Ensayos clínicos

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.