Inclusion Criteria:

• Age > 12 years old with a body surface area (BSA) of at least 1.5 mm2

• DIAGNOSIS: Participants with relapsed, refractory, unresectable or metastatic histologically confirmed NF1 associated or sporadic MPNST.

• Participants must have available archival tissue. Tissue blocks strongly preferred. Exceptions may be made following discussion with study team if tissue has been exhausted.

• MEASURABLE DISEASE: Participants must have measurable disease by RECIST v1.1.

• THERAPEUTIC OPTIONS: Participants must have experienced relapse/progression or demonstrated disease that is refractory to one or more prior regimens of cytotoxic chemotherapy or participants who must have declined cytotoxic chemotherapy.

• PRIOR THERAPY

  • Participants may not have previous exposure to combination treatment with a MEK/FAK inhibitor in combination. Participants may have received MEK inhibitor or FAK inhibitor as a single agent for prior therapy.
  • Participants must have not had a serious adverse event (CTCAE grade III or IV) to prior MEK inhibitor or FAK inhibitor drugs.
  • Participants must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering on this study. If the participant is experiencing unresolved toxicity from previous treatment they may still be enrolled in the study as long as it is not expected to be worsened by active treatment or deemed unsafe by the study team.
  • No limitation on the number of prior chemotherapy regimens the participant may have received before study entry.
  • Myelosuppressive chemotherapy: The last dose of all myelosuppressive anticancer drugs must be at least 2 weeks before study entry as long as hematologic parameters have returned to the minimum study requirements.
  • Immunotherapy: The last dose of immunotherapy (monoclonal antibody or vaccine) must be at least 4 weeks before study entry. Cellular therapies: At least 6-week washout from immune cell engaging bispecific antibodies, genetically modified T cell, NK cell, or dendritic cell therapy.
  • Biologic (anti-cancer agent): The last dose of all biologic agents for the treatment of the participant's cancer (such as retinoids or tyrosine kinase inhibitors) must be at least 14 days prior to study entry.
  • Radiation therapy: The last dose of radiation to more than 25% of marrow-containing bones (pelvis, spine, skull) must be at least 4 weeks before study entry. The last dose of all other local palliative (limited port) radiation must be at least 2 weeks before study entry.
  • Stem Cell Transplantation. At least 2 months post-autologous stem cell transplant or at least 3 months post-allogeneic transplant and recovered from toxicities without evidence of graft versus host disease and on stable doses of immunosuppressive medications if required.

Investigational agents: At least a 4-week washout from other investigational agents.

Interleukins, interferons, and cytokine therapy: At least 3 weeks washout period from the last administered Interleukins, interferons, and cytokine therapy other than hematopoietic growth factors

• Growth Factors. The last dose of colony-stimulating factors, such as filgrastim, sargramostim, and erythropoietin, must be at least 1 week prior to study entry. The last dose of long-acting colony-stimulating factors, such as pegfilgrastim, must be at least 2 weeks prior to study entry.

  • CONCURRENT THERAPIES: No other anti-cancer therapy (chemotherapy, biological therapy, radiation therapy) is permitted while on trial with this regimen.
  • PERFORMANCE STATUS

• Lansky/Karnofsky performance level ≥ 50% (Appendix 4).

• Participants who are unable to walk because of paralysis or motor weakness, but who are up in a wheelchair will be considered ambulatory for the purpose of calculating the performance score.

  - HEMATOLOGIC FUNCTION

• Peripheral absolute neutrophil count (ANC) of ≥1000/μL

• Platelet count ≥75,000/μL.

• Hemoglobin >8 g/dL (transfusion permissible).

  - HEPATIC FUNCTION

• Total bilirubin must be ≤ 1.5 times the upper limit of normal (ULN) (for participants with Gilbert's disease ≤3x ULN)

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN (or < 5 x ULN in participants with liver metastases).

  • RENAL FUNCTION: Serum creatinine ≤ ULN or creatinine clearance >30 ml/min/1.73 m2
  • Serum triglyceride level ≤300 mg/dL and serum cholesterol level ≤ 300 mg/dL (Participant may be on lipid-lowering medicine)
  • International normalized ratio (INR) <1.5
  • Albumin > 3 g/dL (451 μmol/L)
  • Creatine phosphokinase (CPK) < 2.5 x ULN
  • CARDIAC FUNCTION:

• Normal ejection fraction by echocardiogram, cardiac MRI >50%, or institutional standard

• QTcF ≤ 480ms

  • Fertile men and women of childbearing potential must agree to use an effective method of birth control.
  • Participants with central nervous system disease are eligible for enrollment if they have received prior radiotherapy or surgery to sites of CNS metastatic disease and are without evidence of clinical progression or stable disease at 4 weeks.

Exclusion Criteria:

• Current warfarin use. If a participant is currently being treated for a pulmonary embolism with warfarin, they may be eligible if they are able to be converted to a Direct Oral Anticoagulant (DOAC) or low molecular weight heparin.
• History of another active malignancy. Prior malignancy, that has been curatively treated or malignancies with very low potential for recurrence or progression may be included.
• Major surgery within 4 weeks (excluding placement of vascular access, or core needle biopsy), minor surgery within 2 weeks.
• Exposure to medications (with or without prescription), supplements, herbal remedies, or foods with potential for drug-drug interactions with avutometinib and/or defactinib within 5 half-lives (if known), or 14 days prior to the first dose of study intervention, whichever is longer.
• Symptomatic brain metastases requiring steroids above the physiologic dose for adrenal insufficiency or other local interventions. Participants with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment (greater than physiologic dosing) for these metastases for at least 2 weeks prior to first dose of study therapy, and are neurologically stable, with no evidence of interim progression. Participants with new asymptomatic CNS metastases detected during the screening period must receive radiation therapy and/or surgery for CNS metastases. Following treatment, these participants may then be eligible if all other criteria are met.
• Known hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection that is active and/or requires therapy.
• Uncontrolled skin disorders (i.e. psoriasis, lupus dermatitis, rosacea) that may confound the interpretation of the safety findings from the study treatments. If the skin condition is adequately controlled and the participant is on a stable dose of controlling medications, they may be eligible for this study.
• History of medically significant rhabdomyolysis.
• Concurrent ocular disorders:
• Baseline best corrected visual acuity of 20/80 or worse.
• Participants with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes.
• Participants with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure > 21 mm Hg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO.
• Participants with active or chronic, visually significant corneal disorders, other active ocular conditions requiring ongoing therapy or clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy. Examples of visually significant corneal disorders include corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions. Visually significant corneal disorders do NOT include dry eyes, blepharitis, and uncomplicated corneal erosions.
• 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, severe obstructive pulmonary disease, or persistent, uncontrolled hypertension defined as systolic blood pressure >140 mmHg or diastolic blood pressure> 90mmHg. Participants may qualify if their blood pressure is controlled on anti-hypertensive agents.
• Participants with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.
• Participants with a history of hypersensitivity to any of the active or inactive avutometinib and/or defactinib ingredients (hydroxypropylmethylcellulose, mannitol, magnesium stearate).

Female subjects who are pregnant or breastfeeding.

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