Overview

Phase I-II, single-arm, non-randomized, open-label, multicenter, international clinical trial, with two stages. Stage one has two cohorts (soft tissue sarcoma and bone sarcoma) and stage two has eight cohorts (DDCS, EMC, VS, SFT, CCS, ASPS, UPS, LMS and OS). Nine sites in Spain, 3 sites in Italy and 1 site in the United Kingdom.

Stage 1 (PHASE 1 and PHASE 2)

Objective: To determine the recommended dose of the sunitinib plus nivolumab combination for phase II part. To evaluate the efficacy of the sunitinib plus nivolumab combination as measured by the progression-free survival rate (PFSR) at 6 months in patients with advanced soft tissue and bone sarcomas.

Treatment: Adult patients will receive an initial induction phase (IP) from day 1 to day 14 of sunitinib 37.5 mg/day followed by a maintenance phase (MP) of sunitinib 37.5 mg/day continuously + nivolumab 3 mg/kg intravenous every 2 weeks infused over 1 hour. If three or more DLTs occur from day 15 to 42, for an initial set of 10 patients, sunitinib dose will be lowered to 25 mg/day or treatment schedule will be changed to 2 weeks on and one week off until recovery from toxicities.

Stage 2

C1 to 6

Objective: To evaluate the efficacy of the sunitinib plus nivolumab combination as measured by PFSR at 6 months (CS/DDCS, EMC, VS, SFT, CCS cohorts) and at 12 months (ASPS cohort).

Treatment: Adult patients will receive an initial induction phase (IP) from day 1 to day 14 of sunitinib 37.5 mg/day followed by a maintenance phase (MP) of sunitinib 25mg/day continuously + nivolumab 240mg every 2 weeks. Pediatric patients will receive an initial IP from day 1 to day 14 of (<18 years) sunitinib at 25 mg/day unless the body surface area (BSA) of the patient is >1.7. If BSA is >1.7, then sunitinib 37.5 mg/day will be given followed by a MP of sunitinib 25 mg/day continuously + nivolumab 240 mg every 2 weeks regimen (if weight ≥40 kg) or sunitinib 25 mg/day continuously + nivolumab 3 mg/kg every 2 weeks regimen (if weight <40kg).

C 7

Objective: To determine the MTD of the epirubicin + ifosfamide + nivolumab combination in undifferentiated pleomorphic sarcoma and of the doxorubicin + dacarbazine + nivolumab combination in leiomyosarcoma.

Treatment:Cohort 7a dose level 0: Patients will receive epirubicin dose of 60 mg/m2/d, d1 and d2 IV 20 minutes; followed by ifosfamide 3 g/m2/d d1-3, IV 3h with MESNA protection (40% of total dose of ifosfamide in each administration at 0, 3 and 6 h from ifosfamide initiation). Once finished Ifosfamide infusion of day 3, nivolumab is administered during 30 minutes, at dose of 360 mg IV, Q3W. GCSF support is mandatory. If three or more DLTs occur nivolumab dose will be lowered to dose level -1.

Cohort 7b dose level 0: Patients will receive doxorubicin at dose of 75 mg/m2/d, d1 IV 20 minutes; followed by dacarbazine 400 mg//m2/d IV 60 minutes. Dacarbazine is administered also on day 2 of cycle. Once finished Dacarbazine infusion of day 2, nivolumab is administered for 30 minutes, at dose of 360 mg IV, Q3W. GCSF support is mandatory. If three or more DLTs occur nivolumab dose will be lowered to dose level -1 where patients will receive doxorubicin at dose of 75 mg/m2/d, d1 IV 20 minutes; followed by dacarbazine 400 mg//m2/d IV 60 minutes. Dacarbazine is administered also on day 2 of cycle. Once finished dacarbazine infusion of day 2, nivolumab is administered for 30 minutes, at dose of 240 mg IV, Q3W. GCSF support is mandatory. One-year maintenance of nivolumab is foreseen in the absence of progressive disease.

C 8

Objectives:To determine the MTD of the MAP + nivolumab combination (phase I). Proportion of patients achieving good pathological response (phase II)

Treatment dose level 0: In the IP, patients will receive CDDP 120 mg/m2 in 48h IV infusion (days 1-2) followed by doxorubicin 75 mg/m2 in 48h IV infusion (days 3-4). CDDP and doxorubicin will be given on days 1-4 and 36-39. Nivolumab administration will start on day 4 at flat dose 240 mg (after the end of doxorubicin), being the following doses administered on days 18, 39, and 53 (240 mg). HD methotrexate at 12 g/m2 in 2-h infusion will be administered on days 22, 29, 57, and 64. Surgery will be performed after finishing IP. Adjuvant chemotherapy will be administered after surgery. During the MP patients will receive nivolumab on day 210, every two weeks up to day 364. If three or more DLTs occur, then nivolumab dose level -1 will be activated.

Eligibility

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.