1.- Conventional high-grade chondrosarcoma (CS) (grade 2 or 3) and dedifferentiated chondrosarcoma (DDCS) 2.- Extraskeletal myxoid chondrosarcoma (EMC) 3.- Vascular sarcomas (VS) (including angiosarcoma, hemangioendothelioma and intimal sarcomas) 4.- Solitary fibrous tumor (SFT) (excluding dedifferentiated SFT) 5.- Clear cell sarcoma (CCS) 6.- Alveolar soft-part sarcoma (ASPS) MedDRA version: 21.1 Level: PT Classification code 10068595 Term: Sarcoma metastatic System Organ Class: 10029104
Conditions
Interventions
Trade Name: Opdivo
Product Name: Nivolumab
Product Code: L01XC17
Pharmaceutical Form: Concentrate for solution for injection
INN or Proposed INN: NIVOLUMAB
CAS Number: 946414-94-4
Current Sponsor code
Sponsors
GRUPO ESPAñOL DE INVESTIGACIóN EN SARCOMAS
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Stage 1 1. Patients must provide written informed consent 2. 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 sarcomas and extraskeletal myxoid chondrosarcomas) or bone sarcoma (osteosarcoma/high grade bone sarcoma, Ewing’s sarcoma, chondrosarcoma and dedifferentiated chondrosarcoma) confirmed by central pathology review. 4. Metastatic/advanced disease in progression in the last 6 months. 5. Measurable disease according to RECIST 1.1 7. ECOG of 0-1. 8. Adequate hepatic, renal, cardiac, and hematologic function. 9. LVEF 11. 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 measuresPatients must not be pregnant or nursing at study entry. Women/men of reproductive potential must have agreed to use an effective contraceptive method. Stage 2 (Cohorts 1-6) 1. Patients (or legal tutors) must provide written informed consent 2. 12-80 years. 3. Diagnosis of conventional high-grade (grades 2 or 3) and dedifferentiated chondrosarcoma, extraskeletal myxoid chondrosarcoma, vascular sarcomas (including angiosarcoma, hemangioendothelioma and intimal sarcomas), 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 (first biopsy) and at end of month 3 or earlier (second biopsy). 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 conventional CS/DDCS) are eligible even if not previously treated. 7. Previous therapy with antiangiogenics is allowed. 8. Measurable disease according to RECIST 1.1 criteria. 9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 10. Adequate hepatic, renal, cardiac, and hematologic function. 12. Left ventricular ejection fraction = 50% by echocardiogram or MUGA scan. 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 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 55 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 20
Exclusion criteria
Exclusion criteria: Stage 1 1. Four or more previous lines of chemotherapy for the advanced disease. 2. Previous anti-PD-1, anti-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 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 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 TIA • Pulmonary embolism 9. Evidence of a bleeding diathesis. 10. Ongoing cardiac dysrhythmias > G2. 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 = G 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 (Cohorts 1-6) 1. 4 or more previous lines of chemotherapy. 2. Previous antiPD-1, anti-PD-L1 anti PD-L2 or anti CTLA-4 antibody. 3. Prior immune-related adverse event (G3 or higher immune-related pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy 4. Active, known or suspected autoimmune disease. 5. A condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of study drug administration. 6. Uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (NYHA III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration, unstable cardiac arrhythmia, known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (>= G 3). 7. Positive test for HBV sA) or (HCV antibody indicating acute or chronic infection. 8. Other disease or illness within the past 6mo, including any of the following: • MIA • Sever
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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 Stage 1 PHASE 2 •Progression-free survival rate: Efficacy measured by the PFSR at 6 months according to RECIST 1.1. PFSR at 6 months Stage 2 (Cohorts 1-6) PHASE 2 •CS/DDCS, EMC, VS, SFT, and CCS cohorts: 6-month progression-free survival rate Efficacy measured by the PFSR at 6 months according to RECIST 1. •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;Secondary Objective: Stage 1PHASE 1 • Safety profile of the experimental treatment using CTCAE 4.0. •PFSR: •OS •ORR •Contribution to translational studies Stage 1PHASE 2 •OS •ORR •Efficacy according to Choi criteria. •Safety profile of the experimental treatment, through assessment of adverse event type using CTCAE 4.0. •Clinical outcomes of post protocol treatments assessed by observation of such treatments in fup stage. • Contribution to translational studies will be performed by providing biological Stage 2 (Cohorts 1-6):PHASE 2 • OS •ORR •Safety profile of the experimental treatment using CTCAE 5.0. •Clinical outcomes of post protocol treatments assessed by observation in fup stage. • Correlation between efficacy and potential predictive biomarkers assessed by finding relationships between clinical efficacy results and translational data • Prognostic and response correlation witth some biomarkers after 1 month, at progression, and at response. •6-monts PFSR;Primary end point(s): 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 t each cycle Stage 1 P PHASE 2 • | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Stage 1 PHASE 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. • Progression-free survival rate (PFSR): • Overall survival (OS) • Overall Response Rate (ORR) Stage 1 PHASE 2 • Overall survival (OS) • Overall Response Rate (ORR): • Efficacy according to Choi criteria. • Safety profile according CTCAE 4.0. • Clinical outcomes of post protocol treatments assessed by observation of such treatments in follow-up stage. • Contribution to translational studies will be performed by providing biological samples. Stage 2 (Cohorts 1-6): PHASE 2 • Overall survival (OS) • Overall Response Rate (ORR): • Safety profile of the experimental treatment using CTCAE 5.0. • Clinical outcomes of post protocol treatments assessed by observation of such treatments in follow-up stage. • Correlation between efficacy and potential predictive biomarkers assessed by finding relationships between clinical efficacy results and translational data • 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. • 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;Timepoint(s) of evaluation of this end point: Stage 1 PHASE 1 - Safety profile: at each cycle - PFSR at 6Mo - OS : at tiime of death - ORR every 3 months - Efficacy according to Choi criteria.: every 3 months - Contribution to translational studies at Mo3, at the | — |
Countries
Italy, Spain, United Kingdom
Contacts
Public ContactISG
Italian Sarcoma Group
Outcome results
None listed