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

Prior treatment

• Prior treatment with avutometinib, defactinib, or other FAK inhibitors.
• Major surgery within 4 weeks, minor surgery within 1 week, or palliative radiotherapy within 1 week of the first dose of study intervention.
• Symptomatic brain metastases requiring steroids or other interventions, known leptomeningeal metastases, or spinal cord compression.
• For subjects with prior MEK or RAF exposure, Grade 4 toxicity is deemed related to the MEK inhibitor.
• Concurrent ocular disorders.
• Concurrent heart disease or severe obstructive pulmonary disease.
• Subjects with the inability to swallow oral medications.
• 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.

Other illness

• Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy.
• Co-existing high-grade serous ovarian cancer or mixed histology.
• An active skin disorder that has required systemic therapy within one year of the first dose of study intervention.
• History of medically significant rhabdomyolysis.
• Active or past medical history of interstitial lung disease/pneumonitis, including drug-induced or radiation pneumonitis, pulmonary fibrosis, or adult respiratory distress syndrome (ARDS).
• Active, uncontrolled infection (bacterial, viral, or fungal) requiring systemic therapy.

Age

• History of prior malignancy with recurrence \<3 years from the time of enrollment.

Other

• Patients will be excluded from the study if they meet any of the following criteria:
• Symptomatic bowel obstruction within 3 months of the first dose of study intervention
• Pregnant or breastfeeding.

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