Avutometinib vs. Avutometinib + Defactinib for Ovarian Cancer

(RAMP 201 Trial)

Recruiting at 48 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

225 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Avutometinib for ovarian cancer?

Research shows that MEK inhibitors, like trametinib, can increase progression-free survival in women with recurrent low-grade serous ovarian cancer, suggesting that similar drugs like Avutometinib may also be effective. ^{1 2 3 4 5}

What makes the drug Avutometinib unique for treating ovarian cancer?

Avutometinib is unique because it acts as a dual inhibitor targeting both Raf and MEK proteins, which are part of a pathway that helps cancer cells grow. This dual action may offer a novel approach compared to traditional treatments that typically target a single protein or pathway. ^{1 6 7 8 9}

What is the purpose of this trial?

This trial tests avutometinib alone and with defactinib in patients with recurrent Low-Grade Serous Ovarian Cancer. The drugs work by blocking cancer cell growth and survival signals.

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

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

References

1. United States 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). [2023]

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

Rare Ovarian Cancer's First Positive Trial. [2022]

3. England 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. [2023]

4. England 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. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

The MEK1/2 Pathway as a Therapeutic Target in High-Grade Serous Ovarian Carcinoma. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Novel targeted therapies in epithelial ovarian cancer: from basic research to the clinic. [2019]

7. Hungary pubmed.ncbi.nlm.nih.gov

[Treatment of epithelial ovarian cancer]. [2009]

8. England pubmed.ncbi.nlm.nih.gov

AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. [2022]

9. Japan pubmed.ncbi.nlm.nih.gov

[Treatments of epithelial ovarian cancer by histologic subtype]. [2015]