Enasidenib in IDH2-Mutated Malignant Sinonasal and Skull Base Tumors

* INCLUSION CRITERIA: * Histologically or cytologically confirmed locally advanced or metastatic SNUC, ONB, LCNEC, SNAC, and CS with documented somatic (tumor) IDH2 mutations R140 or R172. Primary tumors must be located in the sinonasal cavity and/or skull base. * Locally advanced disease must not be amenable to potentially curative surgery/radiotherapy. * Must have recurred or progressed following prior systemic therapy administered in the recurrent or metastatic setting. Any number of prior systemic therapies is allowed. * Measurable disease, per RECIST 1.1. Lesions in a previously irradiated field are considered measurable if they have been demonstrated as progressing during or following radiotherapy. * Age \>=18 years. * ECOG performance status 0-2 * Adequate organ and marrow function as defined below: * hemoglobin \>=9 g/dL (PRBC transfusion allowed) * absolute neutrophil count (ANC) \>=1,000/mcL * platelets \>=75,000/mcL * total bilirubin \<= 1.5 x institutional upper limit of normal (iULN) (\<=3x in the presence of Gilbert s syndrome or a UGT1A1 gene mutation) * AST/ALT \<=1.5 x iULN (\<=2.5 x iULN if liver metastasis) * Serum Creatinine \<=1.5 x iULN OR * Creatinine Clearance \>=40 mL/min by Cockroft-Gault GFR estimation for subjects with serum creatinine levels \<=1.5 X iULN * Participants with treated brain or central nervous system metastases are eligible if follow-up brain imaging after at least 4 weeks following CNS-directed therapy shows no evidence of progression. * Participants positive for human immunodeficiency virus (HIV) must have CD4 count \>= 200 cells per cubic millimeter at enrollment, be on stable antiretroviral therapy for at least 4 weeks and have no reported opportunistic infections or Castleman s disease within 12 months prior to treatment. * Participants with evidence of chronic hepatitis B virus (HBV) infection, must have HBV viral load that is undetectable on suppressive therapy, if indicated. * Participants with evidence of HCV infection, must have viral load that is undetectable. * Women of reproductive potential (WORP\*) and men with female partners of reproductive potential must agree to abstain from sexual intercourse or to use 1 highly effective method of contraception during the study and for at least 2 months following the last dose of enasidenib. A highly effective form of contraception is one of the following: hormonal contraception (e.g., oral contraceptive pills, intravaginal ring, transdermal patch, injection, implant); intrauterine device (IUD); tubal ligation; or a partner with a vasectomy. * Participants who are breastfeeding or plan to breastfeed must agree to discontinue/postpone breastfeeding while on study therapy and for at least 2 months after the last dose. * Ability of participant to understand and willingness to sign a written informed consent document. * Willingness to provide blood samples and undergo biopsy of tumor for research purposes. Participants may be exempt from biopsy. * Participants must co-enroll in companion protocol study #18-DC-0051 entitled Biospecimen procurement for NIDCD clinical protocols . A separate informed consent will be obtained from study participants for this study. * Participants with ONB must co-enroll in companion protocol #21-C-0009 entitled A Natural History Study of Children and Adults with Olfactory Neuroblastoma . A separate informed consent will be obtained from study participants for this study. * WORP: any woman who has experienced menarche and has not had hysterectomy or bilateral oophorectomy or is not postmenopausal (amenorrheic 12 months or more following cessation of exogenous hormonal treatments; if \<50 years old need follicle stimulating hormone FSH in the post-menopausal range) EXCLUSION CRITERIA: * Prior treatment with IDH1/2 inhibitor. * Use of other investigational agents within 3 weeks or 5 half-lives prior to first treatment administration. * Systemic anticancer treatment within 3 weeks prior to first treatment administration. All residual treatment-related toxicities must have resolved or be minimal and not constitute a safety risk. Note: Bisphosphonates and denosumab are permitted medications. * Large-field radiotherapy within 4 weeks prior to first treatment administration. All residual treatment-related toxicities must have resolved (except xerostomia) or be minimal and not constitute a safety risk. * Major surgery within 2 weeks prior to first treatment administration. If participant underwent major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment. Minimally invasive procedures are permitted. * Participants with new or progressive (active) brain metastases or leptomeningeal disease. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to enasidenib. * Treatment with botanical preparations (e.g., herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to first treatment administration. * Participants taking the following sensitive cytochrome P450 (CYP) substrate medications that have a narrow therapeutic range are excluded from the study unless they can be transferred to other medications prior to enrolling: warfarin, phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline and tizanidine (CYP1A2). Excluded medications should not be given within 3 weeks or 5 half-lives (whichever is shorter) prior to the first dose of study medication. Other CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP1A2 substrates may be given concurrently if medically necessary. * Participants taking sensitive substrates of P-glycoprotein (P-gp), breast cancer resistant protein (BCRP), OAT1, OATP1B1, OATP1B3, and OCT2 should be excluded from the study unless the substrate medication can be dose modified according to the package insert of the substrate (if applicable) and adverse events can be closely monitored during concurrent administration. Alternately, participants can be transferred to other medications prior to enrolling. Excluded medications should not be given within 3 weeks or 5 half-lives (whichever is shorter) prior to the first of study medication. * Participants taking medications that are known to prolong the QT interval unless the participant can be transferred to other medications at least 5 half-lives prior to the start of the study treatment. If equivalent medication is not available, QTc will be closely monitored * Impaired cardiovascular function or clinically significant cardiovascular disease, including, but not limited to, any of the following: * cerebral vascular accident/stroke (\< 3 months prior to enrollment), * uncontrolled hypertension (systolic blood pressure \>180 mmHg or diastolic blood pressure \>100 mmHg) * acute coronary syndromes (including myocardial infarction \< 6 months prior to enrollment, unstable angina), * Symptomatic congestive heart failure * Rate-corrected QT (QTc using Fridericia formula \[QTcF\]) \>450 msec * Severe/uncontrolled ventricular arrhythmia * Known short-gut syndrome, gastroparesis, or other conditions that limit the ingestion of gastrointestinal absorption of drugs administered orally. * Active infection requiring treatment with parenteral antibiotics. * History of second malignancy within 3 years prior to enrollment except for the following: adequately treated localized basal cell or squamous skin cancer, cervical carcinoma in situ, superficial bladder cancer, other localized malignancy which has been adequately treated or malignancy which does not require active systemic treatment (e.g., low risk CLL). * Participant pregnancy * Uncontrolled intercurrent illness (including psychiatric) or social situations, that may limit interpretation of results or increase risk to the participant: