Ph II Nintedanib vs. Ifosfamide in Soft Tissue Sarcoma

Inclusion Criteria/Exclusion Criteria: * Histologically proven advanced, inoperable and/or metastatic malignant STS of intermediate or high grade, excluding the: * Well-differentiated liposarcoma/atypical lipoma * Embryonal rhabdomyosarcoma * Chondrosarcoma (extraskeletal myxoid chondrosarcoma is eligible) * Osteosarcoma (extraskeletal osteosarcoma is eligible) * Ewing family of tumors/primitive neuroectodermal tumor * Gastro-intestinal stromal tumor * Dermatofibrosarcoma protuberans * For STS where no established grading system exists, or sarcoma subtypes which are very indolent or have an unpredictable clinical behavior, patient entry requires prospective approval in writing, on a case-by-case basis by the Study Coordinator of this trial and EORTC Headquarters (HQ). * Representative formalin fixed, paraffin embedded tumor blocks or unstained tissue slides, either from the primary tumor or a metastatic lesion, must be available for histological central review. Histological central review is not required before treatment start but it is mandatory to send unstained tumor slides (blocks optional) at time of study entry. Local histopathological diagnosis will be accepted for entry into this trial. * Prior to study enrolment, all patients need to have confirmed RECIST 1.1 disease progression based on local investigator's assessment. * Presence of measurable disease according to RECIST 1.1. * Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are considered non-measurable unless there has been demonstrated progression (20 % increase) in the assessed lesion since the local treatment. * No radiographic evidence of cavitary lesions (either primary tumor or metastatic lesions). * No centrally located tumors with radiographic evidence of local invasion of major blood vessels. * No history of central nervous system metastasis or leptomeningeal tumor spread. * No active brain metastases (e.g. stable for \<4 weeks, no adequate previous treatment with radiotherapy, symptomatic, requiring treatment with anti-convulsants; dexamethasone therapy will be allowed if administered as stable dose for at least one month before randomization). * One (and no less or more than one) line of previous systemic chemotherapy for advanced, inoperable and/or metastatic malignant STS. * Prior neoadjuvant, adjuvant and or first-line maintenance systemic chemotherapy for locally advanced or metastatic STS is allowed and does count as zero lines of treatment, provided that the disease did not progress during neoadjuvant and/or adjuvant therapy or within 12 weeks after completion of the perioperative treatment. In case the disease progressed during neoadjuvant, adjuvant and or first-line maintenance systemic chemotherapy or within 12 weeks after its completion, the treatment is counted as one line and the patient can theoretically participate in the trial, provided all other selection criteria are met. * No prior exposure to an oxazaphosphorine agent, including but not limited to ifosfamide, cyclophosphamide, trofosfamide or evofosfamide (TH-302). * No prior exposure to oral or intravenous angiogenesis inhibitors, including but not limited to tyrosine kinase inhibitors such as pazopanib, sunitinib, sorafenib, axitinib or similar or monoclonal antibodies targeting angiogenesis. * No other anti-cancer therapy (systemic therapy, radiotherapy (except for brain and extremities), surgery, limb perfusion, immunotherapy) within 28 days prior to randomization. * No treatment with another investigational agent within 28 days prior to randomization. * No treatment with another investigational agent concomitantly with the trial. * No known hypersensitivity to or known specific contraindications for the use of nintedanib or ifosfamide. * No known hypersensitivity to peanut or soy bean. * Age 18 years or older. * WHO performance status (PS) 0-2. * Life expectancy of at least 3 months. * Adequate bone marrow, liver and renal function and coagulation parameters: * neutrophils ≥ 1.5 x 109/L; * hemoglobin ≥ 9 g/dL (or ≥ 5.6 mmol/L). Blood transfusions or the administration of hematopoietic growth factors are allowed to achieve these baseline values; * platelets ≥ 100 x 109/L. Platelet transfusions or the administration of hematopoietic growth factors are allowed to achieve these baseline values; * Total bilirubin ≤ ULN; * Patients with Gilbert syndrome and/or bilirubin \< 2xULN and normal AST/ALT are eligible; * SGPT/ALT and SGOT/AST ≤ 2.5 x ULN for patients with liver metastasis; * SGPT/ALT and SGOT/ AST ≤ 1.5x ULN for patients without liver metastasis; * Serum creatinine or creatinine clearance/eGFR within normal limits to baseline, assessed as per local standard method; * No proteinuria CTCAE grade 2 or greater; * International normalized ratio (INR) ≤ 2; * Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 50% of institutional ULN. * No Child Pugh B or C hepatic impairment. * Normal cardiac function (left ventricular ejection fraction (LVEF) assessed by multi-gated acquisition scan or cardiac ultrasound within normal range of the institution), 12 lead electrocardiogram (ECG) without clinically relevant abnormalities. No Class III or IV congestive heart failure, angina pectoris, myocardial infarction within 1 year before registration/randomization, clinically significant cardiac arrhythmia or pericardial effusion. * No uncontrolled arterial hypertension defined at baseline as blood pressure ≥ 150/100 mmHg despite adequate medical therapy. * No use of therapeutic anticoagulation (except low-dose heparin and/or heparin flush as needed for maintenance of an indwelling intravenous devise) or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid \< 325 mg per day). * No known inherited predisposition for bleeding or thromboembolism. * No history of clinically significant hemorrhagic or thromboembolic event in the past 6 months. * Absence of active or uncontrolled infections in particular if requiring systemic antibiotics or antimicrobial therapy. * No previous encephalopathy of any cause or other significant neurological condition. * No acute or chronic, clinically relevant inflammation of urinary bladder. * Absence of serious illnesses or medical conditions, including a history of chronic alcohol abuse, active and chronic hepatitis B or C, chronic infection with HIV or clinically relevant liver cirrhosis. * Absence of active gastrointestinal disorders or abnormalities that interfere with absorption of the study drug. * No major injuries and/or surgery within the past 28 days prior to randomization with incomplete wound healing and/or planned surgery during the on-treatment study period. * No persistence of clinically relevant therapy-related toxicity from previous chemotherapy and/or radiotherapy. Grade 1 or 2 adverse events (AEs) are acceptable. * No history, within the past five years, of malignancies other than STS (except: basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, resected prostate cancer staged pT1-2 with Gleason Score ≤ 6 and postoperative PSA \< 0.5 ng/ml). Patients with a history of other malignancies who are disease-free from that condition for more than 5 years are eligible. * Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration/randomization in the trial. * No active alcohol or drug abuse. * Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 72 hours prior to randomization. * Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 3 months (nindetanib) and 6 months (ifosfamide) after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. Since the effect of nintedanib on the metabolism and efficacy of contraceptives has not been investigated, barrier methods should be applied as a second form of contraception, to avoid pregnancy. * Female subjects who are breast feeding should discontinue nursing prior to randomization and until 6 months after the last study treatment. * Sexually active male participants must use a barrier method of contraception (e.g., condom) during the study treatment period and for at least 3 months after the last study treatment. * Before patient registration/randomization, written informed consent must be obtained according to international conference on harmonisation/Good clinical practice (ICH/GCP) and national/local regulations. * Patients can only be randomized in this trial once. Important note: All eligibility criteria must be adhered to, in case of potential deviation a discussion with EORTC Headquarters and study coordinator is mandatory.