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

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.

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