Efficacy of the Combination of Nivolumab and Ipilimumab as a Treatment in Patients With Sarcoma of Rare Subtype

Inclusion Criteria: I1. Age ≥ 18 years at the day of consenting to the study; I2. Only histologically confirmed sarcoma of rare subtype, defined as one of the followingsubtypes:

• Angiosarcoma (AS)
• Alveolar Soft Part Sarcoma (ASPS)
• Clear Cell Sarcoma (CCSA)
• Desmoplastic Small Round Cell Tumour (DSRCT)
• Sclerosing Epithelioid Fibrosarcoma (SEF)
• Perivascular Epithelioid Cell Tumour (PEComa)
• Intimal sarcoma (IS)
• Extraskeletal Myxoid Chondrosarcoma (EMC)
• Solitary Fibrous Tumour (SFT)
• Epithelioid HemangioEndothelioma (EHE)
• Inflammatory Myofibroblastic Tumour (IMT)
• Epithelioid sarcoma (ES)
• FibroSarcoma (FS)
• SMARCA-4 deficient sarcoma
• Malign Peripheral Nerve Sheath Tumours (MPNST)
• Chordoma; I3. Metastatic disease or unresectable locally advanced malignancy that is resistant orrefractory to standard therapy or for which standard therapy does not exist or is notconsidered appropriate by the Investigator; I4. Measurable disease as per the RECIST version 1.1; I5. Previously treated with anthracycline-based regimen except for whom standard therapydoes not exist or is not considered appropriate by the Investigator: inclusion in firstline is allowed (randomisation will be stratified according to the number of previoustreatment lines); I6. Performance Status (ECOG) of 0 or 1; I7. Patients must have an adequate organ and bone marrow function at baseline;
• Absolute neutrophil count (ANC) ≥ 1.0 x 10 G/L
• Platelets ≥ 100 x 10 G/L
• Haemoglobin ≥ 9 g/dL (without transfusion within 7 days)
• Serum creatinine OR Calculated creatinine clearance as per MDRD or CKD-EPI formula ≤ 1.5 upper limit of normal (ULN) OR ≥ 40 mL/min /1.73m2
• Serum total bilirubin ≤ 1.5 ULN OR Direct bilirubin ≤ ULN for patients with totalbilirubin levels > 1.5 ULN (except for patients with Gilbert disease for whom a totalserum bilirubin ≤ 3ULN is acceptable).
• AST and ALT ≤ 3 ULN
• International Normalized Ratio (INR) and activated Partial Thromboplastin Time (aPTT) ≤ 1.5 ULN I8. Women of childbearing potential must have a negative serum pregnancy test within 7 daysbefore C1D1. I9. Women of childbearing potential must agree to use 1 highly effective form ofcontraception from the time of the negative pregnancy test up to 3 months after the lastdose of study drugs. I10. Ability to understand and willingness for follow-up visits; I11. Covered by a medical insurance; I12. Signed and dated informed consent document indicating that the patient has beeninformed of all aspects of the trial prior to enrolment.

Exclusion Criteria: E1. Concurrent use of any other approved or investigational antineoplastic agent; E2. Prior or concurrent treatment with any antibody targeting PD1, PDL1, PDL2 or CTLA4; E3. Prior treatment with pazopanib; E4. Symptomatic, untreated, or actively progressing central nervous system (CNS)metastases. Note:

• Asymptomatic patients with treated CNS lesions are eligible.
• Asymptomatic patients with CNS metastases newly detected at screening are eligible forthe study after receiving radiotherapy or surgery, with no need to repeat thescreening brain scan; E5. Patients using, or requirement to use while on the study, or not respecting the minimalwash-out period of medications listed below: Forbidden concomitant medications and minimal wash-out period before Cycle 1 Day1
• Any approved anti-cancer systemic treatment including chemotherapy, hormonotherapy,biological therapy, or immunotherapy : 2 weeks
• Any investigational agents : 4 weeks
• Radiotherapy Note: palliative radiotherapy on non-target lesions is allowed. : 3 weeks
• Surgery
• Major surgical procedure, open biopsy, or significant traumatic injury : 4 weeks
• Abdominal surgery, abdominal interventions or significant abdominal traumatic injury : 60 days
• Live vaccines. Note: Influenza vaccination should be given during influenza season.Patients must not receive live attenuated influenza vaccine (e.g., FluMist®) : 4 weeks
• Systemic immunostimulatory agents, including but not limited to IFN-α, IFN-γ, or IL-2 : 4 weeks
• Immunosuppressive medication (including but not limited to corticosteroids,cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents)with the exceptions of intranasal, inhaled, or topical corticosteroids or systemiccorticosteroids at physiological doses, which are not to exceed 10 mg/day ofprednisone (or 0.1mg/kg for pediatric patients), or an equivalent corticosteroid :2weeks
• P-gp inhibitors : None
• Strong or moderate inhibitors of CYP3A4 : None
• Strong CYP3A4 inducers : None
• Oral or IV antibiotics :2 weeks Note: Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tractinfection, pneumocystis or chronic obstructive pulmonary disease exacerbation) areeligible. E6. History of autoimmune disease including but not limited to myasthenia gravis, myositis,autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatorybowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener'sgranulomatosis, Sjögren's syndrome, Guillain-Barre syndrome, multiple sclerosis,vasculitis, or glomerulonephritis with the following exceptions:
• patients with a history of autoimmune-related hypothyroidism who are on stable thyroidreplacement hormone therapy,
• patients with controlled Type 1 diabetes mellitus,
• patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis would beexcluded) are eligible provided that they meet the following conditions:
• Rash must cover less than 10% of body surface area (BSA).
• Disease is well controlled at baseline and only requiring low potency topicalsteroids.
• No acute exacerbations of underlying condition within the previous 12 monthsrequiring psoralen plus ultraviolet A radiation (PUVA), methotrexate, retinoids,biologic agents, oral calcineurin inhibitors, high potency or oral steroids; E7. Patients with HIV, active B or C hepatitis infection, or any other active infection. E8. Patients with active tuberculosis; E9. Prior allogeneic bone marrow transplantation or solid organ transplant for anothermalignancy in the past; E10. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-inducedpneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizingpneumonia), or evidence of active pneumonitis on screening chest CT scan; E11. Patients with a high-risk of hemorrhage or history of coagulopathy; E12. Any contraindication to nivolumab, to ipilimumab or to pazopanib according to theSummary of Product Characteristics of each drug; E13. History of other malignancy other than study disease (except for basal cell orsquamous cell carcinoma of the skin or carcinoma in situ of the cervix) unless the patienthas been free of disease for at least 3 years; E14. Patient under tutorship or curatorship or deprived of liberty; E15. Pregnant or breast-feeding woman