Phase I/II Randomized Study of NBTXR3 Activated by Abscopal or RadScopal Radiation in Combination With Immunotherapy (Anti-PD-1/L-1) for Patients With Advanced Solid Malignancies

Inclusion Criteria:

1. Patients with metastatic disease in the lung and/or liver, or soft tissue from anyprimary malignancy considered incurable by local therapies. a. One prior anti-PD-1/L1 therapy allowed.

2. The target lesion(s) must be measurable as per irRECIST and repeated measurements atthe same anatomical location should be achievable. a. Participant must have at least 2 measurable lesions at screening. i. Abscopalcohort: At least one lesion will receive NBTXR3 and high dose radiation (high dosetarget lesion). The other lesion(s) (non-treated target lesion) will be followed forresponse and it will not receive NBTXR3 or RT. ii. RadScopal™ cohort: At least one lesion will receive NBTXR3 and high doseradiation (high dose target lesion). The other lesion(s) will only receive low doseradiation (low dose target lesion).

3. Amenable to undergo the image guided (EBUS or CT or MRI) intratumoral injection ofNBTXR3, in up to two (2) high dose target lesions, as determined by the investigatoror treating physician at screening. a. Intratumoral NBTXR3 injections only allowed in lung or liver lesions.

4. Selected high and low dose target lesions must be amenable to receive radiationtherapy as determined by the investigator or treating radiation oncologist.

5. Allowed high dose RT regimens are 50 Gy in 4 fractions or 60 Gy in 10 fractions

6. Allowed low dose RT for RadScopal™ cohort is 1.4 Gy per fraction for 4 - 5fractions to only low dose-target lesion(s) determined by the investigator ortreating physician.

7. Patients can receive radiation therapy for symptomatic metastatic disease prior toenrollment or during the study a.

8. Age ≥ 18 years

9. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

10. Laboratory Values at screening:

11. Hemoglobin ≥ 9.0 g/dL

12. Absolute Neutrophil Count (ANC) ≥ 1,500/mm3

13. Platelet count ≥ 100,000/mm3

14. Leukocytes ≥ 1500/mm3

15. Creatinine ≤ 1.5 x upper limit of normal (ULN)

16. Calc. creatinine clearance > 30mL/min

17. Total bilirubin ≤ 2.0 mg/dL

18. AST / ALT ≤ 2.0 x upper limit of normal (ULN) or ≤ 3 x ULN for patients withliver metastases

19. For participants to be treated for lung metastases, adequate lung function withexpiratory volume in 1 second (FEV1) ≥ 0.8L or ≥ 35% predicted and carbon monoxidediffusing capability (DLCO) ≥ 40% with or without bronchodilator within 30 daysprior to NBTXR3 injection. Participants to be treated for liver metastasis apulmonary function test is not required.

20. Patients who meet the criterion above without oxygen (02), but need acute (startedwithin 7 ± 3 days) supplemental oxygen due to tumor-caused obstruction/hypoxia areeligible, provided the amount of the O2 needed has been stable.

21. Negative urine or serum pregnancy test ≤ 7 days prior to NBTXR3 injection in allwomen of child-bearing potential (WOCBP). WOCBP must agree to follow instructionsfor method(s) of contraception for the duration the entire study period and 160 days (~5.33 months) after the last dose of anti-PD-1/L-1 treatment. Local laws andregulations may require use of alternative and/or additional contraception methods.WOCBP who are continuously not heterosexually active are exempt from contraceptiverequirements but should still undergo pregnancy testing.

22. Signed informed consent form (ICF) indicating that participant understands thepurpose of, and procedures required for, the study and is willing to participate inthe study.

4.2 Exclusion criteria:

1. Prior radiation therapy received to the selected high dose target lesion(s) a. Previous radiation to low dose target lesions allowed as per investigator ortreating radiation oncologist discretion.

2. Symptomatic central nervous system metastases and/or carcinomatous meningitis a. Participants with previously treated brain metastases may participate if thoselesions are radiologically stable (i.e., without evidence of progression for atleast 4 weeks by repeat imaging at screening), clinically stable, and withoutrequirement of steroid treatment for at least 14 days prior to NBTXR3 injection.

3. At screening, past medical history of:

4. Interstitial lung disease

5. Unresolved organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenicorganizing pneumonia)

6. Any Grade 4 radiation toxicity

7. Unresolved, radiation or ICI related i. Pneumonitis ii. Bronchopulmonary hemorrhage iii. Abdominal hemorrhage e.Unresolved GI related events i. Diverticulitis ii. Colitis iii. Intra-abdominalabscess iv. GI obstructions v. Abdominal carcinomatosis vi. Any known risk factorfor bowel perforation

8. History of severe (Grade ≥ 3) immune-related adverse events observed with previousimmunotherapy (anti-PD-1/L1) or known sensitivity (Grade ≥ 3) to any excipients.

9. Has received any approved or investigational anti-neoplastic agent or immunotherapywithin 2 weeks prior to NBTXR3 injection.

10. Except anti-PD-1/L1, which will not require a washout window.

11. A reduced washout window may be considered for therapies with short half-lives (i.e., kinase inhibitors) after discussion with Nanobiotix and investigator.

12. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressivedrugs). a. Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroidreplacement [≤ 10 mg prednisone] therapy for adrenal or pituitary insufficiency,etc.) is not considered a form of systemic treatment.

13. Any live-virus vaccine used for prevention of infectious diseases administeredwithin 4 weeks prior to NBTXR3 injection.

14. Except killed-virus Influenza vaccine

15. Exception of other vaccines (e.g. pneumonia) is at the discretion of thetreating physician after conducting a personalized risk assessment on a case bycase basis.

16. Prior allogenic stem cell transplantation or organ allograft.

17. Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, renalfailure, cardiac arrhythmia, or psychiatric illness that would limit compliance withtreatment.

18. Known active, uncontrolled (high viral load) HIV or hepatitis B or hepatitis Cinfection.

19. Female patients who are pregnant or breastfeeding.

20. Women of child-bearing potential and their male partners who are unwilling or unableto use an acceptable method of birth control to avoid pregnancy for the entire studyperiod and up to 160 days (~5.33 months) for female participants, and 7 months formales participants or female partners of male participants that are of child-bearingpotential, after the last dose of anti-PD-1/L-1. a. Acceptable methods of contraception are those that, alone or in combination,result in a failure rate of < 1% per year when used consistently and correctly.

21. Any condition for which, in the opinion of the investigator, participation would notbe in the best interest of the participant (e.g., compromise the well-being) or thatcould prevent, limit, or confound the protocol-specified assessments.