Inclusion Criteria:
* Age ≥ 12 years of age
* Patients with unresectable or metastatic histologically confirmed sporadic or NF1 associated MPNST.
* Patients must have measureable disease by RECIST.
* Patients must have experienced progression after one or more prior regimens of cytotoxic chemotherapy. Patients who have refused cytotoxic chemotherapy or for whom treatment on this protocol prior to receiving cytotoxic chemotherapy is felt to be in the best interest for the patient by the local investigator will also be eligible.
* Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering on this study.
* No limitation on the number of prior chemotherapy regimens that the patient may have received prior to study entry.
* The last dose of all myelosuppressive anticancer drugs must be at least 3 weeks prior to study entry.
* The last dose of immunotherapy (monoclonal antibody or vaccine) must be at least 4 weeks prior to study entry.
* The last dose of all biologic agents for the treatment of the patient's cancer (such as retinoids or tyrosine kinase inhibitors) must be at least 7 days prior to study entry.
* The last dose of radiation to more than 25% of marrow containing bones (pelvis, spine, skull) must be at least 4 weeks prior to study entry. The last dose of all other local palliative (limited port) radiation must be at least 2 weeks prior to study entry.
* 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.
* 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.
* No other anti-cancer therapy (chemotherapy, biological therapy, radiation therapy) is permitted.
* Karnofsky performance level ≥ 50%.
* Patients 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.
* Peripheral absolute neutrophil count (ANC) of ≥1000/μL
* Platelet count ≥75,000/μL (transfusion independent (no transfusion within at least 7 days prior to enrollment)
* Total bilirubin must be ≤ 1.5 times the upper limit of normal (ULN)
* SGPT (ALT) must be ≤ 3.0 times ULN
* Serum creatinine ≤ ULN or creatinine clearance \>60 ml/min/1.73 m2
* Serum triglyceride level ≤300 mg/dL and serum cholesterol level ≤ 300 mg/dL (Patient may be on lipid-lowering medicine)
* Normal ejection fraction by ECHO or cardiac MRI \>55%
* QTcF ≤ 450ms
* Fertile men and women of childbearing potential must agree to use an effective method of birth control.
* Patients 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:
* Patients receiving other anti-cancer agents are not eligible.
* Patients who cannot swallow whole pills.
* Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent (for example cyclosporine). Topical or inhaled corticosteroids are allowed.
* Patients should not receive immunizations with attenuated live vaccines within four weeks of study entry or during study period.
* Any recent major surgery within a minimum of 4 weeks, with the exception of surgical placement for vascular access, or minor surgery (excluding tumor biopsies) within 14 days.
* Patients who any known severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
* Severely impaired lung function defined as spirometry and DLCO that is 50% of the normal predicted value corrected for hemoglobin and alveolar volume and/or O2 saturation that is 88% or less at rest on room air. For patients who do NOT have respiratory symptoms (e.g. dyspnea at rest, known requirement for supplemental oxygen), pulmonary function test is not required.
* Cardiac conditions as follows:
* Uncontrolled hypertension (blood pressure ≥150/95 mmHg despite medical therapy).
* Acute coronary syndrome within 6 months prior to starting treatment
* Uncontrolled angina despite medical therapy
* Symptomatic heart failure NYHA Class II-IV prior or current cardiomyopathy, or severe valvular disease
* Prior or current cardiomyopathy
* Uncontrolled Type 1 or 2 diabetes as defined by fasting serum glucose \>1.5 x ULN
* Uncontrolled infection
* Pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi Syndrome, or renal tubular acidosis.
* Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of small bowel, symptomatic inflammatory bowel disease, or ulcerative colitis, or partial or complete bowel obstruction.
* Ophthalmological conditions as follows:
* Current or past history of retinal pigment epithelial detachment (RPED)/central serous retinopathy (CSR) or retinal vein occlusion
* Intraocular pressure (IOP) \> 21 mmHg or uncontrolled glaucoma
* Supplementation with vitamin E greater than 100% of the daily recommended dose.
* Hypersensitivity to active or inactive excipients of rapamycins (sirolimus, temsirolimus or everolimus) or selumetinib or drugs with similar chemical structures or class to sirolimus or selumetinib.
* Patients unwilling or unable to comply with the protocol.
* Seville orange, star fruit, grapefruit and their juices, and St. John's Wort use are not allowed while on study.
* Exposure to strong or moderate inhibitors or inducers of CYP3A4/5, Pgp (MDR1) and BCRP if taken within the stated washout periods before the first dose of study treatment.
* Exposure to specific substrates of drug transporters OATP1B1, OATP1B3, MATE1 and MATE2K within the appropriate washout periods (a minimum of 5 x reported elimination half-life) before the first dose of study treatment.
