Atezolizumab Combined With BDB001 AnD Immunogenic Radiotherapy in Patients With Advanced Solid Tumors

Inclusion criteria:

1. histologically confirmed pancreatic cancer, virus-associated tumors [includingpapillomaviruses-related cancers (cervical, head and neck, and nasal), Epstein-Barrvirus (nasopharyngeal carcinoma) and Kaposi's sarcoma-associated herpes virus),non-small cell lung cancer, soft-tissue sarcomas, bladder cancer, triple negativebreast cancer. For population 4, diagnosis must be confirmed by the RRePS Network asrecommended by the French NCI. For population 2, papillomavirus-related cancers mustbe eligible whatever the genotype but in case of viral genotype is not available,IHC p16 positive must be provided, hepatocellular carcinoma must be confirmed byHepatite B or C infection, HHV-8 and Epstein-Barr virus related cancers must beconfirmed by molecular analysis,

2. Metastatic disease,

3. Age ≥ 18 years,

4. ECOG ≤ 1,

5. At least two lesions: one extra cerebral lesion that can be treated by radiotherapyand one site of disease that must be uni-dimensionally ≥ 10 mm considered asmeasurable according to RECIST v1.1. This lesion will not be treated byradiotherapy, however, note that lesion(s) that will be treated by radiotherapy willalso be considered as measurable. Note that the largest size of the metastases to beirradiated will be 3cm and at that previous irradiation of these lesions is notallowed,

6. Life expectancy > 6 months,

7. At least one tumor site that can be biopsied for research purpose. Tumor lesion inclose proximity to vascular structures such as large vessels, aneurysm or pulmonaryarteriovenous malformation will not be considered for biopsy,

8. Availability of archived paraffin-embedded tumor tissue for research purpose,

9. Participant must have advanced disease and must not be a candidate for otherapproved therapeutic regimen known to provide significant clinical benefit based oninvestigator judgement,

10. Participants who received prior anti-PD-1/L1 therapy must fulfill the followingrequirements - population 3 and population 5 only

• Have achieved a complete response, partial response or stable disease andsubsequently had disease progression while still on anti-PD-1/L1 therapy

• Have received at least two doses of an approved anti-PD-1/L1 therapy (by anyregulatory authority)

• Have demonstrated disease progression as defined by RECIST v1.1 within 18 weeksfrom the last dose of the anti- PD-1/L1 therapy.

11. Adequate hematological, renal, metabolic and hepatic functions

12. No prior or concurrent malignant disease needing an active treatment,

13. At least three weeks since last chemotherapy, immunotherapy or any otherpharmacological treatment and/or radiotherapy,

14. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment,excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2,

15. Women of childbearing potential must have a negative serum pregnancy test within 7days prior to inclusion.

16. Both women and men must agree to use an effective method of contraception throughoutthe treatment period and for five months after discontinuation of treatment.

17. Voluntary signed and dated written informed consents prior to any specific studyprocedure,

18. Participants with a social security in compliance with the French law.

Exclusion criteria:

1. Previous treatment with a TLR agonist

2. Evidence of progressive or symptomatic central nervous system (CNS) orleptomeningeal metastases,

3. Women who are pregnant or breast feeding,

4. Participation in a study involving a medical or therapeutic intervention in the last 30 days,

5. Known hypersensitivity to CHO cell products or to any involved study drug or of itsformulation components,

6. History of severe allergic anaphylactic reactions to chimeric, human or humanizedantibodies, or fusion proteins,

7. Treatment with systemic immunosuppressive medications including, but not limited to,cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agentswithin 2 weeks prior to inclusion.

8. Major surgical procedure, open biopsy or significant traumatic injury within 28 daysbefore inclusion,

9. Any of the following cardiac criteria: congestive heart failure ≥ New York HeartAssociation (NYHA) class 2, unstable angina, new-onset angina, myocardial infarctionless than 6 months before inclusion, uncontrolled cardiac arrhythmias, known leftventricular ejection fraction (LVEF) <50%, previously experience of pericardialdisorder

10. Individuals deprived of liberty or placed under legal guardianship,

11. Prior organ transplantation, including allogeneic stem cell transplantation,

12. Known clinically significant liver disease, including active viral, alcoholic, orother hepatitis, cirrhosis, fatty liver and inherited liver disease,

13. History of intra-abdominal inflammatory process within the last 12 months such as,but not limited to, diverticulitis, peptic ulcer disease or colitis.

14. History of autoimmune disease including, but not limited to systemic lupuserythematosus (SLE), Sjögren's syndrome, glomerulonephritis, multiple sclerosis,rheumatoid arthritis, vasculitis, systemic immune activation, inflammatory boweldisease, vascular thrombosis associated with antiphospholipid syndrome, Wegener'sgranulomatosis, Guillain-Barré syndrome, Bell's palsy.

15. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-inducedpneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screeningchest CT scan.

16. Poorly controlled Type II diabetes mellitus defined as a screening fasting plasmaglucose ≥160 mg/dL (or 8.8 mmol/L).

17. Severe infections within 2 weeks prior to inclusion, including but not limited toSARS-Cov-2 infection, hospitalization for complications of infection, bacteremia, orsevere pneumonia.

18. Received therapeutic oral or IV antibiotics within 2 weeks prior to inclusion.

19. Participant has spinal cord compression not definitively treated with surgery and/orradiation or previously diagnosed and treated spinal cord compression withoutevidence that disease is clinically stable at least 14 days prior to inclusion.

20. Administration of a live, attenuated vaccine within 4 weeks before the start ofstudy medication .

21. Has known active hepatitis B or hepatitis C,known history of Human Immunodeficiencyor known acquired immunodeficiency syndrome, known history of tuberculosis

22. Patients with current retinal disorder confirmed by retinal examination (externalocular examination, routine slit lamp biomicroscopy of anterior ocular structuresand evaluation of the anterior and posterior chamber,

23. Patients who wear contact lenses unable to replace them with glasses.