Tocilizumab in Lung Transplantation

Inclusion Criteria:

Study Entry:

1. Subject and/or parent guardian must be able to understand the purpose of the studyand willing to participate and sign informed consent/assent

2. Greater than or equal to 30 kg body weight

3. Listed for a primary lung transplant

4. No previous or planned desensitization therapy prior to transplant

5. Serum Immunoglobulin G (IgG) level greater than 400 mg/dL. Patients treated withintravenous immune globulin (IVIG) for hypogammaglobulinemia are eligible forenrollment if their serum IgG level is greater than 400 mg/dL 14 or more days afterthe most recent IVIG treatment

6. For women of child-bearing potential, willingness to use highly-effectivecontraception; according to the Food and Drug Administration (FDA) Office of Women'sHealth (http://www.fda.gov/birthcontrol). Female participants of child-bearing potential must consult with their physician anddetermine the most suitable method(s) from this list to be used for the duration ofthe study. Those who choose oral contraception must agree to use a second form ofcontraception after administration of study drug for a period of 1 year after thelast dose of study drug

7. Tested negative for latent TB infection (LTBI) using a PPD or interferon-gammarelease assay (i.e., QuantiFERON-TB, T-SPOT.TB) within 1 year prior to transplant orhas completed appropriate LTBI therapy within the 1 year prior to transplant

8. In the absence of contraindication, vaccinations must be up to date per the Divisionof Allergy, Immunology, and Transplantation (DAIT) Guidance for Patients inTransplant Trials

Randomization:

1. Provide written informed consent for the study participation, and agree to continuein the study

2. Undergoing single or bilateral lung transplant

3. Agreement to use contraception; according to the FDA Office of Women's Health (http://www.fda.gov/birthcontrol), there are a number of birth control methods thatare more than 80% effective. Female participants of child-bearing potential mustconsult with their physician and determine the most suitable method(s) from thislist to be used for the duration of the study. Those who choose oral contraceptionmust agree to use a second form of contraception after administration of study drugfor a period of 1 year after the last dose of study drug

4. Negative physical crossmatch, if the results are available at the time ofrandomization

5. No desensitization therapy prior to transplant

6. Negative pregnancy test (serum or urine) for women of child-bearing potential within 48 hours prior to transplant

7. Negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) PolymeraseChain Reaction (PCR) testing for the recipient prior to transplant as perinstitutional policy

8. Negative SARS-CoV2 PCR testing for the donor prior to transplant as perinstitutional policy

9. Recipient of lungs that have been supported with ex vivo lung perfusion (EVLP)devices are permitted

Exclusion Criteria:

Study Entry:

1. Listed for multi-organ transplant (e.g., heart-lung, liver-lung, kidney-lung)

2. Prior history of allogeneic organ or cellular transplantation

3. Received treatment to deplete Human Leukocyte Antigens (HLA) antibodies beforetransplantation

4. Currently breast-feeding a child or plans to become pregnant during the timeframe ofthe study follow up period

5. History of severe allergic and/or anaphylactic reactions to humanized or murinemonoclonal antibodies

6. Known hypersensitivity or previous treatment with ACTEMRA(R) (tocilizumab) withinthe last 3 months

7. Infection with human immunodeficiency virus (HIV)

8. Hepatitis B virus surface antigen or core antibody positive

9. Hepatitis C virus PCR positive (HCV+) patients who have failed to demonstratesustained viral remission (2 consecutive PCR or Nucleic Acid Tests (NAT) negativetests at least 24 weeks apart), with or without anti-viral treatment;

10. Chronic infection with Burkholderia cenocepacia or Burkholderia gladioli

11. Non-tuberculous mycobacterial (NTM) pulmonary disease; if there is a history of NTMpulmonary disease, culture conversion is necessary for eligibility

12. Presence of active malignancy or history of malignancy less than 5 years inremission, excluding adequately treated in-situ cervical carcinoma, low gradeprostate carcinoma, or adequately treated basal or squamous cell carcinoma of theskin

13. History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia purpura

14. History of demyelinating disorders (e.g., multiple sclerosis, chronic inflammationdemyelinating polyneuropathy)

15. Current treatment with alkylating agents such as cyclophosphamide

16. History of gastrointestinal (GI) tract perforation

17. History of inflammatory bowel disease except fully excised ulcerative colitis

18. Any history of diverticulitis (event if not perforated) or confirmed diverticularbleeding. (Diverticulosis is not an exclusion).

19. Patients with a platelet count < 100,000/mm^3 (last measurement within 7 days priorto enrollment)

20. Patients with an absolute neutrophil count (ANC) < 2,000/mm^3 (last measurementwithin 7 days prior to enrollment)

21. Patients with Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT)levels >3 times upper limit of normal

22. Patients who use illegal drugs

23. Use of investigational drugs within 4 weeks prior to enrollment

24. Any condition that in the opinion of the site Principal Investigator (PI) introducesundue risk by participating in this study

Randomization:

1. Recipient of multi-organ or tissue transplants

2. Received a live virus vaccine within 30 days prior to randomization

3. Received treatment to deplete HLA antibodies before transplantation to improve thepossibility of transplantation

4. Patients with known donor-specific antibody that will require intervention based onlocal clinical protocols

5. History of GI tract perforation

6. History of inflammatory bowel disease except fully excised ulcerative colitis

7. History of diverticulitis (diverticulosis is not an exclusion) or diverticularbleeding

8. History of severe allergic anaphylactic reactions to humanized or murine monoclonalantibodies

9. Previous treatment with ACTEMRA(R) (tocilizumab) within the last 3 months.

10. Recipient or donor with infection with human immunodeficiency virus (HIV)

11. Recipient with hepatitis B virus surface antigen or hepatitis B core antibodypositive

12. Hepatitis B negative transplant recipient that received a transplant from aHepatitis B core antibody positive donor unless the recipient has a Hepatitis BSurface Antigen (HBsAb) titer >10U/L

13. Recipient of a hepatitis C virus nucleic acid test (NAT) positive donor organ

14. Latent TB infection (LTBI) and has not completed appropriate therapy

15. Chronic infection with Burkholderia cenocepacia or Burkholderia gladioli

16. Non-tuberculous mycobacterial (NTM) pulmonary disease; if there is a history of NTMpulmonary disease, culture conversion is necessary for eligibility

17. Presence of active malignancy (except for non-melanoma skin cancer)

18. History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia purpura

19. History of demyelinating disorders (e.g., multiple sclerosis, chronic inflammationdemyelinating polyneuropathy)

20. Current treatment with alkylating agents such as cyclophosphamide

21. Patients with AST or ALT levels > 1.5 times upper limit of normal (last measurementwithin 1 day prior to randomization)

22. Patients with platelet count <100,000/mm^3 (last measurement within 1 day prior torandomization)

23. Patients with an absolute neutrophil count (ANC) <2,000/mm^3 (last measurementwithin 1 day prior to randomization)

24. Patients who are administered or intended to be administered cytolytic (such asanti-thymocyte globulin) or anti-CD25 monoclonal antibody agents as inductiontherapy in the immediate post- transplant period

25. Patients who have been treated in the past 3 months, or for whom it is anticipatedthat treatment with any immunomodulatory biological agents post-transplant areexcluded

26. Use of an investigational drug after transplant

27. Any condition that in the opinion of the site PI introduces undue risk byparticipating in this study