Phase II Study of Regorafenib in Metastatic Soft Tissue Sarcoma

Inclusion Criteria: * Age ≥18 years * Histological documentation of soft tissue sarcoma (including uterus)with available Formalin Fixed Paraffin Embedded (FFPE) blocks. Eligible soft tissue sarcomas are non-adipocytic soft tissue sarcomas * Prior treatment with doxorubicin or other anthracycline. Moreover, patients eligible in the Cohort E must have received pazopanib * Metastatic disease not amenable to surgical resection with curative intent * Documentation of progression within the last 6 months * Measurable disease, defined as at least 1 unidimensionally measurable lesion on a CT scan as defined by RECIST 1.1. * Performance status ≤1(ECOG) * Life expectancy ≤ 3 months * Adequate bone marrow, renal, and hepatic function: * INR/PTT ≤1.5 x ULN Patients who are therapeutically 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 will be performed until INR/PTT is stable. * Women of childbearing potential and male patients must agree to use adequate contraception for the duration of study participation and up to 3 months following completion of therapy. * Recovery to NCI-CTCAE v4.0 Grade 0 or 1 level or recovery to baseline preceding the prior treatment from any previous drug/procedure related toxicity (except alopecia, anemia, and hypothyroidism). * In the assessment of the investigator, patient is able to comply with study requirements * Signed, IRB-approved written informed consent Exclusion Criteria: * More than 3 lines of systemic treatment for metastatic sarcoma * Histological subtypes listed in Appendix C (especially GIST, osseous sarcoma, embryonal or alveolar rhabdomyosarcoma). Patients with liposarcoma are not eligible in the cohort E * Primary bone sarcoma * Prior treatment with regorafenib * Known history of or concomitant malignancy likely to affect life expectancy in the judgment of the investigator * Pregnant or breastfeeding patients. Women of childbearing potential must have a pregnancy test performed before start of treatment * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of treatment * Active cardiac disease including any of the following: Congestive heart failure (NYHA) ≥Class 2, Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months), Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) * Uncontrolled hypertension (SBP \>150 mmHg or diastolic pressure \>90 mmHg despite optimal medical management) * Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism (within the last 6 months) * Ongoing infection \>Grade 2 according to NCI-CTCAE v4.0 * Known history of human immunodeficiency virus (HIV) infection * Known history of chronic hepatitis B or C * Patients with seizure disorder requiring medication * History of organ allograft * Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event \> Grade 3 within 4 weeks of start of treatment * Non-healing wound, ulcer, or bone fracture * Renal failure requiring hemo- or peritoneal dialysis * Dehydration according to NCI-CTC v 4.0 Grade \>1 * Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results * Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation, including lactose * Interstitial lung disease with ongoing signs and symptoms at the time of informed consent * Inability to swallow, malabsorption condition * Pleural effusion or ascites that causes respiratory compromise (Grade 2 dyspnea)