A Study of Avutometinib (VS-6766) + Defactinib (VS-6063) in Recurrent Low-Grade Serous Ovarian Cancer

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 diagnostictest.

3. Suitable for treatment with at least one of the Investigator's Choice ofTreatments:pegylated liposomal doxorubicin, paclitaxel, letrozole, anastrozole.

4. Progression or recurrence of LGSOC after at least one prior systemic therapy formetastatic 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 beconfirmed and agreement to use highly effective method of contraceptive.

10. Willingness to comply with the scheduled visits, treatment plan, laboratory testsand 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 palliativeradiotherapy within 1 week of the first dose of study intervention.

6. Symptomatic brain metastases requiring steroids or other interventions, knownleptomeningeal metastases, or spinal cord compression.

7. An active skin disorder that has required systemic therapy within one year of thefirst 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 tothe MEK inhibitor.

10. Symptomatic bowel obstruction within 3 months of the first dose of studyintervention

11. Concurrent ocular disorders.

12. Concurrent heart disease or severe obstructive pulmonary disease.

13. Active or past medical history of interstitial lung disease/pneumonitis, includingdrug-induced or radiation pneumonitis, pulmonary fibrosis, or adult respiratorydistress syndrome (ARDS).

14. Subjects with the inability to swallow oral medications.

15. History of hypersensitivity to any of the active agents or ingredients of studyintervention: peanut, soya, polyoxyl castor oil, etcetc.). Prior hypersensitivity toanthracyclines 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 systemictherapy.