Trial of Sunitinib and/or Nivolumab Plus Chemotherapy in Advanced Soft Tissue and Bone Sarcomas

INCLUSION CRITERIA: Stage 1 1. Patients must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow-up. Informed consent must be obtained prior to start of the screening process. Procedures conducted as part of the patient's routine clinical management (e.g. blood count, imaging tests, etc.) and obtained prior to signature of informed consent may be used for screening or baseline purposes as long as these procedures are conducted as specified in the protocol. 2. Age: 18-80 years. 3. Histologic diagnosis of soft tissue sarcoma (undifferentiated pleomorphic sarcoma, synovial sarcoma, alveolar soft part sarcoma, clear cell sarcoma, angiosarcoma, epithelioid hemangioendothelioma, solitary fibrous tumor,epithelioid sarcoma and extraskeletal myxoid chondrosarcoma) or bone sarcoma (osteosarcoma/high grade bone sarcoma, Ewing's sarcoma, chondrosarcoma and dedifferentiated chondrosarcoma) confirmed by central pathology review. Mandatory paraffin embedded tumor blocks must be provided for all subjects without exception for biomarker analysis before treatment (first biopsy) and at end of month 3 or earlier (second biopsy). 4. Metastatic/advanced disease in progression in the last 6 months. 5. Measurable disease according to RECIST 1.1 criteria. 6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 7. Adequate hepatic, renal, cardiac, and hematologic function. 8. Laboratory tests as follows: * Absolute neutrophil count ≥ 1,200/mm³ * Platelet count ≥ 100,000/mm³ * Bilirubin ≤ 1.5 mg/dL * PT and INR ≤ 1.5 * AST and ALT ≤ 2.5 times upper limit of normal * Creatinine ≤ 1.5 mg/dL * Calcium ≤ 12 mg/dL * Blood glucose \< 150 mg/dL 9. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan. 10. Females of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to enrollment and agree to use birth control measures during study treatment and for 7 months after its completion. Patients must not be pregnant or nursing at study entry. Women/men of reproductive potential must have agreed to use an effective contraceptive method. INCLUSION CRITERIA 1, 5, 6, 7, 8, 9 AND 10 OF STAGE 1, ARE REPEATED IN ALL COHORTS OF STAGE 2. Stage 2 Cohort 1-6 2\. Age: 12-80 years. 3. Diagnosis of dedifferentiated chondrosarcoma, extraskeletal myxoid chondrosarcoma, vascular sarcomas (including angiosarcoma, hemangioendothelioma and intimal sarcomas), solitary fibrous tumor (excluding dedifferentiated SFT), alveolar soft part sarcoma, and clear cell sarcoma confirmed by central pathology review. 4. Mandatory paraffin embedded tumor blocks must be provided for all subjects without exception for biomarker analysis before treatment. 5. Metastatic/locally advanced unresectable disease in progression in the last 6 months according to RECIST 1.1. Patients with recent diagnosis of metastatic disease can be eligible (if they are not candidates to anthracycline-based treatment). 6\. Patients should have previously received at least anthracyclines. Patients in the cohorts of subtypes sensitive to antiangiogenic therapy (SFT, ASPS, CCS, EMC or DDCS) are eligible even if not previously treated. 7. Previous therapy with antiangiogenics is allowed. Cohort 7 2\. Age: 18-80 years. 3. Diagnosis of advanced/metastatic undifferentiated pleomorphic sarcoma (UPS) (cohort 7a) or leiomyosarcoma (LMS) (cohort 7b) confirmed by central pathology review. 4. Mandatory pre-treatment formalin-fixed paraffin embedded (FFPE) tumor tissue must be provided for all subjects without exception for central pathology review and the translational study. Archive tissue can be used for diagnosis confirmation but a recent biopsy (\<3 months) is mandatory for translational research. If it is not available or is older than 3 months, the patient must be willing to have a pre-treatment re-biopsy of primary or metastatic tumor (baseline biopsy) within 28 days prior to enrollment. 7. The patient must be naïve of any previous treatment with anthracyclines (not even in adjuvant chemotherapy). 12. Women and men of reproductive potential must have agreed to use an effective contraceptive method during study treatment and for 6 months after the last dose of study drug. Cohort 8 1. The patient or his/her legal tutors must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow-up. Informed consent must be obtained prior to start of screening process. Procedures conducted as part of the patient's routine clinical management (e.g. blood count, imaging tests, etc.) and obtained prior to signature of informed consent may be used for screening or baseline purposes as long as these procedures are conducted as specified in the protocol. 2. Age: 12-40 years. 3. Diagnosis of resectable primary metastatic high-grade osteosarcoma confirmed by central pathology review. Resection of primary tumor +/- metastatic disease has to be feasible and planned. 4. Mandatory pre-treatment formalin-fixed paraffin embedded (FFPE) tumor tissue must be provided for all subjects without exception for central pathology review and the translational study. The patient must be willing to have a pre-treatment re-biopsy of primary or metastatic tumor (baseline biopsy) within 28 days prior to enrollment if diagnosis biopsy does not have enough remaining tissue for translational purposes. 7\. The patient must be naïve of any previous treatment. 12. Women and men of reproductive potential must have agreed to use an effective contraceptive method during study treatment and for 6 months after the last dose of study drug. EXCLUSION CRITERIA: Stage 1 1. Four or more previous lines of chemotherapy for the advanced disease. 2. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody. 3. Prior immune-related adverse event (Grade 3 or higher immune-related pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer vaccine, cytokine, etc.). 4. Active, known or suspected autoimmune disease. 5. A condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. 6. Uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association \[NYHA\] III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 Grade \>= 2), known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (\>= Grade 3). 7. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. 8. Other disease or illness within the past 6 months, including any of the following: • Myocardial infarction Severe or unstable angina • Coronary or peripheral artery bypass graft • Symptomatic congestive heart failure • Cerebrovascular accident or transient ischemic attack • Pulmonary embolism 9. Evidence of a bleeding diathesis. 10. Ongoing cardiac dysrhythmias \> Grade 2. 11. Uncontrolled hypertension, defined as blood pressure \> 150/100 mm Hg despite optimal medical therapy. 12. Psychiatric illness or social situation that would preclude study compliance. 13. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication. 14. Prolonged QTc interval (i.e., QTc \> 450 msec for males or QTc \> 470 msec for females) on baseline ECG. 15. Hemorrhage ≥ Grade 3 in the past 4 weeks. 16. History of allergy to study drug components. 17. Previous anticoagulants due to thrombotic events. 18. History of another cancer with the exception of adequately treated basal cell carcinoma or cervical cancer in situ. 19. Presence of brain or central nervous system metastases. Stage 2 Cohort 1-6 1. Four or more previous lines of chemotherapy. 2. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody. 3. Prior immune-related adverse event (Grade 3 or higher immune-related pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer vaccine, cytokine, etc.). 4. Active, known or suspected autoimmune disease. 5. A condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. 6. Uncontrolled intercurrent illness (or within 12 months prior to first dose of study drug) including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association \[NYHA\] III/IV), unstable angina pectoris or coronary angioplasty, or stenting, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI-CTCAE\] version 5.0 Grade \>= 2), known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (\>= Grade 3). 7. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. 8. Other disease or illness within the past 12 months, including any of the following: * Myocardial infarction * Severe or unstable angina * Coronary or peripheral artery bypass graft * Symptomatic congestive heart failure * Cerebrovascular accident or transient ischemic attack * Pulmonary embolism 9. Evidence of a bleeding diathesis. 10. Uncontrolled hypertension, defined as blood pressure \> 150/100 mm Hg despite optimal medical therapy. 11. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication. 12. Prolonged QTc interval (i.e., QTc \> 450 msec for males or QTc \> 470 msec for females) on baseline ECG. 13. Hemorrhage ≥ Grade 3 in the past 4 weeks. 14. History of allergy to study drug components. 15. Anticoagulants due to thrombotic events, with the exception of deep venous thrombosis in limbs, with a stable dose of low-weigh heparine and in the absence of secondary hemorrages. 16. History of another cancer in the previous 5 years with the exception of adequately treated squamous or basal cell carcinoma of the skin or cervical cancer in situ. 17. Presence of brain or central nervous system metastases, unless they are controlled (completely resected or irradiated and/or asympthomatic, no need of steroids). 18. Unwilling to participate in the translational study (not providing mandatory biopsies at baseline). 19. Live vaccine 30 days or fewer prior to enrollment. Cohort 7 1. Diagnosis of any sarcoma different from undifferentiated pleomorphic sarcoma and leiomyosarcoma. 2. Previous treatment with anthracyclines or any other systemic therapy for advanced sarcoma. The exception is hormone therapy or previous systemic therapy for a previous neoplasm (see exclusion criteria number 13), if this is controlled as long as previous therapy did not include anthracyclines. Adjuvant therapy not containing anthracyclines (eg: gemcitabine-docetaxel) is allowed. 3. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody. 4. Prior immune-related adverse event (Grade 3 or higher immune-related pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer vaccine, cytokine, etc.). 5. Active, known or suspected autoimmune disease. 6. A condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. 7. Uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association \[NYHA\] III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI-CTCAE\] version 5.0 Grade \>= 2), known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (\>= Grade 3). 8. HBV and HCV serologies must be preformed prior to inclusion. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection is not allowed. 9. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication. 10. Any of the following diseases/illnesses within the previous 6 months: * Myocardial infarction * Severe or unstable angina * Coronary or peripheral artery bypass graft * Symptomatic congestive heart failure * Cerebrovascular accident or transient ischemic attack (TIA) * Pulmonary embolism * Evidence of a bleeding diathesis. * Ongoing cardiac dysrhythmias \> Grade 2. 11. Prolonged QTc interval (i.e., QTc \> 450 msec for males or QTc \> 470 msec for females) on baseline ECG. 12. History of allergy to study drug components. 13. History of another cancer with the exception of adequately treated basal cell carcinoma or in situ cervical cancer, or with a relapse-free interval longer than 3 years after treatment of the primary cancer with no substantial risk of recurrence. 14. Presence of brain or central nervous system metastases at the time of enrollment, unless they are controlled (completely resected or irradiated and/or asympthomatic, no need of steroids). 15. Patient is unwilling to provide mandatory translational tumor samples or biopsies (if required) cannot be easily traken. Cohort 8 1. Diagnosis of parosteal, periosteal osteosarcoma or any other bone sarcoma. 2. Previous systemic therapy. 3. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody. 4. Prior immune-related adverse event (Grade 3 or higher immune-related pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer vaccine, cytokine, etc.). 5. Active, known or suspected autoimmune disease. 6. A condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. 7. Uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association \[NYHA\] III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI-CTCAE\] version 5.0 Grade \>= 2), known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (\>= Grade 3). 8. HBV and HCV serologies must be performed prior to inclusion. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection is not allowed. 9. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication. 10. Any of the following diseases/illnesses within the previous 6 months: * Myocardial infarction * Severe or unstable angina * Coronary or peripheral artery bypass graft * Symptomatic congestive heart failure * Cerebrovascular accident or transient ischemic attack (TIA) * Pulmonary embolism * Evidence of a bleeding diathesis * Ongoing cardiac dysrhythmias \> Grade 2. 11. Prolonged QTc interval (i.e., QTc \> 450 msec for males or QTc \> 470 msec for females) on baseline ECG. 12. History of allergy to study drug components. 13. History of another cancer with the exception of adequately treated basal cell carcinoma or in situ cervical cancer, or with a relapse-free interval longer than 3 years after treatment of the primary cancer with no substantial risk of recurrence. 14. Presence of brain or central nervous system metastases at the time of enrollment, unless they are controlled (completely resected or irradiated and/or asympthomatic, no need of steroids). 15. Patient is unwilling to provide mandatory translational tumor samples or biopsies (if required) cannot be easily taken.