Trametinib in Treating Patients With Epithelioid Hemangioendothelioma That is Metastatic, Locally Advanced, or Cannot Be Removed by Surgery

Inclusion Criteria:

   - Patients must have measurable disease, defined as at least one lesion that can be
   accurately measured in at least one dimension (longest diameter to be recorded for
   non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with
   conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT)
   scan, magnetic resonance imaging (MRI), or calipers by clinical exam; baseline imaging
   must be obtained within 30 days of day 1 of study

   - Patients must have histologically confirmed epithelioid hemangioendothelioma which is
   metastatic or locally advanced (unresectable), and tumor tissue (paraffin-embedded
   tissue block or tumor tissue on unstained glass slides) available for fusion
   fluorescence in situ hybridization (FISH) analysis at Cleveland Clinic; patient tumor
   tissue stored in pathology archives may be used for fusion FISH; a new biopsy is not
   mandatory

   - Patients must have evidence of disease progression per RECIST 1.1 prior to enrollment
   or have evidence of cancer-related pain requiring symptom management with narcotic
   analgesics

   - Because there is no established standard or approved drug therapy for treatment of
   epithelioid hemangioendothelioma (EHE), patients previously untreated or treated with
   drug therapy for EHE are eligible; there is no limit on the number of prior regimens
   used to be eligible

   - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

   - Life expectancy of greater than 6 months

   - Able to swallow orally-administered medication and does not have any clinically
   significant gastrointestinal abnormalities that may alter absorption such as
   malabsorption syndrome or major resection of the stomach or small bowel

   - All prior treatment-related toxicities must be Common Terminology Criteria for Adverse
   Events version 5.0 (CTCAE v5) grade =< 1 (except alopecia) at the time of enrollment

   - Absolute neutrophil count (ANC) >= 1 x 10^9/L (within 2 weeks of patient registration)

   - Hemoglobin >= 9 g/dL, patients may receive transfusion to meet criterion (within 2
   weeks of patient registration)

   - Platelets >= 75 x 10^9/L (within 2 weeks of patient registration)

   - Albumin >= 2.5 g/dL (within 2 weeks of patient registration)

   - Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 2 weeks of
   patient registration); NOTE: patients with elevated bilirubin secondary to Gilbert's
   disease are eligible to participate in the study

   - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
   institutional ULN (within 2 weeks of patient registration)

   - Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault
   formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min (within 2
   weeks of patient registration)

   - Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN)
   by echocardiogram (ECHO) or multigated acquisition scan (MUGA) (within 30 days of
   registration)

   - Trametinib can cause fetal harm when administered to a pregnant woman; women of
   child-bearing potential and men must agree to use adequate contraception (hormonal or
   barrier method of birth control; abstinence) prior to study entry, during the study
   participation, and for four months after the last dose of the drug; women of
   child-bearing potential must have a negative serum pregnancy test within 14 days prior
   to enrollment and agree to use effective contraception throughout the treatment period
   and for 4 months after the last dose of study treatment; should a woman become
   pregnant or suspect she is pregnant while she or her partner is participating in this
   study, she should inform her treating physician immediately

   - Human immunodeficiency virus (HIV)-patients positive for human immunodeficiency virus
   (HIV) are NOT excluded from this study, however HIV-positive patients must meet the
   following criteria:

      - A stable regimen of highly active anti-retroviral therapy (HAART)

      - No requirement for concurrent antibiotics or antifungal agents for the prevention
      of opportunistic infections

      - A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
      polymerase chain reaction (PCR)-based test

Exclusion Criteria:

   - Prior systemic therapy with a MEK inhibitor

   - History of another malignancy

      - Exception: patients who have been disease-free for 3 years or patients with a
      history of completely resected non-melanoma skin cancer and/or patients with
      indolent secondary malignancies, are eligible; consult the Cancer Therapy
      Evaluation Program (CTEP) medical monitor if unsure whether second malignancies
      meet the requirements specified above

   - History of interstitial lung disease or pneumonitis requiring supplemental oxygen or
   treatment with oral or intravenously administered corticosteroids

   - Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity (e.g.
   doxorubicin), biologic therapy, or immunotherapy within 21 days prior to enrollment
   and/or daily or weekly chemotherapy (e.g. sunitinib, sorafenib and pazopanib) without
   the potential for delayed toxicity within 14 days prior to enrollment

   - Use of other investigational drugs within 28 days (or five half-lives, whichever is
   shorter; with a minimum of 14 days from the last dose) preceding the first dose of
   trametinib and during the study

   - Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression

   - Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
   chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO)

   - Current use of a prohibited medication; the following medications or non-drug
   therapies are prohibited:

      - Other anti-cancer therapy while on study treatment; (note: megestrol [Megace] if
      used as an appetite stimulant is allowed)

      - Concurrent treatment with bisphosphonates is permitted; however, treatment must
      be initiated prior to the first dose of study therapy; prophylactic use of
      bisphosphonates in patients without bone disease is not permitted, except for the
      treatment of osteoporosis

      - Because the composition, pharmacokinetics (PK), and metabolism of many herbal
      supplements are unknown, the concurrent use of all herbal supplements is
      prohibited during the study (including, but not limited to, St. John's wort,
      kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe,
      saw palmetto, or ginseng)

   - History or current evidence/risk of retinal vein occlusion (RVO)

   - History or evidence of cardiovascular risk including any of the following:

      - A QT interval corrected for heart rate using the Bazett's formula QTcB >= 480
      msec

      - History or evidence of current clinically significant uncontrolled arrhythmias
      (exception: patients with controlled atrial fibrillation for > 30 days prior to
      randomization are eligible)

      - History of acute coronary syndromes (including myocardial infarction and unstable
      angina), coronary angioplasty, or stenting within 6 months prior to randomization

      - History or evidence of current >= class II congestive heart failure as defined by
      the New York Heart Association (NYHA) functional classification system

      - Treatment-refractory hypertension defined as a blood pressure of systolic > 140
      mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive
      therapy

      - Patients with intra-cardiac defibrillators

      - Known cardiac metastases

   - Known hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with
   chronic or cleared HBV and HCV infection are eligible)

   - Any serious and/or unstable pre-existing medical disorder (aside from malignancy
   exception above), psychiatric disorder, or other conditions that could interfere with
   subject's safety, obtaining informed consent or compliance to the study procedures

   - Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal
   to those resulting in exposures approximately 0.3 times the human exposure at the
   recommended clinical dose. Therefore, the study drug must not be administered to
   pregnant women or nursing mothers; women of childbearing potential should be advised
   to avoid pregnancy and use effective methods of contraception; men with a female
   partner of childbearing potential must have either had a prior vasectomy or agree to
   use effective contraception; if a female patient or a female partner of a patient
   becomes pregnant while the patient receives trametinib, the potential hazard to the
   fetus should be explained to the patient and partner (as applicable)

   - Inability to comply with protocol-required procedures