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

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.
• •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.