild, A., Robert, C., et al.[2022]

KRAS mutations are found in about 30% of lung adenocarcinomas, with the most common mutation being p.G12C, which occurs in 40% of cases, highlighting the need for targeted therapies in this patient population.

The RAMP-202 study is a phase II clinical trial designed to assess the safety and efficacy of the targeted agents VS-6766 and defactinib in patients with advanced KRAS mutant non-small-cell lung cancer who have not responded to previous treatments, potentially offering new hope for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single agent VS-6766 or VS-6766 plus defactinib in KRAS-mutant non-small-cell lung cancer: the RAMP-202 phase II trial. Capelletto, E., Bironzo, P., Denis, L., et al.[2022]

A network meta-analysis of three phase-3 trials involving 1230 patients found that the combinations of BRAF and MEK inhibitors (dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib plus binimetinib) showed similar efficacy in terms of overall survival, progression-free survival, and overall response rate for treating advanced BRAF V600 mutated malignant melanoma.

While the efficacy of these drug combinations was comparable, the safety profiles varied slightly, indicating that specific molecular properties of each drug combination may influence the types and rates of side effects experienced by patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Network indirect comparison of 3 BRAF + MEK inhibitors for the treatment of advanced BRAF mutated melanoma. Consoli, F., Bersanelli, M., Perego, G., et al.[2022]

In the BEACON CRC study involving 665 patients with BRAF V600E-mutant metastatic colorectal cancer, the combination of encorafenib and cetuximab significantly improved overall survival (OS) to 9.3 months compared to 5.9 months for standard chemotherapy, indicating its efficacy as a treatment option.

The triplet regimen of encorafenib, binimetinib, and cetuximab achieved a confirmed objective response rate (ORR) of 26.8%, demonstrating a substantial improvement over the control group's ORR of only 1.8%, while maintaining a manageable safety profile with similar rates of grade ≥ 3 adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E-Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study. Tabernero, J., Grothey, A., Van Cutsem, E., et al.[2022]

In a phase II study involving 53 eligible patients with recurrent KRAS+ non-small cell lung cancer (NSCLC), the combination of docetaxel and trametinib showed an overall response rate of 34%, indicating its potential efficacy in this patient population.

However, the response rate in patients specifically with the KRAS G12C mutation was only 28%, suggesting that this combination therapy may not be as effective for this particular mutation, and that comutations like TP53 may negatively impact treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Docetaxel and Trametinib in Patients with KRAS Mutation Positive Recurrent Non-Small Cell Lung Cancer (NSCLC; SWOG S1507, NCT-02642042). Gadgeel, SM., Miao, J., Riess, JW., et al.[2023]

Apatinib, a VEGFR2 inhibitor, demonstrated significant anti-tumor activity against malignant peritoneal mesothelioma (MPM) by inhibiting cell proliferation and migration in both in vitro studies and patient-derived xenograft (PDX) models.

The treatment with apatinib did not adversely affect the overall health of the models, showing no significant weight loss or organ dysfunction, although some mild liver and cardiac effects were noted in a small percentage of cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apatinib Mesylate Inhibits the Proliferation and Metastasis of Epithelioid Malignant Peritoneal Mesothelioma In Vitro and In Vivo. Yang, ZR., Chen, ZG., Du, XM., et al.[2022]

Vemurafenib treatment is associated with a high incidence of skin side effects, particularly hyperkeratotic perifollicular rash (69%) and photosensitivity (15%), with skin rashes occurring more frequently in the first month of therapy.

The study found that 38% of patients developed squamous cell carcinoma during treatment, and while this was linked to longer overall survival, the results should be interpreted cautiously due to the small sample size and other limitations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Skin toxicity in BRAF(V600) mutated metastatic cutaneous melanoma patients treated with vemurafenib. Nowara, E., Huszno, J., Slomian, G., et al.[2020]

In a study of 118 patients with BRAF-mutated metastatic melanoma, both vemurafenib+cobimetinib (V+C) and dabrafenib+trametinib (D+T) showed favorable efficacy, with overall response rates of 76% for V+C and 82% for D+T.

The median overall survival was longer for the V+C group at 18 months compared to 12 months for the D+T group, while both therapies had similar progression-free survival rates of around 8 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[BRAF-MEK inhibitor therapy in melanoma]. Czirbesz, K., Pánczél, G., Baranyai, F., et al.[2022]

The NEXUS trial is evaluating the safety and efficacy of a triplet regimen (encorafenib, binimetinib, and cetuximab) in 32 patients with resectable BRAF V600E mutant colorectal oligometastases, aiming to improve 1-year progression-free survival rates.

This perioperative treatment strategy is expected to be both safe and effective, potentially reducing the high recurrence rates associated with unresectable BRAF V600E mutant colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NEXUS trial: a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant colorectal oligometastases. Kobayashi, S., Bando, H., Taketomi, A., et al.[2023]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.5515

A phase 2 study of avutometinib (VS-6766) ± defactinib in ... The combination of avutometinib and defactinib has demonstrated a high rate of confirmed and durable responses (overall response rate [ORR] = 46 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05512208

A Phase 2 Study of Avutometinib (VS-6766) Plus Defactinib The purpose of this research is to test the effectiveness and safety of the study drugs (VS-6766 and defactinib), and see what effects (good and bad) these ...

3. investor.verastem.com investor.verastem.com/news-releases/news-release-details/verastem-oncology-announces-nature-medicine-publication-results

Press Release - Verastem, Inc. The first-in-human study to evaluate the safety, tolerability, and efficacy of avutometinib in combination with defactinib in patients with low-grade serous ...

4. gynecologiconcology-online.net gynecologiconcology-online.net/article/S0090-8258(24)00195-1/fulltext

Preclinical in vitro and in vivo activity of the RAF/MEK ... The combination of avutometinib and defactinib demonstrates promising in vitro and in vivo anti-tumor activity against primary UCS cell lines and xenografts.

5. withpower.com withpower.com/trial/phase-2-mesonephric-gynecologic-cancer-2-2023-1ea56

Avutometinib + Defactinib for Endometrial Cancer This study will test if Avutometinib (VS-6766) in combination with Defactinib is an effective treatment for advanced or recurrent mesonephric gynecologic cancer ...

6. targetedonc.com targetedonc.com/view/avutometinib-defactinib-leads-to-positive-response-survival-data-in-ovarian-cancer

Avutometinib/Defactinib Leads to Positive Response ... The combination of avutometinib (previously VS-6766), an oral RAF/MEK clamp, and defactinib, an oral FAK inhibitor, showed positive overall response rate (ORR) ...

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

Defactinib with avutometinib in patients with solid tumors We aimed to explore the combination of the RAF–MEK clamp avutometinib with the FAK inhibitor defactinib in a phase 1 clinical trial evaluating tolerability, ...