Avutometinib + Defactinib for Ovarian Cancer

(RAMP 301 Trial)

Recruiting at 94 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

Trial Summary

What is the purpose of this trial?

This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with defactinib versus Investigator's choice of treatments (ICT) in subjects with recurrent LGSOC who have progressed on a prior platinum-based therapy.

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.

What makes the drug combination Avutometinib + Defactinib unique for ovarian cancer treatment?

The combination of Avutometinib and Defactinib is unique because it targets specific pathways involved in cancer cell growth, potentially offering a new approach for patients with ovarian cancer, especially those with certain genetic profiles. This combination may provide an alternative for patients who do not respond well to standard platinum-based chemotherapy. ^{1 2 3 4 5}

Research Team

Rachel Grisham, MD

Principal Investigator

GOG Foundation

Susana Banerjee, MBBS, MA, PhD

Principal Investigator

European Network of Gynecological Oncological Trial Groups (ENGOT)

Melina Arazy, MD Verastem Medical Monitor

Principal Investigator

[e-mail]

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

References

1. United States 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. [2021]

2. Hungary pubmed.ncbi.nlm.nih.gov

[Treatment of epithelial ovarian cancer]. [2009]

3. England pubmed.ncbi.nlm.nih.gov

Pertuzumab Plus Chemotherapy for Platinum-Resistant Ovarian Cancer: Safety Run-in Results of the PENELOPE Trial. [2022]

4. 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]

5. England pubmed.ncbi.nlm.nih.gov

Role of chemotherapy in the management of epithelial ovarian cancer. [2007]