Stereotaxic Body Irradiation of Oligometastase in Sarcoma (Stereosarc)

Inclusion Criteria:

• • STS (leiomyosarcomas uterine/extra-uterine, liposarcomas, undifferentiatedsarcomas), any grade

• Progressive disease according to RECIST 1.1 criteria,

• Metastatic disease (1-5 synchronous macroscopic metastases by chest andabdominopelvic CT, maximal cumulated diameter 10 cm); any anatomic site

• First or second metastatic line

• Be ≥ 18 years of age on day of signing informed consent.

• Have a performance status of 0 or 1 on the ECOG Performance Scale.

• Have at least one lesion mesurable by RECIST 1.1 for irradiation with a size of < 5 cm.

• Demonstrate adequate organ function: Absolute neutrophil count (ANC) ≥1,500 /mcL; Platelets ≥100,000 / mcL; Hemoglobin ≥9 g/dL or ≥5.6 mmol/L; Serumcreatinine ≤1.5 X upper limit of normal (ULN) OR measured or calculatedcreatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥50mL/min for subject with creatinine levels > 1.5 X institutional ULN; Serumtotal bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with totalbilirubin levels > 1.5 ULN; AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULNfor subjects with liver metastases. All screening labs should be performedwithin 15 days of treatment initiation.

• Female subjects of childbearing potential should have a negative urine or serumpregnancy test within 72 hours prior to receiving the first dose of studymedication. If the urine test is positive or cannot be confirmed as negative, aserum pregnancy test will be required. Female subjects of childbearingpotential should be willing to use 2 methods of birth control or be surgicallysterile, or abstain from heterosexual activity for the course of the studythrough 120 days after the last dose of study medication. Subjects ofchildbearing potential are those who have not been surgically sterilized orhave not been free from menses for > 1 year. Male subjects should agree to usean adequate method of contraception starting with the first dose of studytherapy through 120 days after the last dose of study therapy.

• Surgical ablation (or other ablative methods such as thermal ablative methods)remains possible if needed before SBRT, at least 4 weeks before randomisationand provided that at least one lesion needs to be treated by SBRT.

• FFPE Tumor tissue collected before SBRT is available for immunohistochemistry (optional)

• Archival metastatic biopsy blocks (or slides) on paraffin embedded samplesavailable. If no archival material is available, a fresh biopsy should beperformed if possible.

• Be willing and able to provide written informed consent/assent for the trial.

• affiliated with a health insurance system.

Exclusion Criteria:

• Is currently participating in, or has participated in, a study of an investigationalagent or using an investigational device within 4 weeks prior to randomisation.

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or anyother form of immunosuppressive therapy within 7 days prior to the first dose oftrial treatment.

• Has had a prior monoclonal antibody within 4 weeks prior to randomisation or has notrecovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agentsadministered more than 4 weeks earlier.

• Has had prior chemotherapy or targeted small molecule therapy within 4 weeks priorto randomisation or who has not recovered (i.e. ≤ Grade 1 or at baseline) fromadverse events due to a previously administered agent (Subjects with ≤ Grade 2neuropathy are an exception to this criterion and may qualify for the study). Ifsubjects received major surgery, they must have recovered adequately from thetoxicity and/or complications from the intervention prior to starting therapy.

• Have had previous radical radiation to any tumour site within 4 weeks prior torandomisation

• Have had previous ablative treatment within 4 weeks prior to randomisation (radiofrequency, surgery)

• Has a tumour within 5 mm of the spinal cord (owing to rare reported cases offlare-up after initiation of immunotherapy)

• Has a known additional malignancy that is progressing or requires active treatment.Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of theskin, or in situ cervical cancer that has undergone potentially curative therapy.

• Has an active autoimmune disease requiring systemic treatment within the past 3months or a documented history of clinically severe autoimmune disease, or asyndrome that requires systemic steroids or immunosuppressive agents. Subjects withvitiligo or resolved childhood asthma/atopy would be an exception to this rule.Subjects that require intermittent use of bronchodilators or local steroidinjections would not be excluded from the study. Subjects with hypothyroidism stableon hormone replacement or Sjögren's syndrome will not be excluded from the study.

• Has evidence of symptomatic interstitial lung disease or an active, non-infectiouspneumonitis.

• Has an active infection requiring systemic therapy.

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the trial, interfere with thesubject's participation for the full duration of the trial, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator.

• Has known psychiatric or substance-abuse disorders that would interfere withcooperation with the requirements of the trial.

• Is pregnant or breastfeeding, or expecting to conceive within the projected durationof the trial, starting with the pre-screening or screening visit through 120 daysafter the last dose of trial treatment.

• Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, oranti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (includingipilimumab or any other antibody or drug specifically targeting T-cellco-stimulation or checkpoint pathways).

• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

• Has known active Hepatitis B (e.g. HBsAg reactive) or Hepatitis C (e.g. HCV RNA [qualitative] is detected).

• Has received a live vaccine within 30 days prior to the first dose of trialtreatment.

• Has had major surgery or major blood transfusions (>3 packed cells) in the past 3months.

• Receives IL-2, interferon or other non-study immunotherapy regimens; cytotoxicchemotherapy; immunosuppressive agents; other investigational therapies; or chronicuse of systemic corticosteroids (used in the management of cancer ornon-cancer-related illnesses)

• Under-age patients

• Patients unable to express their consent

• Vulnerable persons as defined by article L1121-5 - 8:

• Pregnant women, women in labor or breast-feeding mothers, persons deprived of theirfreedom by judicial or administrative decision, persons hospitalized without theirconsent by virtue of articles L. 3212-1 and L. 3213-1 and who are not subject to theprovisions of article L. 1121-8

• Persons admitted to a social or health facility for reasons other than research

• Adults subject to a legal protection order or unable to give their consent