Selinexor in Combination With Ixazomib for the Treatment of Advanced Sarcoma

Inclusion Criteria: 1. Signed written informed consent. 2. Age ≥ 14 years 3. Body surface area ≥ 1.2 m2 4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. 5. Histologically confirmed de-differentiated liposarcoma, malignant peripheral nerve sheath tumor, alveolar soft part sarcoma or Ewing sarcoma. Liposarcomas with areas of well-differentiated disease are eligible if there is a biopsy-proven component of dedifferentiated liposarcoma. Pathology is reviewed at Columbia University Medical Center. 6. Disease which is locally advanced and unresectable or metastatic. Disease which may be resected but with an associated level of morbidity deemed unacceptable by the treating clinician is considered eligible. 7. Measurable disease as assessed by RECIST criteria version 1.1. 8. Progression on, or intolerance to, at least one prior systemic regimen for sarcoma (including systemic treatment used in the adjuvant or neoadjuvant settings). For alveolar soft part sarcoma and dedifferentiated liposarcoma, there is no upper limit on the number of prior therapies that may have been received. For Ewing sarcoma and malignant peripheral nerve sheath tumor, patients may have received no more than 3 prior lines of therapy (excluding systemic treatment used in the adjuvant or neoadjuvant settings). 9. Acceptable organ and marrow function as defined below: Absolute neutrophil count (ANC) ≥ 1,500/mm3 Hemoglobin ≥ 8.5 g/dL Platelet count ≥ 100,000/mm3 Calculated creatinine clearance \> 30 mL/min Total bilirubin ≤ 1.5 times upper limit of normal Aspartate Transaminase (AST) /Alanine Transaminase (ALT) ≤ 3.0 times upper limit of normal * Upper limit of normal is defined by the clinical laboratory performing the test. * Creatinine clearance is obtained using the lean body mass formula (Modified Cockcroft Gault) * If transaminase elevation and/or bilirubin elevation is attributed to the presence of liver metastases, a total bilirubin ≤ 2.5 times the upper limit of normal and an Aspartate Transaminase (AST) and Alanine Transaminase (ALT) ≤ 2.5 times the upper limit of normal are permissible. Patients with an elevated bilirubin level that is attributed to an inherited disorder, such as Gilbert's disease, may be enrolled at the discretion of the principal investigator. * Patients may not receive platelet transfusions within 3 weeks of initiating protocol therapy. 10. Meet the following criteria regarding contraception: Female patients who: 1. Are postmenopausal for at least 1 year before the screening visit, OR 2. Are surgically sterile, OR 3. If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR 4. Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.) Male patients who: (must meet criteria even if surgically sterilized, i.e. after vasectomy): 1. Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR 2. Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.) Exclusion Criteria: 1. Received selinexor or another XPO1 inhibitor previously. 2. Received ixazomib or another proteasome inhibitor previously. 3. Currently pregnant or lactating. 4. Prior malignancy that required treatment, or has shown evidence of recurrence (except for non-melanoma skin cancer or adequately treated cervical carcinoma in situ) during the 5 years prior to registration. Cancer treated with curative intent more than 5 years previously and without evidence of recurrence is not an exclusion. 5. Received any systemic anticancer therapy including investigational agents or radiation ≤3 weeks (or ≤5 half-lives of the drug, whichever is longer) prior to registration. Patients must have recovered to grade ≤ 1 or baseline from clinically significant adverse effects associated with prior anti-cancer therapies except for alopecia or controlled endocrinopathies. 6. Major surgery within 2 weeks of first dose of study treatment. 7. Any serious medical or psychiatric illness, medical condition or organ dysfunction which, in the investigator's opinion, could compromise patient safety or compliance with the protocol. 8. Unstable cardiovascular function as defined by: 1. Symptomatic ischemia, or 2. Uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on anti-arrhythmia are excluded; 1st degree arterioventricular block or asymptomatic left anterior fascicular block/right bundle branch block will not be excluded), or 3. Congestive heart failure (CHF) of New York Heart Association (NYHA) Class ≥3, or 4. Myocardial infarction (MI) within 6 months 9. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment. Prophylactic use of antibiotics and/or antivirals is acceptable. 10. Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positivity. 11. History of clinically significant ocular disease manifest by visual defects or disturbances, including those caused by active glaucoma or cataracts, which have not been addressed by surgery or other corrective intervention. If necessary, an opthalmologic exam should be performed at screening. 12. Inability to swallow tablets, clinically significant malabsorption syndrome, or any other GI disease or dysfunction that could interfere with absorption of study drugs. 13. Presence of grade 3 peripheral neuropathy or grade 2 peripheral neuropathy with pain at any time during the screening period. 14. Systemic treatment, within 14 days before initiation of study treatment, with strong CYP3A4 inducers (including, but not limited to rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital) or use of St. John's wort. 15. Unwillingness to comply with the study protocol and/or procedures. 16. Central nervous system involvement. 17. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent. 18. Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial.