SUNITINIB for Advanced soft tissue sarcoma | Advanced bone sarcoma

Inclusion criteria

• {"criterion_text":"- Stage 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.\n- Stage 2. Cohorts 1-6. 8. Measurable disease according to RECIST 1.1 criteria.\n- Stage 2. Cohorts 1-6. 9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.\n- Stage 1. 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.\n- Stage 2. Cohorts 1-6. 10. Adequate hepatic, renal, cardiac, and hematologic function.\n- Stage 2. Cohorts 1-6. 11. 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 in the absence of anticoagulant therapy • AST and ALT ≤ 2.5 times upper limit of normal • Creatinine ≤ 1.5 mg/dL (or Cr clearance ≥ 60 ml/min) • Calcium ≤ 12 mg/dL\n- Stage 2. Cohorts 1-6. 12. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan.\n- Stage 2. Cohorts 1-6. 13. Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to enrollment and agree to use birth control measures during study treatment and for 6 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.\n- Stage 2. Cohort 7. 1. The patient or his/her legal tutors must provide written informed consent prior to performance 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. study-specific procedures and must be willing to comply with treatment and follow-up. Informed consent must be obtained prior to start of\n- Stage 2. Cohort 7. 2. Age: 18-80 years.\n- Stage 2. Cohort 7. 3. Diagnosis of advanced/metastatic undifferentiated pleomorphic sarcoma (UPS) (cohort 7a) or leiomyosarcoma (LMS) (cohort 7b) confirmed by central pathology review.\n- Stage 1. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan.\n- Stage 2. Cohort 7. 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.\n- stage 2. Cohort 7. 5. Measurable disease according to RECIST v1.1 criteria.\n- Stage 2. Cohort 7. 6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.\n- Stage 1. Age: 18-80 years.\n- Stage 2. Cohort 7. 7. The patient must be naïve of any previous treatment with anthracyclines (not even in adjuvant chemotherapy).\n- stage 2. Cohort 7. 8. Adequate organ, hepatic, renal, cardiac, and hematologic function.\n- Stage 2. Cohort 7. 9. Laboratory tests as follows: • Absolute neutrophil count ≥ 1,500/mm³ • Platelet count ≥ 100,000/mm³ • Hg > 9 g/dL • 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 or estimated creatinine clearance ≥ 60 mL/min • Blood glucose < 150 mg/dL\n- Stage 2. Cohort 7. 10. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan assessed within 28 days before enrollment.\n- Stage 2. Cohort 7. 11. Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to enrollment. Patients must not be pregnant or nursing at study entry.\n- Stage 2. Cohort 7. 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.\n- Stage 2. Cohorts 1-6. 1. Patients (or 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 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.\n- Stage 1. 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).\n- Stage 1. Metastatic/advanced disease in progression in the last 6 months.\n- Stage 1. Measurable disease according to RECIST 1.1 criteria.\n- Stage 1. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.\n- Stage 1. Adequate hepatic, renal, cardiac, and hematologic function.\n- Stage 1. 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\n- Stage 2. 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.\n- Stage 2. Cohort 8. 2. Age: 12-40 years.\n- Satge 2. Cohort 8. 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.\n- Stage 2. Cohort 8. 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.\n- Stage 2. Cohort 8. 5. Measurable disease according to RECIST v1.1 criteria.\n- Stage 2. Cohort 8. 6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.\n- Stage 2. Cohort 8. 7. The patient must be naïve of any previous treatment.\n- Stage 2. Cohort 8. 8. Adequate organ, hepatic, renal, cardiac, and hematologic function.\n- Stage 2. Cohort 8. 9. Laboratory tests as follows: • Absolute neutrophil count ≥ 1,500/mm³ • Platelet count ≥ 100,000/mm³ • Hg > 9 g/dL • 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 or estimated creatinine clearance ≥ 60 mL/min • Blood glucose < 150 mg/dL\n- Stage 2. Cohort 8. 10. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan assessed within 28 days before enrollment.\n- Stage 2. Cohort 8. 11. Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to enrollment. Patients must not be pregnant or nursing at study entry.\n- Stage 2. Cohort 8. 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.\n- Stage 2. Cohorts 1-6. 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.\n- Stage 2. Cohorts 1-6. 4. Mandatory paraffin embedded tumor blocks must be provided for all subjects without exception for biomarker analysis before treatment.\n- Stage 2. Cohorts 1-6. 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).\n- Stage 2. Cohorts 1-6. 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.\n- Stage 2. Cohorts 1-6. 7. Previous therapy with antiangiogenics is allowed."}

Exclusion criteria

• {"criterion_text":"- Stage 1. 1. Four or more previous lines of chemotherapy for the advanced disease.\n- Satge 1. 2. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.\n- Stage 1. 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.).\n- Stage 1. 4. Active, known or suspected autoimmune disease.\n- Stage 1. 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.\n- Stage 1. 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).\n- Stage 1. 7. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.\n- Stage 1. 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\n- Stage 1. 9. Evidence of a bleeding diathesis.\n- Stage 1. 10. Ongoing cardiac dysrhythmias > Grade 2.\n- Stage 1. 11. Uncontrolled hypertension, defined as blood pressure > 150/100 mm Hg despite optimal medical therapy.\n- Stage 1. 12. Psychiatric illness or social situation that would preclude study compliance.\n- Stage 1. 13. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication.\n- Stage 1. 14. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.\n- Stage 1. 15. Hemorrhage ≥ Grade 3 in the past 4 weeks.\n- Stage 1. 16. History of allergy to study drug components.\n- Stage 1. 17. Previous anticoagulants due to thrombotic events.\n- Stage 1. 18. History of another cancer with the exception of adequately treated basal cell carcinoma or cervical cancer in situ.\n- Stage 1. 19. Presence of brain or central nervous system metastases.\n- Stage 2. Cohorts 1-6. 1. Four or more previous lines of chemotherapy.\n- Stage 2. Cohorts 1-6. 2. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.\n- Stage 2. Cohorts 1-6. 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.).\n- Stage 2. Cohorts 1-6. 4. Active, known or suspected autoimmune disease.\n- Stage 2. Cohorts 1-6. 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.\n- Stage 2. Cohorts 1-6. 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).\n- Stage 2. Cohorts 1-6. 7. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.\n- Stage 2. Cohorts 1-6. 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\n- Stage 2. Cohorts 1-6. 9. Evidence of a bleeding diathesis.\n- Stage 2. Cohorts 1-6. 10. Uncontrolled hypertension, defined as blood pressure > 150/100 mm Hg despite optimal medical therapy.\n- Stage 2. Cohorts 1-6. 11. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication.\n- Stage 2. Cohorts 1-6. 12. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.\n- Stage 2. Cohorts 1-6. 13. Hemorrhage ≥ Grade 3 in the past 4 weeks.\n- Stage 2. Cohorts 1-6. 14. History of allergy to study drug components.\n- Stage 2. Cohorts 1-6. 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.\n- Stage 2. Cohorts 1-6. 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.\n- Stage 2. Cohorts 1-6. 17. Presence of brain or central nervous system metastases, unless they are controlled (completely resected or irradiated and/or asympthomatic, no need of steroids).\n- Stage 2. Cohorts 1-6. 18. Unwilling to participate in the translational study (not providing mandatory biopsies at baseline).\n- Stage 2. Cohorts 1-6. 19. Live vaccine 30 days or fewer prior to enrollment.\n- Stage 2. Cohort 7. 1. Diagnosis of any sarcoma different from undifferentiated pleomorphic sarcoma and leiomyosarcoma.\n- Stage 2. Cohort 7. 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.\n- Stage 2. Cohort 7. 3. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.\n- Stage 2. Cohort 7. 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.).\n- Stage 2. Cohort 7. 5. Active, known or suspected autoimmune disease.\n- Stage 2. Cohort 7. 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.\n- Stage 2. Cohort 7. 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).\n- Stage 2. Cohort 7. 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.\n- Stage 2. Cohort 7. 9. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication.\n- Stage 2. Cohort 7. 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.\n- Stage 2. Cohort 7. 11. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.\n- Stage 2. Cohort 7. 12. History of allergy to study drug components.\n- Stage 2. Cohort 7. 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.\n- Stage 2. Cohort 7. 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).\n- Stage 2. Cohort 7. 15. Patient is unwilling to provide mandatory translational tumor samples or biopsies (if required) cannot be easily traken.\n- Stage 2. Cohort 8. 1. Diagnosis of parosteal, periosteal osteosarcoma or any other bone sarcoma.\n- Stage 2. Cohort 8. 2. Previous systemic therapy.\n- Stage 2. Cohort 8. 3. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.\n- Stage 2. Cohort 8. 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.).\n- Stage 2. Cohort 8. 5. Active, known or suspected autoimmune disease.\n- Stage 2 . Cohort 8. 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.\n- Stage 1. 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).\n- Stage 2. Cohort 8. 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).\n- Stage 2. Cohort 8. 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.\n- Stage 2. Cohort 8. 9. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication.\n- Stage 2. Cohort 8. 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.\n- Stage 2. Cohort 8. 11. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.\n- Stage 2. Cohort 8. 12. History of allergy to study drug components.\n- Stage 2. Cohort 8. 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.\n- Stage 2. Cohort 8. 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).\n- Stage 2. Cohort 8. 15. Patient is unwilling to provide mandatory translational tumor samples or biopsies (if required) cannot be easily taken.\n- Stage 1. 2. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.\n- Stage 1. 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.).\n- Stage 1. 4. Active, known or suspected autoimmune disease.\n- Stage 1. 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."}

Primary endpoints

• {"endpoint_text":"- Stage 1. Phase 1. The recommended dose of the sunitinib and nivolumab combination for phase II part will be determined by assessing adverse events according to CTCAE 4.0 and they will be used as a rule for escalating or diminishing dose levels according to the dose-limiting toxicities detailed in the protocol.","definition_or_measurement_approach":"Determined by assessing adverse events according to CTCAE 4.0 and used as rules for escalating or diminishing dose levels according to dose-limiting toxicities detailed in the protocol."}
• {"endpoint_text":"- Stage 1. Phase 2. Progression-free survival rate (PFSR): Efficacy measured by the PFSR at 6 months according to RECIST 1.1. PFSR at 6 months is defined as the percentage of patients who did not experience progression or death due to any cause since enrollment until month 6 after enrollment.","definition_or_measurement_approach":"PFSR at 6 months defined as percentage of patients without progression or death from enrollment until month 6; measured according to RECIST 1.1."}
• {"endpoint_text":"- Stage 2. Cohorts 1-6. Phase 2. 1. CS/DDCS, EMC, VS, SFT, and CCS cohorts: 6-month progression-free survival rate (PFSR): Efficacy measured by the PFSR at 6 months according to RECIST 1.1. PFSR at 6 months is defined as the percentage of patients who did not experience progression or death due to any cause since enrollment until month 6 after enrollment.","definition_or_measurement_approach":"PFSR at 6 months per RECIST 1.1; defined as percentage of patients without progression or death from enrollment until month 6."}
• {"endpoint_text":"- Stage 2. Cohorts 1-6. Phase 2. 2. ASPS cohort: 12-month progression-free survival rate (PFSR): Efficacy measured by the PFSR at 12 months according to RECIST 1.1. PFSR at 12 months is defined as the percentage of patients who did not experience progression or death due to any cause since the date of enrollment until month 12 after enrollment.","definition_or_measurement_approach":"PFSR at 12 months per RECIST 1.1; defined as percentage of patients without progression or death from enrollment until month 12."}
• {"endpoint_text":"- Stage 2. Cohort 7. Phase 1b. The maximum tolerated dose (MTD) of the epirubicin + ifosfamide + nivolumab combination will be determined by assessing adverse events according to CTCAE 5.0 and they will be used for adjusting dose levels according to the dose-limiting toxicities detailed in the protocol.","definition_or_measurement_approach":"MTD determined by assessing adverse events per CTCAE 5.0 and adjusting dose levels according to dose-limiting toxicities per protocol."}
• {"endpoint_text":"- Stage 2. Cohort 8. Phase 1. The maximum tolerated dose (MTD) of the MAP + nivolumab combination will be determined by assessing adverse events according to CTCAE 5.0 and they will be used for adjusting dose levels according to the dose-limiting toxicities detailed in the protocol.","definition_or_measurement_approach":"MTD determined by assessing adverse events per CTCAE 5.0 and adjusting dose levels according to protocol-specified DLTs."}
• {"endpoint_text":"- Stage 2. Cohort 8. Phase 2. Proportion of patients achieving good pathological response (≥90% necrosis) in the surgical specimen after neoadjuvant chemotherapy + nivolumab.","definition_or_measurement_approach":"Good pathological response defined as ≥90% necrosis in surgical specimen after neoadjuvant chemotherapy + nivolumab."}

Secondary endpoints

• {"endpoint_text":"- Stage 1. Phase 1. 1. Safety profile of the experimental treatment, through assessment of adverse event type, incidence, severity, time of appearance, related causes, as well as physical explorations and laboratory tests. Toxicity will be graded and tabulated by using CTCAE 4.0.","definition_or_measurement_approach":"Safety assessed via adverse event type, incidence, severity, timing, causality, physical examinations and labs; graded per CTCAE 4.0."}
• {"endpoint_text":"- Stage 1. Phase 1. 2. Progression-free survival rate (PFSR): Efficacy measured by the PFSR at 6 months according to RECIST 1.1. PFSR at 6 months is defined as the percentage of patients who did not experience progression or death due to any cause since enrollment until month 6 after enrollment.","definition_or_measurement_approach":"PFSR at 6 months per RECIST 1.1."}
• {"endpoint_text":"- Stage 1. Phase 1. 3. Overall survival (OS): OS is defined as the time between the date of enrollment and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive.","definition_or_measurement_approach":"OS measured from enrollment to death; censored at last known alive date."}
• {"endpoint_text":"- Stage 1. Phase 1. 4. Overall response rate (ORR): ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable subjects (according to RECIST 1.1 criteria).","definition_or_measurement_approach":"ORR per RECIST 1.1: proportion with BOR of CR or PR among evaluable subjects."}
• {"endpoint_text":"- Stage 1. Phase 1. 5. Contribution to translational studies will be performed by providing biological samples.","definition_or_measurement_approach":"Translational contributions via collection of biological samples."}
• {"endpoint_text":"- Stage 1. Phase 2. 1. Overall survival (OS): OS is defined as the time between the date of enrollment and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive.","definition_or_measurement_approach":"OS measured from enrollment to death; censored at last known alive date."}
• {"endpoint_text":"- Stage 1. Phase 2. 2. Overall response rate (ORR): ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable subjects (according to RECIST 1.1 criteria).","definition_or_measurement_approach":"ORR per RECIST 1.1."}
• {"endpoint_text":"- Stage 1. Phase 2. 3. Efficacy measured through tumor response according to Choi criteria. The evaluation criteria will be based on the identification of target lesions in baseline and their follow up until tumor progression.","definition_or_measurement_approach":"Tumor response per Choi criteria based on target lesion identification and follow-up until progression."}
• {"endpoint_text":"- Stage 1. Phase 2. 4. Safety profile of the experimental treatment, through assessment of adverse event type, incidence, severity, time of appearance, related causes, as well as physical explorations and laboratory tests. Toxicity will be graded and tabulated by using CTCAE 4.0.","definition_or_measurement_approach":"Safety assessed and graded per CTCAE 4.0."}
• {"endpoint_text":"- Stage 1. Phase 2. 5. Clinical outcomes of post protocol treatments assessed by observation of such treatments in follow-up stage.","definition_or_measurement_approach":"Clinical outcomes of post-protocol treatments observed during follow-up."}
• {"endpoint_text":"- Stage 1. Phase 2. 6. Contribution to translational studies will be performed by providing biological samples.","definition_or_measurement_approach":"Translational contributions via biological sample provision."}
• {"endpoint_text":"- Stage 2. Cohorts 1-6. Fase 2. 1. Overall survival (OS): OS is defined as the time between the date of enrollment and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive.","definition_or_measurement_approach":"OS measured from enrollment to death; censored at last known alive date."}
• {"endpoint_text":"- Stage 2. Cohorts 1-6. Fase 2. 2. Overall response rate (ORR): ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable subjects (according to RECIST 1.1 criteria).","definition_or_measurement_approach":"ORR per RECIST 1.1."}
• {"endpoint_text":"- Stage 2. Cohorts 1-6. Fase 2. 3. Safety profile of the experimental treatment, through assessment of adverse event type, incidence, severity, time of appearance, related causes, as well as physical explorations and laboratory tests. Toxicity will be graded and tabulated by using CTCAE 5.0.","definition_or_measurement_approach":"Safety assessed and graded per CTCAE 5.0."}
• {"endpoint_text":"- Stage 2. Cohorts 1-6. Fase 2. 4. Clinical outcomes of post protocol treatments assessed by observation of such treatments in follow-up stage.","definition_or_measurement_approach":"Clinical outcomes of post-protocol treatments observed during follow-up."}
• {"endpoint_text":"- Stage 2. Cohorts 1-6. Fase 2. 5. Correlation between efficacy and potential predictive biomarkers assessed by finding relationships between clinical efficacy results and translational data.","definition_or_measurement_approach":"Correlation analyses between clinical efficacy outcomes and translational biomarker data."}
• {"endpoint_text":"- Stage 2. Cohorts 1-6. Fase 2. 6. Prognostic and response correlation with neutrophils/platelets; lymphocytes/platelets; and red blood cell distribution width (RDW), by assessing hematology tests at baseline, after 2 weeks (before nivolumab), after 1 month, at progression, and at response.","definition_or_measurement_approach":"Hematology measures (neutrophils/platelets, lymphocytes/platelets, RDW) assessed at specified timepoints for prognostic/response correlation."}
• {"endpoint_text":"- Stage 2. Cohorts 1-6. Fase 2. 7. 6-month progression-free survival rate (PFSR): Efficacy measured by the PFSR at 6 months according to RECIST 1.1. PFSR at 6 months is defined as the percentage of patients who did not experience progression or death due to any cause since the date of enrollment until month 6 after enrollment.","definition_or_measurement_approach":"PFSR at 6 months per RECIST 1.1."}
• {"endpoint_text":"- Stage 2. Cohort 7. Phase 1b. 1. Safety profile of the experimental treatment, through assessment of adverse event type, incidence, severity, time of appearance, related causes, as well as physical explorations and laboratory tests. Toxicity will be graded and tabulated by using CTCAE 5.0.","definition_or_measurement_approach":"Safety assessed and graded per CTCAE 5.0."}
• {"endpoint_text":"- Stage 2. Cohort 7. Phase 1b. 2. Overall response rate (ORR): ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable subjects (according to RECIST 1.1 criteria and central review).","definition_or_measurement_approach":"ORR per RECIST 1.1 with central review."}
• {"endpoint_text":"- Stage 2. Cohort 7. Phase 1b. 3. Median progression-free survival (mPFS): PFS is defined as the time between the date of enrollment and the date of progression or death due to any cause.","definition_or_measurement_approach":"mPFS measured from enrollment to progression or death."}
• {"endpoint_text":"- Stage 2. Cohort 7. Phase 1b. 4. Median overall survival (mOS): OS is defined as the time between the date of enrollment and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive.","definition_or_measurement_approach":"mOS measured from enrollment to death; censored at last known alive date."}
• {"endpoint_text":"- Stage 2. Cohort 8. Phase 1. 1. Safety profile of the experimental treatment, through assessment of adverse event type, incidence, severity, time of appearance, related causes, as well as physical explorations and laboratory tests. Toxicity will be graded and tabulated by using CTCAE 5.0.","definition_or_measurement_approach":"Safety assessed and graded per CTCAE 5.0."}
• {"endpoint_text":"- Stage 2. Cohort 8. Phase 1. 2. Pathological response measured by percentage of necrosis in surgical specimen.","definition_or_measurement_approach":"Pathological response measured as percentage necrosis in surgical specimen."}
• {"endpoint_text":"- Stage 2. Cohort 8. Phase 1. 3. Overall response rate (ORR): ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable subjects (according to RECIST 1.1 criteria and central review).","definition_or_measurement_approach":"ORR per RECIST 1.1 with central review."}
• {"endpoint_text":"- Stage 2. Cohort 8. Phase 2. 1. Safety profile of the experimental treatment, through assessment of adverse event type, incidence, severity, time of appearance, related causes, as well as physical explorations and laboratory tests. Toxicity will be graded and tabulated by using CTCAE 5.0.","definition_or_measurement_approach":"Safety assessed and graded per CTCAE 5.0."}
• {"endpoint_text":"- Stage 2. Cohort 8. Phase 2. 2. Overall response rate (ORR): ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable subjects (according to RECIST 1.1 criteria and central review).","definition_or_measurement_approach":"ORR per RECIST 1.1 with central review."}
• {"endpoint_text":"- Stage 2. Cohort 8. Phase 2. 3. 12-month progression-free survival rate (PFSR): Efficacy measured by the PFSR at 12 months after surgery according to RECIST 1.1. PFSR at 12 months is defined as the percentage of patients who did not experience progression or death due to any cause since the date of surgery until month 12 after surgery.","definition_or_measurement_approach":"PFSR at 12 months after surgery per RECIST 1.1."}
• {"endpoint_text":"- Stage 2. Cohort 8. Phase 2. 4. Median progression-free survival (mPFS): PFS is defined as the time between the date of enrollment and the date of progression or death due to any cause.","definition_or_measurement_approach":"mPFS measured from enrollment to progression or death."}
• {"endpoint_text":"- Stage 2. Cohort 8. Phase 2. 5. Median overall survival (mOS): OS is defined as the time between the date of enrollment and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive.","definition_or_measurement_approach":"mOS measured from enrollment to death; censored at last known alive date."}

Italy

Earliest CTIS Part Ii Submission Date

21-11-2024

Latest Decision Or Authorization Date

28-01-2025

Processing Time Days

68

Number Of Sites

3

Number Of Participants

40

Spain

Earliest CTIS Part Ii Submission Date

21-11-2024

Latest Decision Or Authorization Date

13-01-2025

Processing Time Days

53

Number Of Sites

23

Number Of Participants

145

Primary sponsor

Full Name

Asoc Grupo Espanol De Investigacion En Sarcomas

Organisation Type

Patient organisation/association

Country Of Registered Address

Spain