Avutometinib + Defactinib for Ovarian Cancer

(RAMP 301 Trial)

Recruiting at 118 trial locations

Overseen By Verastem Call Center

Age: 18+

Sex: Female

Trial Phase: Phase 3

Sponsor: Verastem, Inc.

Must not be taking: Steroids, FAK inhibitors

Disqualifiers: High-grade serous cancer, Brain metastases, Heart disease, Lung disease, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

270 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination of avutometinib (VS-6766) and defactinib (VS-6063) for individuals with recurrent low-grade serous ovarian cancer (LGSOC). The goal is to determine if this combination outperforms standard treatments, such as certain chemotherapy drugs or hormone pills. The trial seeks participants with LGSOC who know their KRAS mutation status and have undergone at least one prior treatment. As a Phase 3 trial, it represents the final step before FDA approval, providing an opportunity to access potentially effective treatment early.

Will I have to stop taking my current medications?

The trial requires that you have not had any systemic anti-cancer therapy within 4 weeks before starting the study treatment. This means you may need to stop certain cancer medications before joining the trial.

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

Research has shown that the combination of avutometinib and defactinib has been tested in patients with ovarian cancer. These studies found the treatment to be generally well-tolerated, meaning most patients can handle it without major issues. Specifically, patients in these trials had a median progression-free survival of 12.9 months, indicating their cancer did not worsen during this period. This suggests the treatment is effective and warrants further research.

Some patients experienced side effects, but these were not severe enough to stop the treatment. The treatment demonstrated a high rate of confirmed and lasting responses, which is promising for those with recurring low-grade serous ovarian cancer. Importantly, this study is in a later phase, often indicating more evidence supports its safety for patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Avutometinib and Defactinib for ovarian cancer because this duo targets cancer cells in a novel way. Unlike standard treatments like chemotherapy, which often attack both healthy and cancerous cells, these drugs focus more precisely on the cancer's survival mechanisms. Avutometinib disrupts the signaling pathways that cancer cells use to grow, while Defactinib blocks the pathways that help them resist treatment and spread. This targeted approach could potentially enhance effectiveness and reduce side effects compared to traditional options.

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

Research has shown that the combination of avutometinib and defactinib, which participants in this trial may receive, may effectively treat low-grade serous ovarian cancer (LGSOC). One study found that 42.3% of patients with this cancer type experienced tumor shrinkage. In the same study, patients went nearly two years (20.1 months) on average without their cancer worsening. Another study reported a 31% rate of tumor shrinkage with this combination, indicating consistent effectiveness. These findings suggest that this treatment could be a strong option for those with recurrent LGSOC who have previously received platinum-based therapies. ^{1 2 3 5 6}

Who Is on the Research Team?

Craig Berman Verastem Medical Monitor

Principal Investigator

[e-mail]

Rachel Grisham, MD

Principal Investigator

GOG Foundation

Susana Banerjee, MBBS, MA, PhD

Principal Investigator

European Network of Gynecological Oncological Trial Groups (ENGOT)

Are You a Good Fit for This Trial?

This trial is for individuals with recurrent low-grade serous ovarian cancer (LGSOC) who have seen their cancer return or worsen after at least one systemic therapy. Participants must have a certain level of physical fitness (ECOG ≤ 1), measurable disease, and good organ function. They should be recovered from previous treatment side effects and agree to use effective contraception if they can have children.

Inclusion Criteria

Your disease can be accurately measured according to the Response Evaluation Criteria In Solid Tumors version 1.1 guidelines.

I have been diagnosed with low-grade serous ovarian cancer.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either the investigational combination of avutometinib plus defactinib or Investigator's Choice of Treatment in 28-day cycles

24 months

Monthly visits for treatment administration and monitoring

Follow-up

Participants are monitored for safety, overall survival, and progression-free survival after treatment

Up to 5 years

Open-label extension (optional)

Participants may opt into continuation of treatment long-term if they initially received standard care and have progressive disease

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Avutometinib
• Defactinib

Trial Overview The study tests the combination of two drugs, Avutometinib (VS-6766) and Defactinib (VS-6063), against the Investigator's choice of standard treatments like Topotecan or Paclitaxel in patients with LGSOC. The goal is to see which approach is safer and more effective after prior platinum-based therapy failure.

How Is the Trial Designed?

Group I: avutometinib + defactinib Experimental Treatment 2 Interventions

Avutometinib 3.2 mg, PO, twice weekly for 21 days on, 7 days off in a 28-day (4 weeks) cycle in combination with defactinib 200 mg, PO, twice daily for 21 days on, 7 days off in a 28-day(4 week) cycle.

Group II: Investigator Choice of Treatment (ICT) Active Control 4 Interventions

Patients will receive one of the following therapies as determined by the Investigator: * Pegylated liposomal doxorubicin: 40 mg/m2 IV on Day 1 of each 28-day (4 week) cycle. * Paclitaxel: 80 mg/m2 IV on Days 1, 8, and 15 of each 28-day (4 week) cycle. * Anastrozole: 1 mg, PO, once daily of each 28-day (4 week) cycle. * Letrozole: 2.5 mg, PO, once daily of each 28-day (4 week) cycle.

Who Is Running the Clinical Trial?

Verastem, Inc.

Lead Sponsor

Trials

42

Recruited

2,800+

GOG Foundation

Collaborator

Trials

48

Recruited

18,500+

European Network of Gynaecological Oncological Trial Groups (ENGOT)

Collaborator

Trials

41

Recruited

19,200+

Australia New Zealand Gynaecological Oncology Group

Collaborator

Trials

16

Recruited

5,800+

Korean Gynecologic Oncology Group

Collaborator

Trials

14

Recruited

2,700+

Published Research Related to This Trial

In the PENELOPE trial, adding pertuzumab to chemotherapy (either topotecan or paclitaxel) showed a median progression-free survival of about 4.1 to 4.2 months in patients with platinum-resistant ovarian cancer and low HER3 expression, indicating potential efficacy in this specific subgroup.

The treatment was generally well-tolerated, although common adverse events included fatigue, anemia, and neutropenia, with some serious adverse events leading to patient deaths, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab Plus Chemotherapy for Platinum-Resistant Ovarian Cancer: Safety Run-in Results of the PENELOPE Trial. González-Martín, A., Pautier, P., Mahner, S., et al.[2022]

Maintenance therapies for primary ovarian cancer, including olaparib and niraparib, are not considered cost-effective at current prices, even with positive efficacy results from large clinical trials.

For olaparib to be deemed cost-effective for patients with a BRCA variant, its monthly price would need to drop significantly from $17,000 to $9,000, highlighting the economic challenges of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of Maintenance Therapy Based on Molecular Classification Following Treatment of Primary Epithelial Ovarian Cancer in the United States. Penn, CA., Wong, MS., Walsh, CS.[2021]

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]

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]

Current management of ovarian cancer is complex, with ongoing debates about the best chemotherapy options for both early and advanced stages, including the use of taxanes and the role of neoadjuvant chemotherapy.

Recent studies suggest that for relapsed ovarian cancer, carboplatin combined with either paclitaxel or gemcitabine is recommended, while the potential benefits of intraperitoneal chemotherapy are still not widely adopted despite evidence of survival advantages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of chemotherapy in the management of epithelial ovarian cancer. Reed, NS., Sadozye, AH.[2007]

Citations

1. 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) ...

2. cancernetwork.com cancernetwork.com/view/avutometinib-defactinib-display-safety-efficacy-in-ovarian-cancer-subtype

Avutometinib/Defactinib Displays Safety, Efficacy in ... Efficacy data revealed that the objective response rate (ORR) among patients treated with the combination was 31% vs 17% among those treated ...

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-00300

A Study of Avutometinib (VS-6766) + Defactinib (VS-6063) ... This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with defactinib versus Investigator's choice of treatments (ICT)

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

Press Release - Verastem, Inc. FRAME study demonstrated a 42.3% ORR and 20.1 months median PFS for all patients with low-grade serous ovarian cancer (LGSOC), regardless of ...

5. 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 ...

6. 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 ...