Stereotaxic Body Irradiation of Oligometastase in Sarcoma (Stereosarc)

Open label, Phase II, prospective, multicentric, randomized study 2:1, 2 arm study designed to evaluate the efficacy of a Stereotactic Body Radiation Therapy treatment associated with immunotherapy versus a Stereotactic Body Radiation Therapy treatment only.

Primary objective The primary objective is to evaluate the efficacy, in term of progression-free survival (PFS) rate at 6 months, of immunomodulated stereotactic irradiation in oligometastatic sarcoma patients.

Secondary Objectives

• PFS by immune response criteria.
• ratio PFS after radiotherapy/PFS during the previous line of treatment
• Objective response rate.
• Rate of progression-free survival (PFS) at 6 months by line of treatment and histology.
• Evaluation of the toxicity of the treatment.
• Overall survival.
• Evaluation of the quality of life of patient treated by the combination of radio- and immunotherapy or radiotherapy only.
• Evaluation of the cost of treatment.
• Rate of PET-CT at inclusion
• Correlative study: Impact of biomarkers on clinical endpoints.
• Developing a mathematical models for STS treatment by SBRT + immunotherapy predictive of oligo versus poly metastatic evolution

The treatment to be used in this study is the Atezolizumab concomitant with High Dose Radiation (SBRT) or the SBRT Alone Atezolizumab Subjects randomized in the experimental arm will receive Atezolizumab 1200 mg in combination with SBRT, Q3W (6 cycles) for 4 months until progression/completion. The Atezolizumab will be provided by the Sponsor (Centre Antoine Lacassagne).

Chemotherapy will be discontinued in case of progression, unacceptable toxicity, or withdrawal of patient consent to receive study treatment.

Radiation therapy SBRT can be performed with different equipments (CyberKnife, Truebeam, etc.). Adequate tumor tracking and patient setup/repositioning as well as online IGRT (image-guided radiation therapy) must be performed at each fraction. The maximal cumulative tumor diameter is 6 cm to maintain an advantageous risk-benefit ratio with SBRT. Two types of fractionation are proposed to account for tumor size and proximity of the tumor to sensitive organs at risk. Three fractions are proposed in favorable cases, 5 in more delicate cases. Fractions can be performed on consecutive days. Depending on cases, they may be delivered every other day; the whole SBRT duration should not exceed 3 weeks.

Inclusion criteria

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

• Progressive disease according to RECIST 1.1 criteria,
• Metastatic disease (1-5 synchronous macroscopic metastases by chest and abdominopelvic 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; Serum creatinine ≤1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥50 mL/min for subject with creatinine levels > 1.5 X institutional ULN; Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN; AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases. All screening labs should be performed within 15 days of treatment initiation.
• Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy 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 randomisation and 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 samples available. If no archival material is available, a fresh biopsy should be performed 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 investigational agent or using an investigational device within 4 weeks prior to randomisation.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Has had a prior monoclonal antibody within 4 weeks prior to randomisation or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Has had prior chemotherapy or targeted small molecule therapy within 4 weeks prior to randomisation or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent (Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study). If subjects received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Have had previous radical radiation to any tumour site within 4 weeks prior to randomisation
• 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 of flare-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 the skin, or in situ cervical cancer that has undergone potentially curative therapy.
• Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjögren's syndrome will not be excluded from the study.
• Has evidence of symptomatic interstitial lung disease or an active, non-infectious pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance-abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-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 trial treatment.
• Has had major surgery or major blood transfusions (>3 packed cells) in the past 3 months.
• Receives IL-2, interferon or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigational therapies; or chronic use of systemic corticosteroids (used in the management of cancer or non-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 their freedom by judicial or administrative decision, persons hospitalized without their consent by virtue of articles L. 3212-1 and L. 3213-1 and who are not subject to the provisions 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