Study Evaluating the Safety and Efficacy of MEDI5752 in Combination With Stereotactic Radiotherapy in Patients With Metastatic Sarcoma

Inclusion Criteria:

1. Histologically confirmed soft tissue sarcoma of following subtype: undifferentiatedpleomorphic sarcoma, myxofibrosarcoma, leiomyosarcoma, pleomorphic rhabdomyosarcoma,or pleomorphic liposarcoma

2. Patients with metastatic disease, including (but not restricted to) lung metastasis (in case of lung metastasis only, patients must have more than 5 metastasesmeasurable by RECIST 1.1)

3. Patient with at least two metastases measurable by RECIST 1.1, including at leastone lung metastasis amenable for SBRT, defined as following:

• Tumor size between 1cm and 3 cm, AND

• Peripheral tumor located further than 2 cm of the proximal bronchial tree (carina, right and left main bronchi, and bronchial tree to the secondbifurcation)

4. Metastatic disease pretreated by at least one anthracycline based chemotherapy, butno more than 3 lines of standard therapy

5. Age ≥ 18 years at time of study entry

6. ECOG performance status of 0 or 1

7. Body Weight > 35 kg

8. Life expectancy of at least 3 months

9. Previous treatment ended at least 4 weeks prior to first dose

10. Adequate Hematology laboratory data within 28 days prior to start of treatment:Absolute neutrophils ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hemoglobin ≥ 9 g/dL

11. Adequate Biochemistry laboratory data within 28 days prior to start of treatment:Total bilirubin ≤ 1.5 x ULN (except patient with confirmed Gilbert's syndrome orliver metastasis: Total bilirubin ≤ 3 X ULN), Transaminases ≤ 3 x ULN, Alkalinphosphatases ≤ 5 x ULN, Creatinine clearance ≥ 45 mL/min (Cockcroft)

12. Adequate cardiac function defined as follow: LVEF (as assessed by echocardiographyor multiple-gated acquisition scan) ≥ 50% / Troponin I or T ≤ ULN (per institutionalguidelines and/or not clinically significant per investigator judgement) / QTcF ≤ 480msec

13. Women should be post-menopaused or willing to accept the use of at least one highlyeffective method of birth control from screening to 90 days after the last dose ofMEDI5752. All non-menopaused women should have a negative pregnancy test within 72hours prior to study dosing. Men should accept to use an effective contraceptionfrom screening to 90 days after the last dose of MEDI5752

14. Patient is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations includingfollow up

15. Signed written informed consent before any study procedure

16. Patient affiliated to a Social Health Insurance in France

Exclusion Criteria:

1. Patients with no lung metastases amenable for SBRT

2. Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to use effective birth control fromscreening to 90 days after the last dose of MEDI5752

3. Any malignancy other than the disease under study in the past 2 years exceptingcuratively treated skin cancers such as Basal Cell Carcinoma or Squamous CellCarcinoma.

4. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures (once monthly or more frequently). Patients with indwellingcatheters (e.g., PleurX) are allowed.

5. Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL orcorrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued useof bisphosphonate therapy or denosumab.

6. Severe, active co-morbidity, defined as follows:

• Unstable angina, uncontrolled cardiac arrhythmia, uncontrolled hypertension,symptomatic congestive heart failure

• Transmural myocardial infarction within the last 6 months prior to registration

• Acute bacterial or fungal infection requiring intravenous antibiotics at thetime of registration

• Uncontrolled Chronic Obstructive Pulmonary Disease or other respiratory illnessrequiring hospitalization or precluding study therapy within 30 days prior toregistration

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, orevidence of active pneumonitis on screening chest CT scan

• History of radiation pneumonitis in the radiation field (fibrosis) is permitted

• Severe hepatic disease, defined as a diagnosis of Child-Pugh Class B or Chepatic disease

• Known HIV positive status (positive for HIV-1 or HIV-2 antibodies)

• End-stage renal disease (i.e., on dialysis or dialysis has been recommended)

• Active or uncontrolled hepatitis B (HBV) or hepatitis C (HCV). Participants areeligible if they:

1. Have controlled hepatitis C viral load defined as undetectable hepatitis CRNA by PCR either spontaneously or response to a successful prior courseof anti-hepatitis C therapy
2. Have received HBV vaccination with only anti-HBS positivity and noclinical signs of hepatitis
3. Are HBsAg- and anti-HBc+ (ie, those who have cleared HBV after infection)and meet conditions i-iii below:
4. Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) andmeet conditions i-iii below: i. HBV DNA viral load <100 IU/mL ii. Have normal transaminases values, or, ifliver metastases are present, abnormal transaminases, with a result of AST/ALT <3xULN, which are not attributable to HBV infection iii. Start or maintainantiviral treatment if clinically indicated as per the investigator

• Active hepatitis A

• Active infection including tuberculosis (TB) (clinical evaluation that includesclinical history, physical examination, and radiographic findings and TBtesting in line with local practice)

7. Active or prior documented autoimmune or inflammatory disorders includinginflammatory bowel disease (eg, colitis or Crohn's disease), diverticulitis (withthe exception of diverticulosis), systemic lupus erythematosus, Sarcoidosissyndrome, or Wegener syndrome (granulomatosis with polyangiitis), Graves' disease,rheumatoid arthritis, hypophysitis, uveitis, pneumonitis (past medical history ofILD, drug-induced ILD, or radiation pneumonitis requiring steroid treatment, or anyevidence of clinically active ILD), etc. The following are exceptions to thiscriterion:

8. Subjects with vitiligo or alopecia

9. Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable onhormone replacement

10. Any chronic skin condition that does not require systemic therapy

11. Subjects with celiac disease controlled by diet alone.

12. History of organ transplant.

13. History of a reaction to any human gamma globulin therapy.

14. Known allergy or hypersensitivity to investigational product, or any excipients ofthe investigational product

15. Patients with leptomeningeal carcinomatosis

16. Patients with intra cranial metastasis may be eligible if all known lesions havebeen treated (with stereotactic radiotherapy or surgery or both AND there has beenno evidence of disease progression in the CNS for ≥ 4 weeks after treatment andwithin 28 days prior the first dose of study drug administration

17. Previously Irradiation by SBRT should respect following maximal doses to at-riskstructures:

• Spinal cord irradiated to > 40 Gy

• Brachial plexus irradiated to > 50 Gy

• Lung previously with prior V20Gy > 30%

14. Any approved anticancer therapy, including chemotherapy, hormonal therapy orradiotherapy, within 4 weeks prior to initiation of study treatment and while onstudy treatment; however, the following are allowed: Hormone-replacement therapy ororal contraceptives. Palliative radiotherapy for bone metastases > 2 weeks prior toCycle 1, Day 1.

15. Unresolved toxicities from previous anticancer therapy, defined as toxicities (otherthan alopecia) not yet resolved to NCI CTCAE v5.0 Grade ≤ 1 or baseline

16. Major surgery within 4 weeks prior to the first dose of investigational product orstill recovering from prior surgery. Note: Local surgery of isolated lesions forpalliative intent is acceptable

17. Administration of a live, attenuated vaccine within 4 weeks prior to Cycle 1, Day 1.NOTE: Subjects, if enrolled, should not receive live vaccine while receivinginvestigational product and up to 30 days after the last dose of investigationalproduct

18. Current or prior use of treatment with systemic corticosteroids or other systemicimmunosuppressive or immunomodulating medications (including but not limited toprednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate,thalidomide, and anti-tumour necrosis factor [TNF] agents) within 14days prior tothe first dose of investigational product. The following are exceptions to thiscriterion:

19. Intranasal, inhaled, topical steroids, or local steroids injections (eg.Intraarticular injection)

20. Steroids as premedication for hypersensitivity reactions (eg CT scanpremedication; single palliative dose for pain control etc.)

21. Patient already enrolled in another therapeutic trial involving an investigationalsubstance, and when such a substance has been taken during the previous 4 weeks. Thecurrent enrollment in an observational (non interventional) clinical study or thefollow-up period of an interventional study is permitted.

22. Prior treatment with PDL-1, PD-1 or CTLA4 blocking agents

23. Patient who has forfeited his/her freedom by administrative or legal award or who isunder legal protection (curatorship and guardianship, protection of justice)