Avutometinib + Defactinib for Ovarian and Cervical Cancer

(DURAFAK Trial)

Recruiting at 3 trial locations

Overseen By SCC IIT Office

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: University of Oklahoma

Must not be taking: Warfarin, Strong CYP inhibitors, P-gp inhibitors

Disqualifiers: Low grade serous ovarian cancer, Brain metastases, Hepatitis, HIV, 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: 2 years

55 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two drugs, Avutometinib (a Raf/MEK inhibitor) and Defactinib, to evaluate their effectiveness and safety for patients with certain ovarian and cervical cancers. The focus is on cancers with specific genetic changes, such as mutations in the RAS or BRAF genes. Women whose cancers have worsened after at least one other treatment might be suitable candidates. The goal is to determine if these drugs can control the cancer and identify any side effects. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you cannot take certain drugs like warfarin, strong CYP2C9 and CYP3A4 inhibitors or inducers, and P-glycoprotein inhibitors or inducers. 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 shows that the combination of Avutometinib (VS-6766) and Defactinib is being tested for safety and effectiveness in treating certain types of ovarian and cervical cancer. Earlier studies found that most people can handle this treatment well. Some people have experienced side effects, but these are usually manageable.

In one study, researchers administered this combination to patients who had already tried many other treatments. The results were promising, even when other options had not worked. While side effects can differ from person to person, ongoing research suggests that the treatment is generally safe. Always consult a healthcare provider to determine if joining a trial is appropriate. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Avutometinib + Defactinib for ovarian and cervical cancer because these drugs work together to target cancer cells in a unique way. Unlike typical chemotherapies that attack all rapidly dividing cells, Avutometinib (VS-6766) targets a specific pathway involved in cell growth and cancer progression, potentially leading to fewer side effects. Defactinib complements this by inhibiting a protein that helps cancer cells invade and spread, enhancing the overall treatment effectiveness. This combination aims to offer a more precise approach to treating these cancers, potentially improving outcomes for patients.

What evidence suggests that Avutometinib and Defactinib could be effective for ovarian and cervical cancer?

Research has shown that combining the drugs avutometinib and defactinib may help treat certain types of ovarian cancer. One study found that this combination significantly reduced tumor size in 46% of patients with low-grade serous ovarian cancer. The side effects were generally mild and manageable. Although more research is needed, these early results are promising and support further study. Participants in this trial will receive this combination to evaluate its effectiveness and safety in treating ovarian and cervical cancer. ^{1 2 3 5 6}

Who Is on the Research Team?

Christina Washington, MD

Principal Investigator

OU Health Stephenson Cancer Center

Are You a Good Fit for This Trial?

This trial is for women over 18 with certain types of gynecological cancers that have mutated genes and have worsened after at least one treatment. They must be relatively healthy, not pregnant or breastfeeding, able to use birth control, and not have had recent surgeries or certain other treatments.

Inclusion Criteria

You have a disease that can be accurately measured using specific medical guidelines.

My gynecological cancer has specific genetic changes.

There must be enough tissue samples for confirmation before starting treatment.

Exclusion Criteria

I am currently taking warfarin.

I haven't taken any P-gp affecting drugs in the last 14 days.

Subjects with a history of hypersensitivity to any of the inactive ingredients of the investigational product

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 orally as per study procedures

2 years

Regular visits for physical examinations, vitals, and assessments

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 combination of two drugs, Avutometinib (VS-6766) and defactinib, on patients with specific ovarian or cervical cancers. It aims to evaluate their effectiveness in controlling cancer growth and assess the safety profile of this drug regimen.

How Is the Trial Designed?

Group I: Avutometinib (VS-6766) + Defactinib Experimental Treatment 1 Intervention

Avutometinib (VS-6766): will be administered at 3.2 mg orally twice a week Defactinib: will be administered at 200 mg orally twice a day (BID).

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?

University of Oklahoma

Lead Sponsor

Trials

484

Recruited

95,900+

Verastem, Inc.

Industry Sponsor

Trials

42

Recruited

2,800+

Published Research Related to This Trial

The combination of trametinib and afuresertib was poorly tolerated at the starting dose, leading to dose-limiting toxicities, but an intermittent dosing schedule showed better tolerability, suggesting a potential for safer administration.

Among 20 patients with advanced solid tumors, the study reported one partial response and four cases of stable disease, indicating some efficacy, but the overall response rate was low, warranting further investigation into alternative dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Tolcher, AW., Patnaik, A., Papadopoulos, KP., et al.[2015]

The Phase III NeoADAURA study is designed to evaluate the effectiveness of neoadjuvant osimertinib, an advanced EGFR inhibitor, in combination with chemotherapy compared to chemotherapy alone in patients with resectable stage II-IIIB N2 EGFR mutation-positive non-small-cell lung cancer (NSCLC).

The primary goal of the study is to assess the major pathological response at the time of surgery, while also examining secondary outcomes such as event-free survival and overall survival, ensuring a comprehensive evaluation of osimertinib's safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for EGFR-mutated resectable non-small-cell lung cancer: NeoADAURA. Tsuboi, M., Weder, W., Escriu, C., et al.[2022]

A 54-year-old male with metastatic squamous cell lung cancer (SqCLC) had a complex EGFR mutation that initially responded to erlotinib and osimertinib, but eventually progressed, highlighting the challenges of treatment resistance in this cancer type.

The case revealed the EGFR p.G724S mutation as a potential mechanism of resistance to osimertinib, emphasizing the importance of understanding tumor molecular features for guiding treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Third-generation tyrosine kinase inhibitor in the treatment of epidermal growth factor receptor mutated squamous cell lung cancer: a tailored therapy approach. Cortiula, F., De Maglio, G., Cangi, MG., et al.[2020]

The combination of the pan-AKT inhibitor afuresertib with paclitaxel and carboplatin showed efficacy in treating recurrent platinum-resistant ovarian cancer, achieving an overall response rate of 32% according to RECIST criteria and 52% based on CA125 criteria.

The maximum tolerated dose (MTD) of afuresertib was established at 125 mg/day, with common side effects including nausea, diarrhea, and fatigue, indicating a manageable safety profile for this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase IB Dose Escalation and Expansion Study of AKT Inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-resistant Ovarian Cancer. Blagden, SP., Hamilton, AL., Mileshkin, L., et al.[2020]

Combining osimertinib with either selumetinib or cetuximab significantly improved treatment response rates in EGFR-mutated non-small cell lung cancer (NCLC) models, achieving response rates of 50% to 90% and median progression-free survival times of up to 28 weeks.

The study identified that resistance to these combination therapies is linked to Hedgehog pathway activation, suggesting that targeting this pathway alongside EGFR inhibition could enhance treatment efficacy in resistant cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor Efficacy of Dual Blockade of EGFR Signaling by Osimertinib in Combination With Selumetinib or Cetuximab in Activated EGFR Human NCLC Tumor Models. Della Corte, CM., Ciaramella, V., Cardone, C., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04625270

NCT04625270 | A Study of Avutometinib (VS-6766) v. ... This study will assess the safety and efficacy of avutometinib (VS-6766) monotherapy and in combination with defactinib in subjects with recurrent Low-Grade ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12393057/

Efficacy and Safety of Avutometinib ± Defactinib in Recurrent ... This study evaluated the efficacy and safety of avutometinib (rapidly accelerated fibrosarcoma/mitogen-activated extracellular signal-regulated ...

3. 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 ...

4. clinicaltrials.gov clinicaltrials.gov/show/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 ...

5. onclive.com onclive.com/view/avutometinib-defactinib-combo-generates-early-efficacy-signals-in-low-grade-serous-ovarian-cancer

Avutometinib/Defactinib Combo Generates Early Efficacy ... A novel area of exploration that has displayed clinical activity and a manageable safety profile in patients with low-grade serous ovarian cancer.

6. asco.org asco.org/abstracts-presentations/ABSTRACT411174

A phase 2 study of avutometinib (VS-6766) ± defactinib in ... The interim data support avutometinib + defactinib as an active go-forward regimen in heavily-pretreated recurrent LGSOC, regardless of KRAS status.