Daily Oral Regorafenib for Chemotherapy-Refractory, Metastatic and Locally Advanced Angiosarcoma

The purpose of this study is to see whether a drug called regorafenib might be effective in treating angiosarcoma. This study is for patients who have angiosarcoma that has gotten worse after they received chemotherapy. Regorafenib is a type of drug called a kinase inhibitor. Regorafenib interferes with how some kinase proteins work. Some of these kinases in cancer cells might normally help the cancer cells grow or form new blood vessels that could feed a growing tumor. By blocking these proteins, regorafenib may help stop the growth of certain cancers.

PRIMARY OBJECTIVES:

I. To define the progression-free survival (PFS) at 4 months with daily oral regorafenib (160 mg) in previously treated locally advanced/metastatic angiosarcoma patients

SECONDARY OBJECTIVES:

I. Progression-free rate at 3 and 6 months. II. Progression-free survival. III. Overall survival (up to 5 years). IV. Response rate (by Response Evaluation Criteria in Solid Tumors \[RECIST\] version \[v\] 1.1).

V. Rate and duration of tumor control (complete response \[CR\] + partial response \[PR\] + stable disease \[SD\]).

VI. Safety/tolerability of regorafenib.

OUTLINE:

Patients receive regorafenib orally (PO) once daily (QD) on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 5 years.

Eligibility Criteria:
Inclusion Criteria:

* Life expectancy of at least 4 months
* Histologically confirmed angiosarcoma
* Tumor deemed unresectable or metastatic
* Measurable disease per RECIST v 1.1
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
* Progressive disease under last palliative therapy with a history of prior ifosfamide, doxorubicin or taxane therapy for angiosarcoma; up to 4 prior therapies are allowed
* All acute toxic effects of any prior treatment have resolved to grade 1 or less (by National Cancer Institute-Common Terminology Criteria for Adverse Events \[NCI-CTCAE\] v 4.0) at the time of registration; NOTE: Exceptions to this criterion will include alopecia and fatigue
* Total bilirubin =\< 1.5 x the upper limits of normal (ULN)
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 2.5 x ULN (=\< 5 x ULN for subjects with liver involvement of their cancer)
* Alkaline phosphatase limit =\< 2.5 x ULN (=\< 5 x ULN for subjects with liver involvement of their cancer)
* Lipase =\< 1.5 x the ULN
* Serum creatinine =\< 1.5 x the ULN
* International normalized ratio (INR)/partial thromboplastin time (PTT) \< 1.5 x ULN
* Platelet count \> 100000/mm\^3
* Hemoglobin \> 9 g/dL
* Absolute neutrophil count \> 1500/mm\^3
* If baseline urine protein creatinine (UPC) \>= 1, a 24-hour urine protein must be assessed; patients must have a 24-hour urine protein value \< grade 3 (\> 3.5 g/24 hours) to be eligible
* NOTE: Blood transfusion to meet the above criteria will not be allowed; NOTE: Patients who are prophylactically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists; close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care
* Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study drug; post-menopausal women (defined as age \>= 50 years and no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test
* Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at registration until at least 3 months after the last dose of study drug; the definition of adequate contraception will be based on the judgment of the principal investigator
* Subject must be able to swallow and retain oral medication
* Subjects must be able to understand and be willing to sign the written informed consent form; a signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure

Exclusion Criteria:

* Uncontrolled hypertension (systolic pressure \> 140 mmHg or diastolic pressure \> 90 mmHg on repeated measurement) despite optimal medical management
* Active or clinically significant cardiac disease including:

  * Congestive heart failure - New York Heart Association \> class II
  * Active coronary artery disease
  * Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin
  * Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before registration, or myocardial infarction within 6 months before registration
* Evidence or history of bleeding diathesis or coagulopathy
* Any hemorrhage or bleeding event grade 3 within 4 weeks prior to registration
* Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months of informed consent
* Subjects with any previously untreated or concurrent cancer unrelated to angiosarcoma; NOTE: Exceptions include cervical cancer in-situ, treated basal cell carcinoma, or superficial bladder tumor; subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before registration are allowed; all treatments must have been completed at least 3 years prior to registration
* Patients with pheochromocytoma
* Patients with severe hepatic impairment (Child-Pugh class C)
* Known history of human immunodeficiency virus (HIV) infection or current chronic or active hepatitis B or C infection requiring treatment with antiviral therapy
* Ongoing infection \> grade 2
* Evidence of significant central nervous system disease including seizure disorder requiring medication, symptomatic metastatic brain or meningeal tumors
* Presence of a non-healing wound, non-healing ulcer, or bone fracture
* Renal failure requiring hemo-or peritoneal dialysis
* Dehydration \> grade 1
* Interstitial lung disease with ongoing signs and symptoms at the time of registration
* Pleural effusion or ascites that causes respiratory compromise (\>= grade 2 dyspnea)
* History of organ allograft (including corneal transplant)
* Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or excipients of the formulations given during the course of this trial
* Any malabsorption condition
* Evidence of abdominal fistula, gastrointestinal (GI) perforation or intraabdominal abscess
* Women who are pregnant or breast-feeding
* Concurrent anti-cancer therapy (chemotherapy, surgery, immunotherapy, biologic therapy, or tumor embolization) other than study treatment (regorafenib)
* Prior use of regorafenib
* Prior use of sorafenib
* Use of cytotoxic chemotherapy within 21 days of registration
* Use of targeted therapy within two half-lives of registration
* Radiation directed at target lesion within 28 days of registration
* Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before registration
* Therapeutic anticoagulation with Vitamin-K antagonists (e.g., warfarin) or with heparins and heparinoids; NOTE: Prophylactic anticoagulation as described below is allowed:

  * Low dose warfarin (1 mg orally, once daily) with prothrombin time (PT)-international normalized ratio (INR) =\< 1.5 x ULN is permitted; infrequent bleeding or elevations in PT-INR have been reported in some subjects taking warfarin while on regorafenib therapy; therefore, subjects taking concomitant warfarin should be monitored regularly for changes in PT, PT-INR or clinical bleeding episodes
  * Low dose aspirin (=\< 100 mg daily)
  * Prophylactic doses of heparin
* Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation
* Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results