Avutometinib vs. Avutometinib + Defactinib for Ovarian Cancer

(RAMP 201 Trial)

Not currently recruiting at 53 trial locations

Overseen By Premal Thaker, MD

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Verastem, Inc.

Must not be taking: Steroids

Disqualifiers: High-grade ovarian cancer, Brain metastases, Heart disease, 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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of a new treatment, avutometinib (a Raf/MEK inhibitor), for individuals with recurrent or worsening low-grade serous ovarian cancer. Researchers are testing avutometinib alone and in combination with another drug, defactinib, to determine the most effective option. Individuals who have experienced cancer progression after at least one previous treatment and have a confirmed diagnosis of low-grade serous ovarian cancer may be suitable candidates for this study. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that you stop any systemic anti-cancer therapy at least 4 weeks before starting the study treatment. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

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

Research has shown that avutometinib, either alone or with defactinib, may effectively treat recurrent low-grade serous ovarian cancer. Studies have found that patients generally tolerate the treatment well. Specifically, one study found that about 31% of patients experienced a reduction in tumor size or slower disease progression with the combination treatment.

The FDA has granted accelerated approval for using avutometinib and defactinib together in certain ovarian cancer cases, indicating that the treatment is considered safe for its intended use.

While side effects can occur, these findings suggest that both treatments are usually well-tolerated by patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about avutometinib, especially in combination with defactinib, for treating ovarian cancer because these drugs work differently from existing treatments. Unlike standard treatments like chemotherapy, which target rapidly dividing cells, avutometinib targets specific pathways involved in cancer cell growth and survival. Avutometinib (VS-6766) inhibits MEK and RAF proteins, which are part of a signaling pathway often overactive in cancers. Additionally, combining avutometinib with defactinib, which inhibits focal adhesion kinase (FAK), may enhance the treatment's effectiveness by disrupting cancer cell resistance mechanisms. This dual-target approach offers a potentially more precise and effective treatment strategy for patients with ovarian cancer.

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

This trial will compare the effectiveness of avutometinib alone to the combination of avutometinib and defactinib for ovarian cancer. Research has shown that avutometinib alone has a 7% success rate in shrinking tumors in patients with recurring low-grade serous ovarian cancer. This success rate increases to 28% when combined with defactinib. For patients with KRAS mutations, the combination treatment proves even more effective, achieving a 44% success rate. On average, patients using the combination therapy experience about 12.9 months without cancer progression. Additionally, the combination of avutometinib and defactinib is approved for treating KRAS-positive ovarian cancer, indicating effectiveness for some patients. ^{2 6 7 8 9}

Who Is on the Research Team?

MD Verastem

Principal Investigator

Verastem, Inc.

Susana Banerjee, MBBS,MA,PhD

Principal Investigator

European Network of Gynaecological Oncological Trial Groups (ENGOT)

Rachel Grisham, MD

Principal Investigator

GOG Foundation

Are You a Good Fit for This Trial?

This trial is for individuals with recurrent Low-Grade Serous Ovarian Cancer who've had at least one prior treatment. Participants must have good organ function, manageable side effects from previous treatments, measurable disease, and an ECOG performance status ≤ 1. They should not have severe concurrent diseases or a recent history of certain conditions like SARS-CoV-2 infection.

Inclusion Criteria

My low-grade serous ovarian cancer has worsened after treatment.

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

My cancer is low-grade serous ovarian or peritoneal.

Exclusion Criteria

I cannot swallow pills.

I have not had major surgery in the last 4 weeks.

I have high-grade ovarian cancer or another type of cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part A

Determine the optimal regimen of avutometinib (VS-6766) monotherapy or in combination with defactinib

24 weeks

Treatment Part B

Evaluate the efficacy of the optimal regimen identified from Part A

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Avutometinib (VS-6766)
• Defactinib

Trial Overview The study is testing the effectiveness and safety of avutometinib alone versus in combination with defactinib for those with LGSOC. It aims to see which treatment works better for patients who have seen their cancer return after other therapies.

How Is the Trial Designed?

Group I: Part D Experimental Treatment 1 Intervention

To evaluate additional efficacy parameters for a lower dose of avutometinib in combination with defactinib

Group II: Part C: Experimental Treatment 1 Intervention

To evaluate additional efficacy parameters for the optimal regimen identified in Part A.

Group III: Part B Experimental Treatment 2 Interventions

To determine the efficacy of the optimal regimen identified from Part A

Group IV: Part A Experimental Treatment 2 Interventions

To determine the optimal regimen, either avutometinib(VS-6766) monotherapy or avutometinib (VS-6766) in combination with defactinib, for subsequent evaluation for efficacy in the Expansion Phase (Part B)

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?

Verastem, Inc.

Lead Sponsor

Trials

42

Recruited

2,800+

European Network of Gynaecological Oncological Trial Groups (ENGOT)

Collaborator

Trials

41

Recruited

19,200+

GOG Foundation

Collaborator

Trials

48

Recruited

18,500+

Published Research Related to This Trial

A functional precision oncology (fPO) strategy using patient-derived ovarian cancer cells (PDCs) revealed that low-grade serous ovarian cancers (LGSOCs) respond better to targeted inhibitors compared to high-grade serous ovarian cancers (HGSOCs), indicating potential for tailored treatments.

In a clinical case study, fPO-guided therapy for a patient with metastatic LGSOC led to significant tumor reduction and disease control over five years, demonstrating the effectiveness of personalized treatment approaches in ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug response profiles in patient-derived cancer cells across histological subtypes of ovarian cancer: real-time therapy tailoring for a patient with low-grade serous carcinoma. Murumägi, A., Ungureanu, D., Khan, S., et al.[2023]

New targeted therapies for epithelial ovarian cancer are being developed, focusing on overcoming drug resistance and targeting specific receptors like HER, with combinations of drugs like erlotinib and cetuximab showing feasibility and good tolerance alongside standard chemotherapy.

Emerging treatments include proteasome inhibitors, mTOR inhibitors, and angiogenesis inhibitors, with ongoing trials exploring their effectiveness, indicating a shift towards personalized medicine based on genetic and molecular profiles of tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel targeted therapies in epithelial ovarian cancer: from basic research to the clinic. Gadducci, A., Cosio, S., Genazzani, AR.[2019]

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]

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]

Epithelial ovarian cancer is the most deadly gynecological cancer, often diagnosed at an advanced stage, requiring a combination of surgery and platinum-based chemotherapy, yet over 50% of patients experience relapse.

Current treatments for platinum-refractory ovarian cancer include various chemotherapies, but none provide a long-lasting response, highlighting the need for ongoing research into new therapies like immunotherapy and gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of epithelial ovarian cancer]. Langmár, Z., Csömör, S.[2009]

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 ... In evaluable patients, a confirmed ORR of 7% (2/30) was observed for mono (13% KRAS mt, 0% KRAS wt), and an ORR of 28% (8/29) was observed for ...

2. 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.

3. conference-correspondent.com conference-correspondent.com/highlights/aacr/aacr-asco-2021-midyear-review/phase-1-trial-of-vs-6766-a-dual-raf-mek-inhibitor-and-defactinib-an-fak-inhibitor

Phase 1 Trial of VS-6766, a Dual RAF-MEK Inhibitor, and ... As reported by Guo et al, VS-6766, a dual RAF-MEK inhibitor, has shown single-agent activity against KRAS G12V–mutated NSCLC.2. Based on preclinical data, ...

4. 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 ...

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

Efficacy and Safety of Avutometinib ± Defactinib in Recurrent ... ORR was 44% in KRAS-mutant and 17% in KRAS wild-type cohorts. The median progression-free survival was 12.9 months (95% CI, 10.9 to 20.2) ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00112

Primary Analysis of ENGOT-OV60/GOG-3052/RAMP 201 This study evaluated the efficacy and safety of avutometinib (rapidly accelerated fibrosarcoma/mitogen-activated extracellular ...

7. 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.

8. onclive.com onclive.com/view/raf-mek-inhibitor-vs-6766-plus-defactinib-under-exploration-in-recurrent-low-grade-serous-ovarian-cancer

RAF/MEK Inhibitor VS-6766 Plus Defactinib Under ... VS-6766 was designed to inhibit the RAF/MEK signaling pathway in a way that differs from other MEK inhibitors in development. Specifically, the ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT05512208

A Phase 2 Study of Avutometinib (VS-6766) Plus Defactinib ... This is a single-stage exploratory, Phase 2, multicenter, parallel cohort, open label study designed to evaluate efficacy and safety of VS-6766 + defactinib.