Avutometinib + Defactinib + Everolimus for Uterine Lining Cancer

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Warfarin, Strong CYP3A4 inhibitors

Disqualifiers: Pregnancy, Sarcoma, CHF, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of three drugs—avutometinib, defactinib, and everolimus—to determine the optimal dose for treating recurrent endometrial cancer with abnormal RAS activity (a specific gene change). The study also evaluates the safety of this drug combination and its effects on the cancer. It suits individuals diagnosed with endometrial cancer that recurs, have a specific gene change related to RAS, and have previously undergone treatments like immune therapies. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug combination.

Will I have to stop taking my current medications?

The trial requires you to stop taking certain medications, supplements, and foods that could interact with the study drugs at least 14 days before starting the trial. This includes specific medications that affect liver enzymes and certain foods like grapefruit. Please consult with the study team for a detailed list.

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

Earlier studies have shown that the combination of avutometinib and defactinib holds promise for treating certain cancers. These studies have assessed patient tolerance to the treatment. Research indicates that while some side effects occurred, they were generally manageable.

Everolimus, another drug in this combination, has FDA approval for other uses, suggesting its safety when used alone. However, combining it with other drugs requires monitoring for any new effects.

In summary, while researchers continue to study the combination of avutometinib, defactinib, and everolimus, earlier results are encouraging. Patients have tolerated the treatment with some manageable side effects. More research is needed to fully understand its safety in treating uterine lining cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Avutometinib, Defactinib, and Everolimus for uterine lining cancer because these treatments target cancer differently than current options. Unlike standard treatments like hormonal therapy or chemotherapy, which can affect healthy cells, these drugs specifically inhibit pathways crucial for cancer cell growth and survival. Avutometinib and Defactinib work by blocking signals that help cancer cells resist death and spread, while Everolimus disrupts a protein that helps tumors grow. This targeted approach could mean fewer side effects and more effective treatment for patients.

What evidence suggests that this trial's treatments could be effective for uterine lining cancer?

This trial will evaluate the combination of three drugs—avutometinib, defactinib, and everolimus—for treating endometrial cancer with abnormal RAS activity. Research has shown that this combination may help treat similar gynecologic cancers. Avutometinib and defactinib have been tested together in other cancers, such as low-grade serous ovarian cancer, suggesting they might also be effective for endometrial cancer. Everolimus blocks certain pathways that help cancer cells grow, potentially enhancing the combination's effectiveness. Early results suggest that these three drugs might work well together to target and treat cancers with this specific genetic profile. Participants in this trial will join either a dose escalation or dose expansion arm to determine the optimal dosing strategy. ^{2 3 4 6 7}

Who Is on the Research Team?

Shannon N Westin, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for individuals with recurrent endometrial cancer that has specific mutations known as RAS pathway mutations. Participants must have tried immune checkpoint inhibitors before and can have had any number of treatments, including MEK inhibitors. They should be in good physical condition (ECOG 0-1) and able to follow the study's procedures.

Inclusion Criteria

I am willing and able to follow the study's requirements, including treatments and visits.

I meet the specific requirements needed to participate.

I am fully active or can carry out light work.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive avutometinib, defactinib, and everolimus per dose level during Days 1-21 to identify the recommended phase 2 dosing

3 weeks

Dose Expansion

Participants receive the identified RP2D of avutometinib, defactinib, and everolimus during Days 1-2

2 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Avutometinib
• Defactinib
• Everolimus

Trial Overview

The study aims to determine the appropriate dose and assess the safety of a drug combination: Avutometinib, Defactinib, and Everolimus in patients with abnormal RAS activity in their endometrial cancer. It will also evaluate how effective this combination is.

How Is the Trial Designed?

Group I: Dose Expansion Experimental Treatment 3 Interventions

To be administered per identified RP2D during Days 1-2

Group II: Dose Escalation Experimental Treatment 3 Interventions

To be administered per dose level during Days 1-21

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Verastem, Inc.

Industry Sponsor

Trials

42

Recruited

2,800+

Citations

1.

onclive.com

onclive.com/view/avutometinib-defactinib-combo-shows-potential-in-recurrent-mesonephric-gynecologic-cancer

Avutometinib/Defactinib Combo Shows Potential in ...

Rachel N. Grisham, MD, discusses the preliminary results of avutometinib plus defactinib in mesonephric and mesonephric-like cancers.

2.

ctv.veeva.com

ctv.veeva.com/study/phase-ib-study-of-avutometinib-defactinib-and-everolimus-in-ras-pathway-mutant-endometrial-cancer

Phase Ib Study of Avutometinib, Defactinib, and Everolimus in ...

To find the recommended dose of the combination of avutometinib, defactinib, and everolimus in patients with endometrial cancer that is ...

3.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/41384753/

The combination of avutometinib and defactinib in treating ...

The combination of avutometinib and defactinib in treating recurrent low-grade serous ovarian cancer: a plain language summary of the Phase II ...

4.

clin.larvol.com

clin.larvol.com/trial-detail/NCT07318324

Phase Ib Study of Avutometinib, Defactinib, and Everolimus ...

Phase Ib Study of Avutometinib, Defactinib, and Everolimus in RAS Pathway Mutant Endometrial Cancer. P1. M.D. Anderson Cancer Center. N=31. Not yet recruiting.

5.

trial.medpath.com

trial.medpath.com/clinical-trial/ead206f22e94fd6e/nct07318324-avutometinib-defactinib-everolimus-ras-mutant-endometrial-cancer

Phase Ib Study of Avutometinib, Defactinib, and Everolimus in ...

To find the recommended dose of the combination of avutometinib, defactinib, and everolimus in patients with endometrial cancer that is recurrent and has ...

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT07318324

Phase Ib Study of Avutometinib, Defactinib, and Everolimus ...

To find the recommended dose of the combination of avutometinib, defactinib, and everolimus in patients with endometrial cancer that is ...

7.

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 ...