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