A Study to Investigate Treatment of HU and VPA, or 6-MP and VPA in Unfit AML/HR-MDS Patients

Summary

The purpose of this study is to investigate the safety, tolerability, and preliminary efficacy of the combination treatment of hydroxyurea capsules and valproic acid capsules, or the combination treatment of 6-mercaptopurine tablets and valproic acid capsules in male and female patients aged 18 years or older with acute myeloid leukemia or high- risk myelodysplastic syndrome. The population to be studied is newly diagnosed AML patients who are considered unfit for standard induction chemotherapy, HR-MDS unfit/ineligible for standard treatment, and relapsed/refractory AML/HR-MDS patients who are considered unfit for standard therapy ,or are, for some reason, ineligible for another type of therapy. Clinically, hydroxyurea, valproic acid and 6-mercaptopurine are historically very well-known therapeutic agents with low toxicity profiles. The rationale for this study is that the combination of these drugs with low toxicity will be well tolerated in elderly AML patients with comorbidities, or lower performance status. This combination could have a beneficial therapeutic effect on overall survival and contribute to a better quality of life.

Timeline

Start

2024-05-23

Primary completion

2025-11-30

Completion

2029-09-30

Publications

• Background Dohner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, Ebert BL, Fenaux P, Godley LA, Hasserjian RP, Larson RA, Levine RL, Miyazaki Y, Niederwieser D, Ossenkoppele G, Rollig C, Sierra J, Stein EM, Tallman MS, Tien HF, Wang J, Wierzbowska A, Lowenberg B. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022 Sep 22;140(12):1345-1377. doi: 10.1182/blood.2022016867.
• Background Lowenberg B, Downing JR, Burnett A. Acute myeloid leukemia. N Engl J Med. 1999 Sep 30;341(14):1051-62. doi: 10.1056/NEJM199909303411407. No abstract available.
• Background Musialek MW, Rybaczek D. Hydroxyurea-The Good, the Bad and the Ugly. Genes (Basel). 2021 Jul 19;12(7):1096. doi: 10.3390/genes12071096.
• Background Fredly H, Gjertsen BT, Bruserud O. Histone deacetylase inhibition in the treatment of acute myeloid leukemia: the effects of valproic acid on leukemic cells, and the clinical and experimental evidence for combining valproic acid with other antileukemic agents. Clin Epigenetics. 2013 Jul 30;5(1):12. doi: 10.1186/1868-7083-5-12.
• Background Leitch C, Osdal T, Andresen V, Molland M, Kristiansen S, Nguyen XN, Bruserud O, Gjertsen BT, McCormack E. Hydroxyurea synergizes with valproic acid in wild-type p53 acute myeloid leukaemia. Oncotarget. 2016 Feb 16;7(7):8105-18. doi: 10.18632/oncotarget.6991.
• Background Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR; International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009 Mar;10(3):223-32. doi: 10.1016/S1470-2045(09)70003-8. Epub 2009 Feb 21.
• Background Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F, Cortes J, Wierda WG, Ouzounian S, Quezada A, Pierce S, Estey EH, Issa JP, Kantarjian HM, Garcia-Manero G. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007 Oct 1;110(7):2302-8. doi: 10.1182/blood-2007-03-078576. Epub 2007 Jun 27.
• Background Chateauvieux S, Morceau F, Dicato M, Diederich M. Molecular and therapeutic potential and toxicity of valproic acid. J Biomed Biotechnol. 2010;2010:479364. doi: 10.1155/2010/479364. Epub 2010 Jul 29.
• Background Tassara M, Dohner K, Brossart P, Held G, Gotze K, Horst HA, Ringhoffer M, Kohne CH, Kremers S, Raghavachar A, Wulf G, Kirchen H, Nachbaur D, Derigs HG, Wattad M, Koller E, Brugger W, Matzdorff A, Greil R, Heil G, Paschka P, Gaidzik VI, Gottlicher M, Dohner H, Schlenk RF. Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients. Blood. 2014 Jun 26;123(26):4027-36. doi: 10.1182/blood-2013-12-546283. Epub 2014 May 5.
• Background Elion GB. Historical background of 6-mercaptopurine. Toxicol Ind Health. 1986 Sep;2(2):1-9. doi: 10.1177/074823378600200201. No abstract available.
• Background BURCHENAL JH, MURPHY ML, ELLISON RR, SYKES MP, TAN TC, LEONE LA, KARNOFSKY DA, CRAVER LF, DARGEON HW, RHOADS CP. Clinical evaluation of a new antimetabolite, 6-mercaptopurine, in the treatment of leukemia and allied diseases. Blood. 1953 Nov;8(11):965-99. No abstract available.
• Background Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011 Feb 10;29(5):487-94. doi: 10.1200/JCO.2010.30.1820. Epub 2011 Jan 10.
• Background Estey E. Acute myeloid leukemia and myelodysplastic syndromes in older patients. J Clin Oncol. 2007 May 10;25(14):1908-15. doi: 10.1200/JCO.2006.10.2731.
• Background Hiddemann W, Kern W, Schoch C, Fonatsch C, Heinecke A, Wormann B, Buchner T. Management of acute myeloid leukemia in elderly patients. J Clin Oncol. 1999 Nov;17(11):3569-76. doi: 10.1200/JCO.1999.17.11.3569.
• Background Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysak D, Minden M, Arthur C. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012 Jul 20;30(21):2670-7. doi: 10.1200/JCO.2011.38.9429. Epub 2012 Jun 11.
• Background Wei AH, Panayiotidis P, Montesinos P, Laribi K, Ivanov V, Kim I, Novak J, Stevens DA, Fiedler W, Pagoni M, Bergeron J, Ting SB, Hou JZ, Anagnostopoulos A, McDonald A, Murthy V, Yamauchi T, Wang J, Chyla B, Sun Y, Jiang Q, Mendes W, Hayslip J, DiNardo CD. 6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy (141/150). Blood Cancer J. 2021 Oct 1;11(10):163. doi: 10.1038/s41408-021-00555-8.
• Background Pollyea DA, DiNardo CD, Arellano ML, Pigneux A, Fiedler W, Konopleva M, Rizzieri DA, Smith BD, Shinagawa A, Lemoli RM, Dail M, Duan Y, Chyla B, Potluri J, Miller CL, Kantarjian HM. Impact of Venetoclax and Azacitidine in Treatment-Naive Patients with Acute Myeloid Leukemia and IDH1/2 Mutations. Clin Cancer Res. 2022 Jul 1;28(13):2753-2761. doi: 10.1158/1078-0432.CCR-21-3467.
• Background Steensma DP, Tefferi A. The myelodysplastic syndrome(s): a perspective and review highlighting current controversies. Leuk Res. 2003 Feb;27(2):95-120. doi: 10.1016/s0145-2126(02)00098-x.
• Background Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Krieger O, Luebbert M, Maciejewski J, Magalhaes SM, Miyazaki Y, Pfeilstocker M, Sekeres M, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012 Sep 20;120(12):2454-65. doi: 10.1182/blood-2012-03-420489. Epub 2012 Jun 27.
• Background Catenacci DV, Schiller GJ. Myelodysplasic syndromes: a comprehensive review. Blood Rev. 2005 Nov;19(6):301-19. doi: 10.1016/j.blre.2005.01.004.
• Background Greenberg PL, Stone RM, Al-Kali A, Barta SK, Bejar R, Bennett JM, Carraway H, De Castro CM, Deeg HJ, DeZern AE, Fathi AT, Frankfurt O, Gaensler K, Garcia-Manero G, Griffiths EA, Head D, Horsfall R, Johnson RA, Juckett M, Klimek VM, Komrokji R, Kujawski LA, Maness LJ, O'Donnell MR, Pollyea DA, Shami PJ, Stein BL, Walker AR, Westervelt P, Zeidan A, Shead DA, Smith C. Myelodysplastic Syndromes, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017 Jan;15(1):60-87. doi: 10.6004/jnccn.2017.0007.
• Background Lubbert M. DNA methylation inhibitors in the treatment of leukemias, myelodysplastic syndromes and hemoglobinopathies: clinical results and possible mechanisms of action. Curr Top Microbiol Immunol. 2000;249:135-64. doi: 10.1007/978-3-642-59696-4_9. No abstract available.
• Background Pfeilstocker M, Tuechler H, Sanz G, Schanz J, Garcia-Manero G, Sole F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Levis A, Luebbert M, Maciejewski J, Machherndl-Spandl S, Magalhaes SM, Miyazaki Y, Sekeres MA, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D, Greenberg PL. Time-dependent changes in mortality and transformation risk in MDS. Blood. 2016 Aug 18;128(7):902-10. doi: 10.1182/blood-2016-02-700054. Epub 2016 Jun 22.
• Background Rowley JD, Golomb HM, Dougherty C. 15/17 translocation, a consistent chromosomal change in acute promyelocytic leukaemia. Lancet. 1977 Mar 5;1(8010):549-50. doi: 10.1016/s0140-6736(77)91415-5. No abstract available.
• Background Grignani F, Ferrucci PF, Testa U, Talamo G, Fagioli M, Alcalay M, Mencarelli A, Grignani F, Peschle C, Nicoletti I, et al. The acute promyelocytic leukemia-specific PML-RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell. 1993 Aug 13;74(3):423-31. doi: 10.1016/0092-8674(93)80044-f.
• Background Lo-Coco F, Cicconi L. History of acute promyelocytic leukemia: a tale of endless revolution. Mediterr J Hematol Infect Dis. 2011;3(1):e2011067. doi: 10.4084/MJHID.2011.067. Epub 2011 Dec 21. No abstract available.
• Background Breitman TR, Selonick SE, Collins SJ. Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc Natl Acad Sci U S A. 1980 May;77(5):2936-40. doi: 10.1073/pnas.77.5.2936.
• Background Park JH, Qiao B, Panageas KS, Schymura MJ, Jurcic JG, Rosenblat TL, Altman JK, Douer D, Rowe JM, Tallman MS. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood. 2011 Aug 4;118(5):1248-54. doi: 10.1182/blood-2011-04-346437. Epub 2011 Jun 8.
• Background Mantha S, Tallman MS, Devlin SM, Soff GA. Predictive factors of fatal bleeding in acute promyelocytic leukemia. Thromb Res. 2018 Apr;164 Suppl 1:S98-S102. doi: 10.1016/j.thromres.2018.01.038.
• Background Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E, Faderl S, O'Brien S, Wierda W, Pierce S, Brandt M, McCue D, Luthra R, Patel K, Kornblau S, Kadia T, Daver N, DiNardo C, Jain N, Verstovsek S, Ferrajoli A, Andreeff M, Konopleva M, Estrov Z, Foudray M, McCue D, Cortes J, Ravandi F. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood. 2017 Mar 9;129(10):1275-1283. doi: 10.1182/blood-2016-09-736686. Epub 2016 Dec 21.
• Background Iland HJ, Collins M, Bradstock K, Supple SG, Catalano A, Hertzberg M, Browett P, Grigg A, Firkin F, Campbell LJ, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R, Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial. Lancet Haematol. 2015 Sep;2(9):e357-66. doi: 10.1016/S2352-3026(15)00115-5. Epub 2015 Aug 20.
• Background Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Woods WG, Ogden A, Weinstein H, Shepherd L, Willman C, Bloomfield CD, Rowe JM, Wiernik PH. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood. 2002 Dec 15;100(13):4298-302. doi: 10.1182/blood-2002-02-0632. Epub 2002 Aug 15.
• Background Dresler WFC, Stein R. Über den hydroxylharnstoff. Justus Liebigs Ann Chem. 1869;150:242- 52. https://doi.org/10.1002/jlac.18691500212.
• Background Lancet JE, Moseley A, Komrokji RS, Coutre SE, DeAngelo DJ, Tallman MS, Litzow M, Othus M, Appelbaum FR. ATRA, Arsenic Trioxide (ATO), and Gemtuzumab Ozogamicin (GO) Is Safe and Highly Effective in Patients with Previously Untreated High-Risk Acute Promyelocytic Leukemia (APL): Final Results of the SWOG/Alliance/ ECOG S0535 Trial. Blood. 2016; 128:896. https://doi. org/10.1182/blood.V128.22.896.896
• Background Rosenthal F, Wislicki L, Kollek L: Über die Beziehungen von schwersten Blutgiften zu Abbauproducten des Eiweisses: ein Beitrag zum Einstehungsmechanismus der perniziösen änamie. Klin Wochenschr 7:972-977, 1928
• Background STEARNS B, LOSEE KA, BERNSTEIN J. HYDROXYUREA. A NEW TYPE OF POTENTIAL ANTITUMOR AGENT. J Med Chem. 1963 Mar;6:201. doi: 10.1021/jm00338a026. No abstract available.
• Background Gwilt PR, Tracewell WG. Pharmacokinetics and pharmacodynamics of hydroxyurea. Clin Pharmacokinet. 1998 May;34(5):347-58. doi: 10.2165/00003088-199834050-00002.
• Background Leavell UW Jr, Yarbro JW. Hydroxyurea. A new treatment for psoriasis. Arch Dermatol. 1970 Aug;102(2):144-50. doi: 10.1001/archderm.102.2.144. No abstract available.
• Background Cannas G, Poutrel S, Thomas X. Hydroxycarbamine: from an Old Drug Used in Malignant Hemopathies to a Current Standard in Sickle Cell Disease. Mediterr J Hematol Infect Dis. 2017 Feb 15;9(1):e2017015. doi: 10.4084/MJHID.2017.015. eCollection 2017.
• Background BS B. On the propyl derivatives and decomposition products of ethylacetoacetate. Am Chem J 1882;3:385-395.
• Background MEUNIER H, CARRAZ G, NEUNIER Y, EYMARD P, AIMARD M. [Pharmacodynamic properties of N-dipropylacetic acid]. Therapie. 1963 Mar-Apr;18:435-8. No abstract available. French.
• Background Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F, Nervi C, Pelicci PG, Heinzel T. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001 Dec 17;20(24):6969-78. doi: 10.1093/emboj/20.24.6969.
• Background Chen Y, Tsai YH, Tseng SH. Combined valproic acid and celecoxib treatment induced synergistic cytotoxicity and apoptosis in neuroblastoma cells. Anticancer Res. 2011 Jun;31(6):2231-9.
• Background Das CM, Aguilera D, Vasquez H, Prasad P, Zhang M, Wolff JE, Gopalakrishnan V. Valproic acid induces p21 and topoisomerase-II (alpha/beta) expression and synergistically enhances etoposide cytotoxicity in human glioblastoma cell lines. J Neurooncol. 2007 Nov;85(2):159-70. doi: 10.1007/s11060-007-9402-7. Epub 2007 May 30.
• Background McCormack E, Haaland I, Venas G, Forthun RB, Huseby S, Gausdal G, Knappskog S, Micklem DR, Lorens JB, Bruserud O, Gjertsen BT. Synergistic induction of p53 mediated apoptosis by valproic acid and nutlin-3 in acute myeloid leukemia. Leukemia. 2012 May;26(5):910-7. doi: 10.1038/leu.2011.315. Epub 2011 Nov 8.
• Background Steinberg MH, McCarthy WF, Castro O, Ballas SK, Armstrong FD, Smith W, Ataga K, Swerdlow P, Kutlar A, DeCastro L, Waclawiw MA; Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia and MSH Patients' Follow-Up. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up. Am J Hematol. 2010 Jun;85(6):403-8. doi: 10.1002/ajh.21699.
• Background Hankins JS, Aygun B, Nottage K, Thornburg C, Smeltzer MP, Ware RE, Wang WC. From infancy to adolescence: fifteen years of continuous treatment with hydroxyurea in sickle cell anemia. Medicine (Baltimore). 2014 Dec;93(28):e215. doi: 10.1097/MD.0000000000000215.
• Background Fredly H, Stapnes Bjornsen C, Gjertsen BT, Bruserud O. Combination of the histone deacetylase inhibitor valproic acid with oral hydroxyurea or 6-mercaptopurin can be safe and effective in patients with advanced acute myeloid leukaemia--a report of five cases. Hematology. 2010 Oct;15(5):338-43. doi: 10.1179/102453310X12647083620967.
• Background Andresen V, Gjertsen BT. Drug Repurposing for the Treatment of Acute Myeloid Leukemia. Front Med (Lausanne). 2017 Nov 29;4:211. doi: 10.3389/fmed.2017.00211. eCollection 2017.
• Background Jadersten M, Lilienthal I, Tsesmetzis N, Lourda M, Bengtzen S, Bohlin A, Arnroth C, Erkers T, Seashore-Ludlow B, Giraud G, Barkhordar GS, Tao S, Fogelstrand L, Saft L, Ostling P, Schinazi RF, Kim B, Schaller T, Juliusson G, Deneberg S, Lehmann S, Rassidakis GZ, Hoglund M, Henter JI, Herold N. Targeting SAMHD1 with hydroxyurea in first-line cytarabine-based therapy of newly diagnosed acute myeloid leukaemia: Results from the HEAT-AML trial. J Intern Med. 2022 Dec;292(6):925-940. doi: 10.1111/joim.13553. Epub 2022 Aug 18.
• Background Mamez AC, Raffoux E, Chevret S, Lemiale V, Boissel N, Canet E, Schlemmer B, Dombret H, Azoulay E, Lengline E. Pre-treatment with oral hydroxyurea prior to intensive chemotherapy improves early survival of patients with high hyperleukocytosis in acute myeloid leukemia. Leuk Lymphoma. 2016 Oct;57(10):2281-8. doi: 10.3109/10428194.2016.1142083. Epub 2016 Feb 5.
• Background Grund FM, Armitage JO, Burns P. Hydroxyurea in the prevention of the effects of leukostasis in acute leukemia. Arch Intern Med. 1977 Sep;137(9):1246-7.
• Background Berg J, Vincent PC, Gunz FW. Extreme leucocytosis and prognosis of newly diagnosed patients with acute non-lymphocytic leukaemia. Med J Aust. 1979 Jun 2;1(11):480-2. doi: 10.5694/j.1326-5377.1979.tb119318.x.
• Background Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Lowenberg B, Bloomfield CD. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017 Jan 26;129(4):424-447. doi: 10.1182/blood-2016-08-733196. Epub 2016 Nov 28.
• Background Fredly H, Ersvaer E, Kittang AO, Tsykunova G, Gjertsen BT, Bruserud O. The combination of valproic acid, all-trans retinoic acid and low-dose cytarabine as disease-stabilizing treatment in acute myeloid leukemia. Clin Epigenetics. 2013 Aug 1;5(1):13. doi: 10.1186/1868-7083-5-13.
• Background Kuendgen A, Strupp C, Aivado M, Bernhardt A, Hildebrandt B, Haas R, Germing U, Gattermann N. Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood. 2004 Sep 1;104(5):1266-9. doi: 10.1182/blood-2003-12-4333. Epub 2004 May 20.
• Background Raffoux E, Chaibi P, Dombret H, Degos L. Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukemia. Haematologica. 2005 Jul;90(7):986-8.
• Background STOCK CC, CLARKE DA, PHILIPS FS, BARCLAY RK, MYRON SA. Sarcoma 180 screening data. Cancer Res. 1960 Jun;20(5)Pt 2:193-381. No abstract available.

Drugs

Indications