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.

This international, randomized, open-label, Phase 3 study will compare the investigational combination of avutometinib plus defactinib versus Investigator's Choice of Treatments (ICT) in patients with recurrent LGSOC who have progressed on a prior platinum-based therapy. Avutometinib and defactinib are both types of drugs called kinase inhibitors. Kinase inhibitors block cancer cell growth. The study will compare the progression-free survival (PFS) of the combination of avutometinib plus defactinib versus ICT. The study will also evaluate the effect of the combination on safety, overall survival, other efficacy endpoints, and health-related quality of life and disease related symptoms. The study is being conducted by gynecological cancer specialists. Patients who are eligible and agree to participate in this study will be treated with either a combination of avutometinib with defactinib, or with one of four standard of care NCCN and ESMO treatment recommendations for recurrent LGSOC, and then with subsequent follow up appointments. Patients who originally received one of the standards of care treatments who are determined to have progressive disease may be eligible to crossover to receive the investigational combination avutometinib plus defactinib.Avutometinib and defactinib are investigational drugs that have not been approved by the U.S. Food and Drug Administration (FDA)

Inclusion Criteria:

Patients may be eligible for inclusion in the study if they meet the following criteria:

1. Histologically proven LGSOC (ovarian, fallopian, peritoneal)
2. Documented mutational status of KRAS by a validated tumor-tissue based diagnostic test.
3. Suitable for treatment with at least one of the Investigator's Choice of Treatments:pegylated liposomal doxorubicin, paclitaxel, letrozole, anastrozole.
4. Progression or recurrence of LGSOC after at least one prior systemic therapy for metastatic disease.
5. Measurable disease according to RECIST v1.1.
6. An Eastern Cooperative Group (ECOG) performance status ≤ 1.
7. Adequate organ function.
8. Adequate recovery from toxicities related to prior treatments.
9. For patients with reproductive potential, a negative pregnancy test must be confirmed and agreement to use highly effective method of contraceptive.
10. Willingness to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion Criteria:

Patients will be excluded from the study if they meet any of the following criteria:

1. Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy.
2. Co-existing high-grade serous ovarian cancer or mixed histology.
3. Prior treatment with avutometinib, defactinib, or other FAK inhibitors.
4. History of prior malignancy with recurrence <3 years from the time of enrollment.
5. Major surgery within 4 weeks, minor surgery within 1 week, or palliative radiotherapy within 1 week of the first dose of study intervention.
6. Symptomatic brain metastases requiring steroids or other interventions, known leptomeningeal metastases, or spinal cord compression.
7. An active skin disorder that has required systemic therapy within one year of the first dose of study intervention.
8. History of medically significant rhabdomyolysis.
9. For subjects with prior MEK or RAF exposure, Grade 4 toxicity is deemed related to the MEK inhibitor.
10. Symptomatic bowel obstruction within 3 months of the first dose of study intervention
11. Concurrent ocular disorders.
12. Concurrent heart disease or severe obstructive pulmonary disease.
13. Active or past medical history of interstitial lung disease/pneumonitis, including drug-induced or radiation pneumonitis, pulmonary fibrosis, or adult respiratory distress syndrome (ARDS).
14. Subjects with the inability to swallow oral medications.
15. History of hypersensitivity to any of the active agents or ingredients of study intervention: peanut, soya, polyoxyl castor oil, etcetc.). Prior hypersensitivity to anthracyclines or anthracenediones if the use of pegylated liposomal doxorubicin (PLD) is planned.
16. Pregnant or breastfeeding.
17. Active, uncontrolled infection (bacterial, viral, or fungal) requiring systemic therapy.