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

PRIMARY OBJECTIVES:

I. Estimate the objective response rate (ORR) using Response Evaluation Criteria in Solid
Tumors version 1.1 (RECIST 1.1).

SECONDARY OBJECTIVES:

I. Estimate the 6-month and median progression free survival (PFS) rates. II. Estimate the
2-year and median overall survival (OS) rates. III. Evaluate the safety of trametinib in
patients with epithelioid hemangioendothelioma.

IV. Evaluate patient-reported symptoms using National Institutes of Health Patient Reported
Outcomes Measurement Information System (NIH PROMIS) global health; pain intensity,
interference and behavior short form inventories prior to, after 4 weeks and after 6 months
(if stable or better disease) of treatment, and on evidence of disease progression.

EXPPLORATORY OBJECTIVES:

I. Compare the rates of epithelioid hemangioendothelioma progression prior to starting
trametinib to rates on treatment by central review of radiology images.

II. Evaluate the effect of trametinib on change in tumor volume and compare to RECIST 1.1
response through central imaging review.

III. Evaluate the effect of trametinib on markers of inflammation including c-reactive
protein (CRP), erythrocyte sedimentation rate (ESR) and plasma connective tissue growth
factor (CTGF).

OUTLINE:

Patients receive trametinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28
days for up to 52 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 6 months.

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

- Patients previously untreated or treated with drug therapy for epithelioid
hemangioendothelioma (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
[for blood results] and 30 days of registration for left ventricular ejection fraction
[LVEF] assessment)

- Hemoglobin >= 9 g/dL, patients may receive transfusion to meet criterion (within 2
weeks of patient registration [for blood results] and 30 days of registration for LVEF
assessment)

- Platelets >= 75 x 10^9/L (within 2 weeks of patient registration [for blood results]
and 30 days of registration for LVEF assessment)

- Albumin >= 2.5 g/dL (within 2 weeks of patient registration [for blood results] and 30
days of registration for LVEF assessment)

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 2 weeks of
patient registration [for blood results] and 30 days of registration for LVEF
assessment); 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 [for blood results] and 30
days of registration for LVEF assessment)

- 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 [for blood results] and 30 days of registration for LVEF
assessment)

- LVEF >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or
multigated acquisition scan (MUGA) (within 2 weeks of patient registration [for blood
results] and 30 days of registration for LVEF assessment)

- 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

- 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

- 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