Azacytidine During Anti-tuberculosis Therapy

NCT03941496 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: H-45051
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Tuberculosis has been shown to make immune genes inaccessible and slows immune response The purpose of this research is to see if if azacitidine is safe and can return the ability of the body to resist tuberculosis (TB), a contagious infection that attacks the lungs. Individuals with tuberculosis are being asked to participate. Some will receive a drug to restore a host immunity while others can choose to receive standard of care. All patients will continue to receive standard of care tuberculosis therapy regardless of whether they chose to participate in the study. This study is a Phase Ib/IIa single-institution, open-label, non-randomized clinical trial of sub-cutaneous azacitidine in pulmonary TB patients during the continuation phase of ATT.

Conditions

Tuberculosis, Pulmonary

Keywords

Tuberculosis; TB; Mycobacterium tuberculosis; Mtb; anti-TB therapy; ATT; rifampin (R), isoniazid (H) pyrazinamide (Z) ethambutol (E); RHZE; rifampin (R), isoniazid (H); RH

Outcome Measures

Primary Outcomes (3)

• Overall incidence of all IP-related adverse events

  using Common Terminology Criteria for Adverse Events (CTCAE) v 5.0.

  2 years

• Overall severity of all IP-related adverse events

  using Common Terminology Criteria for Adverse Events (CTCAE) v 5.0

  4 months

• Measurement of epigenetic-mediated immune exhaustion

  measured by using 1) a standardized mycobacterial growth inhibition assay (MGIA) that measures ex vivo mycobacterial killing; 2) 18-parameter flow cytometry based multi-dimensional immune profiling (MDIP); and 3) epigenetic assays

  baseline and Week 16

Study Arms (1)

AZA Treatment

EXPERIMENTAL

In Phase Ib dose escalation stage, participants will receive subcutaneous (SQ) AZA once daily x 5 days. Results from Phase Ib are sent to FDA/IRB for approval before proceeding to Phase IIa. 36 subjects will receive AZA treatment in total (Phase Ib/IIa). All participants receive standard of care antibiotics against tuberculosis. Dose Escalation Strategy to identify the lowest dose of AZA that decreases DNA methylation and restores immune function is listed below. Proceeding to Phase IIa will proceed if stopping criteria are met at any of the steps below and FDA/IRB approval is obtained: 1. 5 mg/m\^2 subcutaneous (SQ) once daily x 5 days for 8 individuals 2. 15 mg/m\^2 subcutaneous (SQ) once daily x 5 days for 8 individuals 3. 30 mg/m\^2 subcutaneous (SQ) once daily x 5 days for 8 individuals 4. 50 mg/m\^2 SQ once daily x 5 days for 8 individuals 5. 75 mg/m\^2 once daily x 5 days for 8 individuals

Drug: Azacitidine Injection

Interventions

Azacitidine Injection DRUG

In Phase Ib dose escalation stage, 24 participants will receive AZA subcutaenously once a day for 5 days as follows: 1. 5 mg/m\^2 2. 15 mg/m\^2 3. 30 mg/m\^2 4. 50 mg/m\^2 5. 75 mg/m\^2 Results from Phase Ib are sent to FDA/IRB for approval before proceeding to Phase IIa. 36 subjects will receive AZA treatment in total (Phase Ib/IIa). Subjects in Phase II will receive a dose that induces two of the three following: 1. a decrease DNA methylation levels in genes previously identified to be persistently hyper-methylated despite successful anti-TB therapy 2. an increase in TNF and IFN-γ signaling pathways 3. an increase in ex vivo mycobacterial growth inhibition assay

Also known as: AZA Group

AZA Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 years or older
• Microbiologically confirmed pulmonary Tuberculosis, including cavitary, lymph node or military pulmonary TB
• Asymptomatic by the end of intense phase ATT (8 weeks) and remains asymptomatic until AZA dosing.
• Acid-Fast Bacilli (AFB)-smear negative at the end of intensive phase.
• month sputum culture negative and 2-month sputum with no growth at time of study entry.
• HIV-negative.
• Adequate hepatic function (direct bilirubin 1.5 x upper limit of normal (ULN) or less, alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 1.5 x ULN or less) at the end of ATT intensive phase.
• Adequate renal function (creatinine 2 mg/dl or less and glomular filtration rate (GFR) 60 or greater).
• Written informed consent obtained
• Women and men of childbearing potential must agree to use 2 clinically effective methods of contraception (e.g., oral, intrauterine device \[IUD\], diaphragm plus spermicide, injectable, transdermal or implantable contraception) during the study and at least 3 months after the last treatment.

You may not qualify if:

• HIV-infection
• Pre-existing liver disease as defined by imaging or pathology consistent with moderate or worse firbrosis or cirrhosis (Metavir scoring system F2)
• Smear-positive at 2 months
• month or 2 month sputum culture positive at time of study entry.
• Participants with extrapulmonary TB.
• History or current drug-resistant tuberculosis
• After consent and within two weeks before Investigational Product (IP), a study complete blood count (CBC) will be performed and individuals with cytopenias (Hemoglobin \<12 g/dL, WBC \< 3 cells/ mm3, Absolute Neutrophil Count (ANC) \< 2,000 cells/mm3, or platelets \< 110,000 platelets/mm3) will be excluded.
• Any concurrent uncontrolled medical condition, laboratory abnormality, or psychiatric illness which could place the patient at unacceptable risk of study treatment.
• Pregnant or breast feeding females.
• Uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing signs/symptoms related the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment)
• History of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), celiac disease (ie. sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity
• Cancer (excluding surgically treated skin cancer) or hematologic malignancy currently active or active in the past three years.
• Abnormal coagulation parameters (Prothrombin Time (PT) \>15 seconds, Partial Thromboplastin (PTT) \>40 seconds, and/or international normalized ratio (INR) \>1.5)
• Significant active cardiac disease within the previous 6 months including:
• New York Heart Association (NYHA) class 4 congestive heart failure (CHF)

Sponsors & Collaborators

• Andrew Dinardo: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Harris Health System - Ben Taub Hospital

Houston, Texas, 77030, United States

Location

Related Publications (69)

• DiNardo AR, Mace EM, Lesteberg K, Cirillo JD, Mandalakas AM, Graviss EA, Orange JS, Makedonas G. Schistosome Soluble Egg Antigen Decreases Mycobacterium tuberculosis-Specific CD4+ T-Cell Effector Function With Concomitant Arrest of Macrophage Phago-Lysosome Maturation. J Infect Dis. 2016 Aug 1;214(3):479-88. doi: 10.1093/infdis/jiw156. Epub 2016 Apr 18.

  PMID: 27389351 BACKGROUND

• Starke JR. Mortality in childhood tuberculosis: has there been progress? Lancet Infect Dis. 2017 Mar;17(3):239-241. doi: 10.1016/S1473-3099(16)30537-0. Epub 2016 Dec 8. No abstract available.

  PMID: 27964821 BACKGROUND

• van der Walt M, Lancaster J, Shean K. Tuberculosis Case Fatality and Other Causes of Death among Multidrug-Resistant Tuberculosis Patients in a High HIV Prevalence Setting, 2000-2008, South Africa. PLoS One. 2016 Mar 7;11(3):e0144249. doi: 10.1371/journal.pone.0144249. eCollection 2016.

  PMID: 26950554 BACKGROUND

• Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-gamma immunity. Semin Immunol. 2014 Dec;26(6):454-70. doi: 10.1016/j.smim.2014.09.008. Epub 2014 Oct 26.

  PMID: 25453225 BACKGROUND

• DiNardo AR, Rajapakshe K, Nishiguchi T, Grimm SL, Mtetwa G, Dlamini Q, Kahari J, Mahapatra S, Kay A, Maphalala G, Mace EM, Makedonas G, Cirillo JD, Netea MG, van Crevel R, Coarfa C, Mandalakas AM. DNA hypermethylation during tuberculosis dampens host immune responsiveness. J Clin Invest. 2020 Jun 1;130(6):3113-3123. doi: 10.1172/JCI134622.

  PMID: 32125282 BACKGROUND

• Youngblood B, Noto A, Porichis F, Akondy RS, Ndhlovu ZM, Austin JW, Bordi R, Procopio FA, Miura T, Allen TM, Sidney J, Sette A, Walker BD, Ahmed R, Boss JM, Sekaly RP, Kaufmann DE. Cutting edge: Prolonged exposure to HIV reinforces a poised epigenetic program for PD-1 expression in virus-specific CD8 T cells. J Immunol. 2013 Jul 15;191(2):540-4. doi: 10.4049/jimmunol.1203161. Epub 2013 Jun 14.

  PMID: 23772031 BACKGROUND

• Durzynska J, Lesniewicz K, Poreba E. Human papillomaviruses in epigenetic regulations. Mutat Res Rev Mutat Res. 2017 Apr-Jun;772:36-50. doi: 10.1016/j.mrrev.2016.09.006. Epub 2016 Sep 19.

  PMID: 28528689 BACKGROUND

• Li H, Chiappinelli KB, Guzzetta AA, Easwaran H, Yen RW, Vatapalli R, Topper MJ, Luo J, Connolly RM, Azad NS, Stearns V, Pardoll DM, Davidson N, Jones PA, Slamon DJ, Baylin SB, Zahnow CA, Ahuja N. Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget. 2014 Feb 15;5(3):587-98. doi: 10.18632/oncotarget.1782.

  PMID: 24583822 BACKGROUND

• Mikovits JA, Young HA, Vertino P, Issa JP, Pitha PM, Turcoski-Corrales S, Taub DD, Petrow CL, Baylin SB, Ruscetti FW. Infection with human immunodeficiency virus type 1 upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-gamma) promoter and subsequent downregulation of IFN-gamma production. Mol Cell Biol. 1998 Sep;18(9):5166-77. doi: 10.1128/MCB.18.9.5166.

  PMID: 9710601 BACKGROUND

• Wen H, Dou Y, Hogaboam CM, Kunkel SL. Epigenetic regulation of dendritic cell-derived interleukin-12 facilitates immunosuppression after a severe innate immune response. Blood. 2008 Feb 15;111(4):1797-804. doi: 10.1182/blood-2007-08-106443. Epub 2007 Nov 30.

  PMID: 18055863 BACKGROUND

• Sahiratmadja E, Alisjahbana B, de Boer T, Adnan I, Maya A, Danusantoso H, Nelwan RH, Marzuki S, van der Meer JW, van Crevel R, van de Vosse E, Ottenhoff TH. Dynamic changes in pro- and anti-inflammatory cytokine profiles and gamma interferon receptor signaling integrity correlate with tuberculosis disease activity and response to curative treatment. Infect Immun. 2007 Feb;75(2):820-9. doi: 10.1128/IAI.00602-06. Epub 2006 Dec 4.

  PMID: 17145950 BACKGROUND

• Zumla A, Rao M, Dodoo E, Maeurer M. Potential of immunomodulatory agents as adjunct host-directed therapies for multidrug-resistant tuberculosis. BMC Med. 2016 Jun 15;14:89. doi: 10.1186/s12916-016-0635-1.

  PMID: 27301245 BACKGROUND

• Tough DF, Tak PP, Tarakhovsky A, Prinjha RK. Epigenetic drug discovery: breaking through the immune barrier. Nat Rev Drug Discov. 2016 Dec;15(12):835-853. doi: 10.1038/nrd.2016.185. Epub 2016 Oct 21.

  PMID: 27765940 BACKGROUND

• Maio M, Covre A, Fratta E, Di Giacomo AM, Taverna P, Natali PG, Coral S, Sigalotti L. Molecular Pathways: At the Crossroads of Cancer Epigenetics and Immunotherapy. Clin Cancer Res. 2015 Sep 15;21(18):4040-7. doi: 10.1158/1078-0432.CCR-14-2914.

  PMID: 26374074 BACKGROUND

• Tumes DJ, Onodera A, Suzuki A, Shinoda K, Endo Y, Iwamura C, Hosokawa H, Koseki H, Tokoyoda K, Suzuki Y, Motohashi S, Nakayama T. The polycomb protein Ezh2 regulates differentiation and plasticity of CD4(+) T helper type 1 and type 2 cells. Immunity. 2013 Nov 14;39(5):819-32. doi: 10.1016/j.immuni.2013.09.012.

  PMID: 24238339 BACKGROUND

• Cole J, Morris P, Dickman MJ, Dockrell DH. The therapeutic potential of epigenetic manipulation during infectious diseases. Pharmacol Ther. 2016 Nov;167:85-99. doi: 10.1016/j.pharmthera.2016.07.013. Epub 2016 Aug 9.

  PMID: 27519803 BACKGROUND

• DuPage M, Bluestone JA. Harnessing the plasticity of CD4(+) T cells to treat immune-mediated disease. Nat Rev Immunol. 2016 Mar;16(3):149-63. doi: 10.1038/nri.2015.18. Epub 2016 Feb 15.

  PMID: 26875830 BACKGROUND

• Wrangle J, Wang W, Koch A, Easwaran H, Mohammad HP, Vendetti F, Vancriekinge W, Demeyer T, Du Z, Parsana P, Rodgers K, Yen RW, Zahnow CA, Taube JM, Brahmer JR, Tykodi SS, Easton K, Carvajal RD, Jones PA, Laird PW, Weisenberger DJ, Tsai S, Juergens RA, Topalian SL, Rudin CM, Brock MV, Pardoll D, Baylin SB. Alterations of immune response of Non-Small Cell Lung Cancer with Azacytidine. Oncotarget. 2013 Nov;4(11):2067-79. doi: 10.18632/oncotarget.1542.

  PMID: 24162015 BACKGROUND

• Ghoneim HE, Fan Y, Moustaki A, Abdelsamed HA, Dash P, Dogra P, Carter R, Awad W, Neale G, Thomas PG, Youngblood B. De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation. Cell. 2017 Jun 29;170(1):142-157.e19. doi: 10.1016/j.cell.2017.06.007. Epub 2017 Jun 22.

  PMID: 28648661 BACKGROUND

• Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, Hein A, Rote NS, Cope LM, Snyder A, Makarov V, Budhu S, Slamon DJ, Wolchok JD, Pardoll DM, Beckmann MW, Zahnow CA, Merghoub T, Chan TA, Baylin SB, Strick R. Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses. Cell. 2015 Aug 27;162(5):974-86. doi: 10.1016/j.cell.2015.07.011.

  PMID: 26317466 BACKGROUND

• Scarpa M, Scarpa M, Castagliuolo I, Erroi F, Basato S, Brun P, Angriman I, Castoro C. CD80 down-regulation is associated to aberrant DNA methylation in non-inflammatory colon carcinogenesis. BMC Cancer. 2016 Jul 4;16:388. doi: 10.1186/s12885-016-2405-z.

  PMID: 27377375 BACKGROUND

• Wang LX, Mei ZY, Zhou JH, Yao YS, Li YH, Xu YH, Li JX, Gao XN, Zhou MH, Jiang MM, Gao L, Ding Y, Lu XC, Shi JL, Luo XF, Wang J, Wang LL, Qu C, Bai XF, Yu L. Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses. PLoS One. 2013 May 9;8(5):e62924. doi: 10.1371/journal.pone.0062924. Print 2013.

  PMID: 23671644 BACKGROUND

• Wang L, Amoozgar Z, Huang J, Saleh MH, Xing D, Orsulic S, Goldberg MS. Decitabine Enhances Lymphocyte Migration and Function and Synergizes with CTLA-4 Blockade in a Murine Ovarian Cancer Model. Cancer Immunol Res. 2015 Sep;3(9):1030-41. doi: 10.1158/2326-6066.CIR-15-0073. Epub 2015 Jun 8.

  PMID: 26056145 BACKGROUND

• Laille E, Shi T, Garcia-Manero G, Cogle CR, Gore SD, Hetzer J, Kumar K, Skikne B, MacBeth KJ. Pharmacokinetics and Pharmacodynamics with Extended Dosing of CC-486 in Patients with Hematologic Malignancies. PLoS One. 2015 Aug 21;10(8):e0135520. doi: 10.1371/journal.pone.0135520. eCollection 2015.

  PMID: 26296092 BACKGROUND

• Griffiths EA, Srivastava P, Matsuzaki J, Brumberger Z, Wang ES, Kocent J, Miller A, Roloff GW, Wong HY, Paluch BE, Lutgen-Dunckley LG, Martens BL, Odunsi K, Karpf AR, Hourigan CS, Nemeth MJ. NY-ESO-1 Vaccination in Combination with Decitabine Induces Antigen-Specific T-lymphocyte Responses in Patients with Myelodysplastic Syndrome. Clin Cancer Res. 2018 Mar 1;24(5):1019-1029. doi: 10.1158/1078-0432.CCR-17-1792. Epub 2017 Sep 25.

  PMID: 28947565 BACKGROUND

• Vasu S, He S, Cheney C, Gopalakrishnan B, Mani R, Lozanski G, Mo X, Groh V, Whitman SP, Konopitzky R, Kossl C, Bucci D, Lucas DM, Yu J, Caligiuri MA, Blum W, Adam PJ, Borges E, Rueter B, Heider KH, Marcucci G, Muthusamy N. Decitabine enhances anti-CD33 monoclonal antibody BI 836858-mediated natural killer ADCC against AML blasts. Blood. 2016 Jun 9;127(23):2879-89. doi: 10.1182/blood-2015-11-680546. Epub 2016 Mar 24.

  PMID: 27013443 BACKGROUND

• Chen J, Lopez-Moyado IF, Seo H, Lio CJ, Hempleman LJ, Sekiya T, Yoshimura A, Scott-Browne JP, Rao A. NR4A transcription factors limit CAR T cell function in solid tumours. Nature. 2019 Mar;567(7749):530-534. doi: 10.1038/s41586-019-0985-x. Epub 2019 Feb 27.

  PMID: 30814732 BACKGROUND

• Martinez GJ, Pereira RM, Aijo T, Kim EY, Marangoni F, Pipkin ME, Togher S, Heissmeyer V, Zhang YC, Crotty S, Lamperti ED, Ansel KM, Mempel TR, Lahdesmaki H, Hogan PG, Rao A. The transcription factor NFAT promotes exhaustion of activated CD8(+) T cells. Immunity. 2015 Feb 17;42(2):265-278. doi: 10.1016/j.immuni.2015.01.006. Epub 2015 Feb 10.

  PMID: 25680272 BACKGROUND

• Ahn E, Youngblood B, Lee J, Lee J, Sarkar S, Ahmed R. Demethylation of the PD-1 Promoter Is Imprinted during the Effector Phase of CD8 T Cell Exhaustion. J Virol. 2016 Sep 12;90(19):8934-46. doi: 10.1128/JVI.00798-16. Print 2016 Oct 1.

  PMID: 27466420 BACKGROUND

• Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P, Utzschneider DT, von Hoesslin M, Cullen JG, Fan Y, Eisenberg V, Wohlleber D, Steiger K, Merkler D, Delorenzi M, Knolle PA, Cohen CJ, Thimme R, Youngblood B, Zehn D. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature. 2019 Jul;571(7764):265-269. doi: 10.1038/s41586-019-1326-9. Epub 2019 Jun 17.

  PMID: 31207605 BACKGROUND

• Nakayama-Hosoya K, Ishida T, Youngblood B, Nakamura H, Hosoya N, Koga M, Koibuchi T, Iwamoto A, Kawana-Tachikawa A. Epigenetic repression of interleukin 2 expression in senescent CD4+ T cells during chronic HIV type 1 infection. J Infect Dis. 2015 Jan 1;211(1):28-39. doi: 10.1093/infdis/jiu376. Epub 2014 Jul 7.

  PMID: 25001463 BACKGROUND

• Scharer CD, Barwick BG, Youngblood BA, Ahmed R, Boss JM. Global DNA methylation remodeling accompanies CD8 T cell effector function. J Immunol. 2013 Sep 15;191(6):3419-29. doi: 10.4049/jimmunol.1301395. Epub 2013 Aug 16.

  PMID: 23956425 BACKGROUND

• Youngblood B, Reich NO. The early expressed HIV-1 genes regulate DNMT1 expression. Epigenetics. 2008 May-Jun;3(3):149-56. doi: 10.4161/epi.3.3.6372. Epub 2008 May 31.

  PMID: 18567946 BACKGROUND

• Botha T, Ryffel B. Reactivation of latent tuberculosis infection in TNF-deficient mice. J Immunol. 2003 Sep 15;171(6):3110-8. doi: 10.4049/jimmunol.171.6.3110.

  PMID: 12960337 BACKGROUND

• Ehlers S. Role of tumour necrosis factor (TNF) in host defence against tuberculosis: implications for immunotherapies targeting TNF. Ann Rheum Dis. 2003 Nov;62 Suppl 2(Suppl 2):ii37-42. doi: 10.1136/ard.62.suppl_2.ii37.

  PMID: 14532147 BACKGROUND

• Linnekamp JF, Butter R, Spijker R, Medema JP, van Laarhoven HWM. Clinical and biological effects of demethylating agents on solid tumours - A systematic review. Cancer Treat Rev. 2017 Mar;54:10-23. doi: 10.1016/j.ctrv.2017.01.004. Epub 2017 Jan 18.

  PMID: 28189913 BACKGROUND

• Garcia-Manero G, Gore SD, Cogle C, Ward R, Shi T, Macbeth KJ, Laille E, Giordano H, Sakoian S, Jabbour E, Kantarjian H, Skikne B. Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J Clin Oncol. 2011 Jun 20;29(18):2521-7. doi: 10.1200/JCO.2010.34.4226. Epub 2011 May 16.

  PMID: 21576646 BACKGROUND

• Bernstein I, Byun HM, Mohrbacher A, Douer D, Gorospe G 3rd, Hergesheimer J, Groshen S, O'Connell C, Yang AS. A phase I biological study of azacitidine (Vidaza) to determine the optimal dose to inhibit DNA methylation. Epigenetics. 2010 Nov-Dec;5(8):750-7. doi: 10.4161/epi.5.8.13105. Epub 2010 Nov 1.

  PMID: 20861661 BACKGROUND

• Savona MR, Kolibaba K, Conkling P, Kingsley EC, Becerra C, Morris JC, Rifkin RM, Laille E, Kellerman A, Ukrainskyj SM, Dong Q, Skikne BS. Extended dosing with CC-486 (oral azacitidine) in patients with myeloid malignancies. Am J Hematol. 2018 Oct;93(10):1199-1206. doi: 10.1002/ajh.25216. Epub 2018 Sep 3.

  PMID: 30016552 BACKGROUND

• Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015 Aug;15(8):486-99. doi: 10.1038/nri3862.

  PMID: 26205583 BACKGROUND

• Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE, Attanasio J, Stelekati E, McLane LM, Paley MA, Delgoffe GM, Wherry EJ. Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion. Immunity. 2016 Aug 16;45(2):358-73. doi: 10.1016/j.immuni.2016.07.008. Epub 2016 Aug 2.

  PMID: 27496729 BACKGROUND

• Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, Khan O, Drake AM, Chen Z, Sen DR, Kurachi M, Barnitz RA, Bartman C, Bengsch B, Huang AC, Schenkel JM, Vahedi G, Haining WN, Berger SL, Wherry EJ. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science. 2016 Dec 2;354(6316):1160-1165. doi: 10.1126/science.aaf2807. Epub 2016 Oct 27.

  PMID: 27789795 BACKGROUND

• Sen DR, Kaminski J, Barnitz RA, Kurachi M, Gerdemann U, Yates KB, Tsao HW, Godec J, LaFleur MW, Brown FD, Tonnerre P, Chung RT, Tully DC, Allen TM, Frahm N, Lauer GM, Wherry EJ, Yosef N, Haining WN. The epigenetic landscape of T cell exhaustion. Science. 2016 Dec 2;354(6316):1165-1169. doi: 10.1126/science.aae0491. Epub 2016 Oct 27.

  PMID: 27789799 BACKGROUND

• Singal R, Ramachandran K, Gordian E, Quintero C, Zhao W, Reis IM. Phase I/II study of azacitidine, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy. Clin Genitourin Cancer. 2015 Feb;13(1):22-31. doi: 10.1016/j.clgc.2014.07.008. Epub 2014 Aug 1.

  PMID: 25178642 BACKGROUND

• Schneider BJ, Shah MA, Klute K, Ocean A, Popa E, Altorki N, Lieberman M, Schreiner A, Yantiss R, Christos PJ, Palmer R, You D, Viale A, Kermani P, Scandura JM. Phase I Study of Epigenetic Priming with Azacitidine Prior to Standard Neoadjuvant Chemotherapy for Patients with Resectable Gastric and Esophageal Adenocarcinoma: Evidence of Tumor Hypomethylation as an Indicator of Major Histopathologic Response. Clin Cancer Res. 2017 Jun 1;23(11):2673-2680. doi: 10.1158/1078-0432.CCR-16-1896. Epub 2016 Nov 10.

  PMID: 27836862 BACKGROUND

• Juergens RA, Wrangle J, Vendetti FP, Murphy SC, Zhao M, Coleman B, Sebree R, Rodgers K, Hooker CM, Franco N, Lee B, Tsai S, Delgado IE, Rudek MA, Belinsky SA, Herman JG, Baylin SB, Brock MV, Rudin CM. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 2011 Dec;1(7):598-607. doi: 10.1158/2159-8290.CD-11-0214. Epub 2011 Nov 9.

  PMID: 22586682 BACKGROUND

• Fu S, Hu W, Iyer R, Kavanagh JJ, Coleman RL, Levenback CF, Sood AK, Wolf JK, Gershenson DM, Markman M, Hennessy BT, Kurzrock R, Bast RC Jr. Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer. Cancer. 2011 Apr 15;117(8):1661-9. doi: 10.1002/cncr.25701. Epub 2010 Nov 8.

  PMID: 21472713 BACKGROUND

• Cohen AL, Ray A, Van Brocklin M, Burnett DM, Bowen RC, Dyess DL, Butler TW, Dumlao T, Khong HT. A phase I trial of azacitidine and nanoparticle albumin bound paclitaxel in patients with advanced or metastatic solid tumors. Oncotarget. 2016 Dec 26;8(32):52413-52419. doi: 10.18632/oncotarget.14183. eCollection 2017 Aug 8.

  PMID: 28881739 BACKGROUND

• DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, Frankfurt O, Konopleva M, Wei AH, Kantarjian HM, Xu T, Hong WJ, Chyla B, Potluri J, Pollyea DA, Letai A. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019 Jan 3;133(1):7-17. doi: 10.1182/blood-2018-08-868752. Epub 2018 Oct 25.

  PMID: 30361262 BACKGROUND

• Tyrrell FC, Budnick GE, Elliott T, Gillim-Ross L, Hildred MV, Mahlmeister P, Parrish N, Pentella M, Vanneste J, Wang YF, Starks AM. Probability of negative mycobacterium tuberculosis complex cultures based on time to detection of positive cultures: a multicenter evaluation of commercial-broth-based culture systems. J Clin Microbiol. 2012 Oct;50(10):3275-82. doi: 10.1128/JCM.01225-12. Epub 2012 Jul 25.

  PMID: 22837326 BACKGROUND

• Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, Chaisson LH, Chaisson RE, Daley CL, Grzemska M, Higashi JM, Ho CS, Hopewell PC, Keshavjee SA, Lienhardt C, Menzies R, Merrifield C, Narita M, O'Brien R, Peloquin CA, Raftery A, Saukkonen J, Schaaf HS, Sotgiu G, Starke JR, Migliori GB, Vernon A. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis. 2016 Oct 1;63(7):e147-e195. doi: 10.1093/cid/ciw376. Epub 2016 Aug 10.

  PMID: 27516382 BACKGROUND

• DiNardo AR, Nishiguchi T, Mace EM, Rajapakshe K, Mtetwa G, Kay A, Maphalala G, Secor WE, Mejia R, Orange JS, Coarfa C, Bhalla KN, Graviss EA, Mandalakas AM, Makedonas G. Schistosomiasis Induces Persistent DNA Methylation and Tuberculosis-Specific Immune Changes. J Immunol. 2018 Jul 1;201(1):124-133. doi: 10.4049/jimmunol.1800101. Epub 2018 May 11.

  PMID: 29752313 BACKGROUND

• Carson WF, Cavassani KA, Dou Y, Kunkel SL. Epigenetic regulation of immune cell functions during post-septic immunosuppression. Epigenetics. 2011 Mar;6(3):273-83. doi: 10.4161/epi.6.3.14017. Epub 2011 Mar 1.

  PMID: 21048427 BACKGROUND

• Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD, Irizarry RA. Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. 2014 May 15;30(10):1363-9. doi: 10.1093/bioinformatics/btu049. Epub 2014 Jan 28.

  PMID: 24478339 BACKGROUND

• Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015 Dec 23;1(6):417-425. doi: 10.1016/j.cels.2015.12.004.

  PMID: 26771021 BACKGROUND

• Onuchic V, Hartmaier RJ, Boone DN, Samuels ML, Patel RY, White WM, Garovic VD, Oesterreich S, Roth ME, Lee AV, Milosavljevic A. Epigenomic Deconvolution of Breast Tumors Reveals Metabolic Coupling between Constituent Cell Types. Cell Rep. 2016 Nov 15;17(8):2075-2086. doi: 10.1016/j.celrep.2016.10.057.

  PMID: 27851969 BACKGROUND

• Lutsik P, Slawski M, Gasparoni G, Vedeneev N, Hein M, Walter J. MeDeCom: discovery and quantification of latent components of heterogeneous methylomes. Genome Biol. 2017 Mar 24;18(1):55. doi: 10.1186/s13059-017-1182-6.

  PMID: 28340624 BACKGROUND

• Wallis RS, Vinhas SA, Johnson JL, Ribeiro FC, Palaci M, Peres RL, Sa RT, Dietze R, Chiunda A, Eisenach K, Ellner JJ. Whole blood bactericidal activity during treatment of pulmonary tuberculosis. J Infect Dis. 2003 Jan 15;187(2):270-8. doi: 10.1086/346053. Epub 2003 Jan 6.

  PMID: 12552451 BACKGROUND

• Gurumurthy M, Verma R, Naftalin CM, Hee KH, Lu Q, Tan KH, Issac S, Lin W, Tan A, Seng KY, Lee LS, Paton NI. Activity of faropenem with and without rifampicin against Mycobacterium tuberculosis: evaluation in a whole-blood bactericidal activity trial. J Antimicrob Chemother. 2017 Jul 1;72(7):2012-2019. doi: 10.1093/jac/dkx081.

  PMID: 28333342 BACKGROUND

• Wallis RS, Jakubiec W, Mitton-Fry M, Ladutko L, Campbell S, Paige D, Silvia A, Miller PF. Rapid evaluation in whole blood culture of regimens for XDR-TB containing PNU-100480 (sutezolid), TMC207, PA-824, SQ109, and pyrazinamide. PLoS One. 2012;7(1):e30479. doi: 10.1371/journal.pone.0030479. Epub 2012 Jan 18.

  PMID: 22279595 BACKGROUND

• Fletcher HA, Tanner R, Wallis RS, Meyer J, Manjaly ZR, Harris S, Satti I, Silver RF, Hoft D, Kampmann B, Walker KB, Dockrell HM, Fruth U, Barker L, Brennan MJ, McShane H. Inhibition of mycobacterial growth in vitro following primary but not secondary vaccination with Mycobacterium bovis BCG. Clin Vaccine Immunol. 2013 Nov;20(11):1683-9. doi: 10.1128/CVI.00427-13. Epub 2013 Aug 28.

  PMID: 23986316 BACKGROUND

• Jayashankar L, Hafner R. Adjunct Strategies for Tuberculosis Vaccines: Modulating Key Immune Cell Regulatory Mechanisms to Potentiate Vaccination. Front Immunol. 2016 Dec 16;7:577. doi: 10.3389/fimmu.2016.00577. eCollection 2016.

  PMID: 28018344 BACKGROUND

• Joosten SA, van Meijgaarden KE, Arend SM, Prins C, Oftung F, Korsvold GE, Kik SV, Arts RJ, van Crevel R, Netea MG, Ottenhoff TH. Mycobacterial growth inhibition is associated with trained innate immunity. J Clin Invest. 2018 May 1;128(5):1837-1851. doi: 10.1172/JCI97508. Epub 2018 Apr 3.

  PMID: 29461976 BACKGROUND

• Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, Albright A, Cheng JD, Kang SP, Shankaran V, Piha-Paul SA, Yearley J, Seiwert TY, Ribas A, McClanahan TK. IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017 Aug 1;127(8):2930-2940. doi: 10.1172/JCI91190. Epub 2017 Jun 26.

  PMID: 28650338 BACKGROUND

• Waddell SJ, Popper SJ, Rubins KH, Griffiths MJ, Brown PO, Levin M, Relman DA. Dissecting interferon-induced transcriptional programs in human peripheral blood cells. PLoS One. 2010 Mar 22;5(3):e9753. doi: 10.1371/journal.pone.0009753.

  PMID: 20339534 BACKGROUND

• Verma D, Parasa VR, Raffetseder J, Martis M, Mehta RB, Netea M, Lerm M. Anti-mycobacterial activity correlates with altered DNA methylation pattern in immune cells from BCG-vaccinated subjects. Sci Rep. 2017 Sep 26;7(1):12305. doi: 10.1038/s41598-017-12110-2.

  PMID: 28951586 BACKGROUND

• Tsai PC, Bell JT. Power and sample size estimation for epigenome-wide association scans to detect differential DNA methylation. Int J Epidemiol. 2015 Aug;44(4):1429-1441. doi: 10.1093/ije/dyv041. Epub 2015 May 13.

  PMID: 25972603 BACKGROUND

• Cook PC, Owen H, Deaton AM, Borger JG, Brown SL, Clouaire T, Jones GR, Jones LH, Lundie RJ, Marley AK, Morrison VL, Phythian-Adams AT, Wachter E, Webb LM, Sutherland TE, Thomas GD, Grainger JR, Selfridge J, McKenzie AN, Allen JE, Fagerholm SC, Maizels RM, Ivens AC, Bird A, MacDonald AS. A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells. Nat Commun. 2015 Apr 24;6:6920. doi: 10.1038/ncomms7920.

  PMID: 25908537 BACKGROUND

• Imperial MZ, Nahid P, Phillips PPJ, Davies GR, Fielding K, Hanna D, Hermann D, Wallis RS, Johnson JL, Lienhardt C, Savic RM. A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis. Nat Med. 2018 Nov;24(11):1708-1715. doi: 10.1038/s41591-018-0224-2. Epub 2018 Nov 5.

  PMID: 30397355 BACKGROUND

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis

Interventions

Azacitidine

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Andrew DiNardo

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator / Assistant Professor

Model Details: This study is a Phase Ib/IIa single-institution, open-label, non-randomized clinical trial of using azacitidine in pulmonary TB patients during the continuation phase of ATT.

Study Record Dates

• First Submitted: May 6, 2019
• First Posted: May 8, 2019
• Study Start: October 1, 2022
• Primary Completion: May 1, 2023
• Study Completion: May 1, 2023
• Last Updated: February 8, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)