This pilot phase I clinical trial studies the side effects and best dose of toll-like receptor 4 (TLR4) agonist glucopyranosyl lipid A (GLA)-stable-emulsion (SE) when given together with radiation therapy in treating patients with soft tissue sarcoma that has spread to other parts of the body (metastatic) or cannot be removed by surgery (unresectable). TLR4 agonist GLA-SE may stimulate the immune system to kill sarcoma cells. Radiation therapy uses high energy x rays to kill tumor cells. Giving TLR4 agonist GLA-SE with radiation therapy may be a better treatment to treat sarcoma that cannot be removed by surgery.

PRIMARY OBJECTIVES:

I. To evaluate the safety of weekly injections of GLA-SE (TLR4 agonist GLA-SE) in combination with palliative radiation in patients with metastatic sarcoma.

SECONDARY OBJECTIVES:

I. To look for preliminary evidence of efficacy at distant tumor sites following the combination of radiation and intra-tumor injection of GLA-SE.

II. To analyze changes in tumor-immune infiltrates following radiation and intra-tumor injection of GLA-SE.

OUTLINE: This is a dose-escalation study of TLR4 agonist GLA-SE.

Patients receive TLR4 agonist GLA-SE intratumorally once weekly for 8 weeks. Within 2 weeks of starting treatment, patients also undergo radiation therapy over 2 weeks for a total of 5-6 fractions.

After completion of study treatment, patients are followed up every 6 weeks for 6 months and then every 3 months for up to 1 year.

Inclusion Criteria:

• A diagnosis of metastatic or unresectable sarcoma
• Patient must have a palpable, superficial tumor, safely accessible for bedside injection that will be radiated and can be accurately localized and stabilized if needed
• Patient must have consulted with a radiation oncologist who is planning radiation; radiation should be completed within a 2-week window from start to finish
• Patient must be willing to undergo biopsies as specified by the protocol; the biopsy requirement can only be waived if deemed unsafe by the patient's treating physician or the principal investigator (PI)
• Zubrod (Eastern Cooperative Oncology Group [ECOG]) performance status of '0-2'
• Serum creatinine =< 1.5 times the upper limit of normal
• Total bilirubin =< 1.5 times the upper limit of normal
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times the upper limit of normal
• Prothrombin time (PT) =< 1.5 times the upper limit of normal
• Partial thromboplastin time (PTT) =< 1.5 times the upper limit of normal
• Absolute neutrophil > 1000/uL
• Platelet count > 75,000/uL
• For patients who will be entering the "expansion phase" of the trial, the patient must be able to safely delay radiation by at least 6 weeks

Exclusion Criteria:

• Pregnant women, nursing women, men and women of reproductive ability who are unwilling to use effective contraception or abstinence; women of childbearing potential must have a negative pregnancy test within two weeks prior to study entry
• Known active symptomatic congestive heart failure
• Known clinically significant hypotension
• Known newly diagnosed cardiac arrhythmia; patients with an arrhythmia that has been stable for at least 3 months will be allowed to participate
• Known untreated central nervous system (CNS) metastasis
• Patients with known systemic infections requiring antibiotics or chronic maintenance/suppressive therapy
• Systemic anticancer therapy (chemotherapy, "biologics", immunotherapy) less than two weeks prior to starting radiation
• Known clinically significant autoimmune disorders requiring on-going systemic immune-suppression for control
• Current treatment with steroids
• Patients who are known to be human immunodeficiency virus (HIV) positive must have a normal cluster of differentiation (CD)4 count and undetectable viral load
• Current treatment with warfarin; for patients not on an anti-platelet agent such as aspirin, other anticoagulation is acceptable so long as the treating physician feels that it is safe to hold it on the day of the biopsy until after the biopsy has been safely completed
• Known allergy(ies) to any component of the study agent GLA-SE including egg lecithin