Combination of MK3475 and Metronomic Cyclophosphamide in Patients With Advanced Sarcomas : Multicentre Phase II Trial

Inclusion Criteria: 1. Histology : Leiomyosarcoma, or UPS, or other sarcoma, or GIST or osteosarcoma, or soft-tissue sarcoma with presence of tertiary lymphoid structures (stratum 6) histologically confirmed by central review. 2. Advanced non resectable / metastatic disease for strata 1 to 6. For stratum 7: locally advanced or metastatic disease with at least one injectable lesion. 3. Documented progression according to RECIST criteria. Progression on the last line of treatment should be confirmed by central review with two radiological assessments identical obtained at less than 6 months interval within the 12 months before inclusion. 4. For stratum 5, documented disease progression according to RECIST criteria after the first line imatinib and second line sunitinib. 5. Have provided tissue of a tumor lesion from an archival tissue sample obtained on metastasis or on locally advanced disease, or newly obtained core or excisional biopsy. For strata 6 and 7, tissue \< 3 months old and with no subsequent treatment since or from a newly obtained biopsy. 6. For strata 1, 2, 3 and 6: no more of four previous lines of systemic therapy for metastatic disease and no more than 2 previous line for stratum 7. 7. Age ≥ 18 years. 8. ECOG performance status ≤ 1. 9. Measurable disease according to RECIST v1.1 outside any previously irradiated field. At least one site of disease must be uni-dimensionally ≥ 10 mm. 10. Life expectancy \> 3 months (except for stratum 7 \> 6 months). 11. ≥ 1 previous line (s) of chemotherapy in the palliative setting for strata 1 to 5. For other strata, participant must have advanced disease and must not be a candidate for other approved therapeutic regimen known to provide significant clinical benefit based on investigator judgement. 12. No symptomatic central nervous system disease. 13. No chronic use of glucocorticoids. 14. Adequate hematological, renal, metabolic and hepatic function: 1. Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell transfusion); ANC ≥ 1.5 x 109/l and platelet count ≥ 100 x 109/l. For stratum 7: lymphocyte count ≥ 0.5.109 /l 2. ALT and AST ≤ 2.5 x upper limit of normality (ULN) (≤ 5 in case of liver metastasis) 3. Total bilirubin ≤ 1.5 x ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels ≥ 1.5 x ULN 4. Albumin ≥ 25g/l 5. Serum creatinine ≤ 1.5 x ULN OR CrCl ≥ 60 ml/min for subject with creatinine levels ≥ 1.5 x ULN, 6. Creatine phosphokinase ≤ 2.5 x ULN 7. INR ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants 8. aPTT ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants 15. No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma. 16. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy. 17. Recovery to grade ≤ 1 from any adverse event from previous treatment (excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2 (NCI-CTCAE, v 4.0). 18. Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for four months after discontinuation of treatment. Acceptable methods for contraception include intrauterine device, oral contraceptive, subdermal implant and double barrier. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for ≥ 1 year. 19. Voluntary signed and dated written informed consents prior to any specific study procedure. 20. Patients with a French social security in compliance with the Law relating to biomedical research (Article 1121-11 of French Public Health Code). Exclusion Criteria: 1. Previous treatment with MK3475 or CP or G100. 2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). 3. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases. 4. Men or women of childbearing potential who are not using an effective method of contraception as previously described; women who are pregnant or breast feeding. 5. Participation to a study involving a medical or therapeutic intervention in the last 30 days. 6. Previous enrolment in the present study. 7. Patient unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons. 8. Known hypersensitivity to any involved study drug or of its formulation components. 9. 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 Sjorgen's syndrome will not be excluded from the study. 10. 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. 11. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 12. Has known active hepatitis B or hepatitis C. 13. Has a known history of HIV (HIV1/2 antibodies). 14. Has received a live vaccine within 30 days prior to the first dose of trial treatment. 15. For strata 6 to 7: * patients with oral anticoagulation therapy * known urinary tract obstruction * previous allogenic bone marrow transplant * has an active infection requiring systemic treatment within 14 days prior to study