A Phase 2 Study of Avutometinib (VS-6766) Plus Defactinib

Inclusion Criteria:

1. Female subjects ≥ 18 years of age.

2. Histologically proven gynecological cancers (endometrioid, MOC, HGSOC and solidgynecological cancers) with mutated RAS, BRAF (type I, II, and/or III), NF-1 loss offunction, and/or RAS activation.

3. Mutational status will be taken from the previous next-gen sequencing (NGS) ormolecular testing results and reviewed by the Principal Investigator prior tothe start of treatment.

4. Adequate pathology material (as defined in the lab manual) must be availableprior to treatment assignment to be used for confirmation.

5. Tumor with known RAS mutation, BRAF (type I, II, and/or III) mutation, NF-1 and/orRAS activation status determined from previous NGS or molecular testing. Adequatearchival tumor tissue less than 5 years old or fresh biopsy tissue samples (asdefined in the lab manual) must be available.

6. Progression (radiographic or clinical) or recurrence of gynecological cancer afterat least one prior systemic therapy for metastatic disease. Below are additionalprior treatments that are allowed once the requirement of prior platinum therapy issatisfied. a. Prior systemic therapy for metastatic disease (FIGO stage II-IV) may consist ofchemotherapy administered as single agent or a platinum or another chemotherapydoublet with or without bevacizumab, with or without maintenance therapy orradiation therapy; and/or hormonal therapy.

7. Measurable disease according to RECIST 1.1.

8. An Eastern Cooperative Group (ECOG) performance status ≤ 2.

9. Must have adequate organ function defined by the following laboratory parameters:

10. Adequate hematologic function including: hemoglobin [Hb] ≥9.0 g/dL; platelets ≥100,000/mm3; and absolute neutrophil count [ANC] ≥1500/mm3). If a red bloodcell transfusion has been administered the Hb must remain stable and ≥9 g/dLfor at least 1 week prior to first dose of study therapy.

11. Adequate hepatic function: (i) total bilirubin ≤1.5 × upper limit of normal [ULN] for the institution; subjects with Gilbert syndrome may enroll if totalbilirubin is <3.0 mg/dL (51 μmole/L) upon discussion with the PrincipalInvestigator (PI). (ii) alanine aminotransferase (ALT) and alanineaminotransferase (AST) ≤2.5 × ULN (or <5x ULN in subjects with livermetastases).

12. Adequate renal function with creatinine clearance rate of ≥50 mL/min ascalculated by the Cockcroft-Gault formula or serum creatinine of ≤ 1.5 x ULN.

13. International normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 1.5 x ULN in the absence of anticoagulation or therapeutic levels inthe presence of anticoagulation.

14. Albumin ≥3.0 g/dL (451 μmole/L).

15. Creatine phosphokinase (CPK) ≤2.5 x ULN.

16. Adequate cardiac function with left ventricular ejection fraction ≥ 55% byechocardiography (ECHO) or multiple-gated acquisition (MUGA) scan.

17. Baseline QTc interval < 460 ms (average of triplicate readings) (CTCAE Grade1) usingFredericia's QT correction formula. NOTE: This criterion does not apply to subjectswith a right or left bundle branch block.

18. Adequate recovery from toxicities related to prior treatments to at least Grade 1 byCTCAE v 5.0

19. Exceptions include alopecia and peripheral neuropathy Grade ≤2. Subjects with othertoxicities that are stable on supportive therapy may be allowed to participate withprior approval by the Sponsor.

20. Females with reproductive potential and their male partners agree to use highlyeffective method of contraceptive (per recommendations in Section 13.4) during thetrial and for 1 month following the last dose of Avutometinib for female patients.

Exclusion Criteria:

1. Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy.

2. Prior MEKi or RAFi exposure.

3. Low grade serous ovarian cancer (LGSOC).

4. History of prior malignancy with recurrence <3 years from the time of enrollment.Subjects with basal cell carcinoma of the skin, superficial bladder cancer, squamouscell carcinoma of the skin, and in situ cervical cancer that has undergonepotentially curative therapy with no evidence of disease recurrence for ≥1 yearsince completion of the appropriate therapy may be included. Subjects with othermalignancies associated with very low risk of metastasis or death may be includedupon discussion with the PI.

5. Subjects who are deemed in the opinion of their treating physician to be appropriatecandidates for a debulking surgery. These subjects should preferentially receivesurgery prior to consideration of trial therapy.

6. Major surgery within 4 weeks (excluding placement of vascular access), minor surgerywithin 2 weeks, or palliative radiotherapy within 1 week (7 days) of the first doseof study therapy.

7. Treatment with warfarin. Subjects on warfarin for DVT/PE can be converted tolow-molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs).

8. Exposure to strong CYP2C9 and CYP3A4 inhibitors or inducers within 14 days prior tothe first dose and during the course of therapy. See Table 14 and Table 15 forrepresentative lists of CYP inhibitors and inducers. For additional guidance, seehttps://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-druginteractions-table-substrates-inhibitors-and-inducers.

9. Exposure to P-glycoprotein (P-gp) inhibitors or inducers within 14 days prior to thefirst dose and during the course of the study. See Table 16 for a representativelist of P-gp inhibitors and inducers.

10. Symptomatic brain metastases requiring steroids or other interventions. Thesemetastases may manifest as altered mental status, persistent headaches, persistentnausea, focal weakness or numbness, and seizures. Subjects with previously diagnosedbrain metastases are eligible if they have completed their treatment and haverecovered from the acute effects of radiation therapy or surgery prior to studyentry, have discontinued corticosteroid treatment for these metastases for at least 2 weeks prior to first dose of study therapy, and are neurologically stable, with noevidence of interim progression. Subjects with new asymptomatic CNS metastasesdetected during the screening period must receive radiation therapy and/or surgeryfor CNS metastases. Following treatment, these subjects may then be eligible if allother criteria are met.

11. Known SARS-Cov2 infection (clinical symptoms) ≤28 days prior to first dose of studytherapy.

12. Known hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection thatis active and/or requires therapy.

13. Active skin disorder that has required systemic therapy within the past year.

14. History of rhabdomyolysis.

15. Concurrent ocular disorders:

16. Subjects with history of glaucoma, history of retinal vein occlusion (RVO),predisposing factors for RVO, including uncontrolled hypertension, uncontrolleddiabetes.

17. Subject with history of retinal pathology or evidence of visible retinalpathology that is considered a risk factor for RVO, intraocular pressure > 21mm Hg as measured by tonometry, or other significant ocular pathology, such asanatomical abnormalities that increase the risk for RVO.

18. Subjects with a history of corneal erosion (instability of corneal epithelium),corneal degeneration, active or recurrent keratitis, and other forms of seriousocular surface inflammatory conditions.

19. Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA]), myocardial infarction within the last 6 months,unstable arrhythmias, unstable angina, or severe obstructive pulmonary disease.

20. Subjects with the inability to swallow oral medications or impaired gastrointestinalabsorption due to gastrectomy or active inflammatory bowel disease.

21. Subjects with a history of hypersensitivity to any of the active or inactiveAvutometinib ingredients (hydroxypropylmethylcellulose, mannitol, magnesiumstearate) of the investigational product.

22. Female subjects who are pregnant or breastfeeding.

23. Any other medical condition (e.g. cardiac, gastrointestinal, pulmonary, psychiatric,neurological, genetic, etc.) that in the opinion of the investigator would place thesubject at unacceptably high risk for toxicity.