Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy

Blood

Volumn 124, Issue 9, 2014, Pages 1426-1433

  Döhner, Hartmut ^a   Lübbert, Michael ^b   Fiedler, Walter ^c   Fouillard, Loic ^d   Haaland, Alf ^e   Brandwein, Joseph M ^f   Lepretre, Stephane ^g   Reman, Oumedaly ^h   Turlure, Pascal ⁱ   Ottmann, Oliver G ^j   Müller Tidow, Carsten ^k   Krämer, Alwin ^l   Raffoux, Emmanuel ^m   Döhner, Konstanze ^a   Schlenk, Richard F ^a   Voss, Florian ⁿ   Taube, Tillmann ⁿ   Fritsch, Holger ⁿ   Maertens, Johan ^o  

^a UNIVERSITY HOSPITAL ULM   (Germany)

^b UNIVERSITY OF FREIBURG   (Germany)

^c UNIVERSITY MEDICAL CENTER HAMBURG EPPENDORF   (Germany)

^d CENTRE HOSPITALIER RENÉ DUBOS   (France)

^e OSLO UNIVERSITY HOSPITAL   (Norway)

^f PRINCESS MARGARET HOSPITAL   (Canada)

^g Centre de Lutte Contre le Cancer Henri Becquerel   (France)

^h CAEN UNIVERSITY HOSPITAL   (France)

ⁱ LIMOGES UNIVERSITY HOSPITAL   (France)

^j GOETHE UNIVERSITY   (Germany)

^k INST OF REPRO MED OF THE UNIV   (Germany)

^l UNIVERSITY OF HEIDELBERG   (Germany)

^m SAINT LOUIS HOSPITAL   (France)

ⁿ BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

^o UNIVERSITY HOSPITALS LEUVEN   (Belgium)

more..

Author keywords

[No Author keywords available]

Indexed keywords

C REACTIVE PROTEIN; CYTARABINE; VOLASERTIB; ANTINEOPLASTIC AGENT; PROTEIN KINASE INHIBITOR; PTERIDINE DERIVATIVE;

ACUTE GRANULOCYTIC LEUKEMIA; AGED; AREA UNDER THE CURVE; ARTICLE; BONE MARROW SUPPRESSION; CANCER COMBINATION CHEMOTHERAPY; CANCER MORTALITY; CANCER SURVIVAL; CELLULITIS; CLOSTRIDIUM DIFFICILE INFECTION; COMPARATIVE EFFECTIVENESS; CONTROLLED STUDY; CYTOGENETICS; DIARRHEA; DRUG EFFICACY; DRUG HALF LIFE; DRUG SAFETY; DRUG WITHDRAWAL; DYSPNEA; EPISTAXIS; EVENT FREE SURVIVAL; FEBRILE NEUTROPENIA; FEMALE; GENERAL CONDITION DETERIORATION; GRAM NEGATIVE SEPSIS; HUMAN; HYPOGLYCEMIA; HYPOKALEMIA; HYPOXIA; LOW DRUG DOSE; LUNG EDEMA; LUNG INFECTION; MAJOR CLINICAL STUDY; MALE; MONOTHERAPY; MUCOSA INFLAMMATION; MULTIPLE CYCLE TREATMENT; OVERALL SURVIVAL; PHASE 2 CLINICAL TRIAL; PNEUMONIA; PRIORITY JOURNAL; RESPIRATORY FAILURE; SEPSIS; SIDE EFFECT; TREATMENT OUTCOME; TREATMENT RESPONSE; URINARY TRACT INFECTION; AGE; CLINICAL TRIAL; CONTRAINDICATIONS; DISEASE FREE SURVIVAL; GENETICS; INDUCTION CHEMOTHERAPY; KAPLAN MEIER METHOD; LEUKEMIA, MYELOID, ACUTE; METABOLISM; MIDDLE AGED; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL; VERY ELDERLY;

AGE FACTORS; AGED; AGED, 80 AND OVER; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CYTARABINE; DISEASE-FREE SURVIVAL; FEMALE; HUMANS; INDUCTION CHEMOTHERAPY; KAPLAN-MEIER ESTIMATE; LEUKEMIA, MYELOID, ACUTE; MALE; MIDDLE AGED; PROTEIN KINASE INHIBITORS; PTERIDINES; TREATMENT OUTCOME;

EID: 84907300532     PISSN: 00064971     EISSN: 15280020     Source Type: Journal    
DOI: 10.1182/blood-2014-03-560557     Document Type: Article

References (36)

1. Juliusson G, Antunovic P, Derolf A, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood. 2009;113(18):4179-4187.
2. SEER. Cancer Statistics Review 1975-2009. http://seer.cancer.gov.
3. Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 2006; 107(9):3481-3485.
4. Estey E. AML in older patients: are we making progress? Best Pract Res Clin Haematol. 2009; 22(4):529-536.
5. Döhner H, Estey EH, Amadori S, et al; European LeukemiaNet. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453-474.
6. Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007;109(6):1114-1124.
7. Sekeres MA, Steensma DP. Boulevard of broken dreams: drug approval for older adults with acute myeloid leukemia. J Clin Oncol. 2012;30(33): 4061-4063.
8. Schöffski P. Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist. 2009;14(6):559-570.
9. Strebhardt K. Multifaceted polo-like kinases: drug targets and antitargets for cancer therapy. Nat Rev Drug Discov. 2010;9(8):643-660.
10. Lens SM, Voest EE, Medema RH. Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat Rev Cancer. 2010;10(12): 825-841.
11. Degenhardt Y, Lampkin T. Targeting Polo-like kinase in cancer therapy. Clin Cancer Res. 2010; 16(2):384-389.
12. Renner AG, Dos Santos C, Recher C, et al. Pololike kinase 1 is overexpressed in acute myeloid leukemia and its inhibition preferentially targets the proliferation of leukemic cells. Blood. 2009; 114(3):659-662.
13. Strebhardt K, Ullrich A. Targeting polo-like kinase 1 for cancer therapy. Nat Rev Cancer. 2006;6(4):321-330.
14. Rudolph D, Steegmaier M, Hoffmann M, et al. BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin Cancer Res. 2009;15(9):3094-3102.
15. Steegmaier M, Hoffmann M, Baum A, et al. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol. 2007;17(4):316-322.
16. Hofheinz RD, Al-Batran SE, Hochhaus A, et al. An open-label, phase I study of the polo-like kinase-1 inhibitor, BI 2536, in patients with advanced solid tumors. Clin Cancer Res. 2010;16(18):4666-4674.
17. Müller-Tidow C, Bug G, Lübbert M, et al. A randomized, open-label, phase I/II trial to investigate the maximum tolerated dose of the Polo-like kinase inhibitor BI 2536 in elderly patients with refractory/relapsed acute myeloid leukaemia. Br J Haematol. 2013;163(2):214-222.
18. Hikichi Y, Honda K, Hikami K, et al. TAK-960, a novel, orally available, selective inhibitor of pololike kinase 1, shows broad-spectrum preclinical antitumor activity in multiple dosing regimens. Mol Cancer Ther. 2012;11(3):700-709.
19. Valsasina B, Beria I, Alli C, et al. NMS-P937, an orally available, specific small-molecule polo-like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies. Mol Cancer Ther. 2012;11(4):1006-1016.
20. Bug G, Schlenk R, Müller-Tidow C, et al. Phase I/II study of BI 6727 (volasertib), an intravenous polo-like kinase-1 (PLK1) inhibitor, in patients with acute myeloid leukemia (AML): results of the dose finding for BI 6727 in combination with low-dose cytarabine [abstract]. Blood. 2010;116(suppl).
21. Wheatley K, Brookes CL, Howman AJ, et al; United Kingdom National Cancer Research Institute Haematological Oncology Clinical Studies Group and Acute Myeloid Leukaemia Subgroup. Prognostic factor analysis of the survival of elderly patients with AML in the MRC AML11 and LRF AML14 trials. Br J Haematol. 2009;145(5):598-605.
22. Cheson BD, Bennett JM, Kopecky KJ, et al; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia [published correction appears in J Clin Oncol. 2004;22(3):576]. J Clin Oncol. 2003;21(24):4642-4649.
23. Lachin JM. A review of methods for futility stopping based on conditional power. Stat Med. 2005;24(18):2747-2764.
24. Shih WJ, Quan H, Li G. Two-stage adaptive strategy for superiority and non-inferiority hypotheses in active controlled clinical trials. Stat Med. 2004;23(18):2781-2798.
25. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53(282):457-481.
26. Schöffski P, Awada A, Dumez H, et al. A phase I, dose-escalation study of the novel Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours. Eur J Cancer. 2012;48(2):179-186.
27. Rücker FG, Schlenk RF, Bullinger L, et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood. 2012;119(9):2114-2121.
28. Guan R, Tapang P, Leverson JD, Albert D, Giranda VL, Luo Y. Small interfering RNAmediated Polo-like kinase 1 depletion preferentially reduces the survival of p53- defective, oncogenic transformed cells and inhibits tumor growth in animals. Cancer Res. 2005;65(7):2698-2704.
29. Liu X, Lei M, Erikson RL. Normal cells, but not cancer cells, survive severe Plk1 depletion. Mol Cell Biol. 2006;26(6):2093-2108.
30. Harousseau JL, Martinelli G, Jedrzejczak WW, et al; FIGHT-AML-301 Investigators. A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood. 2009;114(6):1166-1173.
31. Kantarjian HM, Erba HP, Claxton D, et al. Phase II study of clofarabine monotherapy in previously untreated older adults with acute myeloid leukemia and unfavorable prognostic factors. J Clin Oncol. 2010;28(4):549-555.
32. Burnett AK, Russell NH, Kell J, et al. European development of clofarabine as treatment for older patients with acute myeloid leukemia considered unsuitable for intensive chemotherapy. J Clin Oncol. 2010;28(14):2389-2395.
33. Burnett AK, Russell NH, Hunter AE, et al; UK National Cancer Research Institute AML Working Group. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013;122(8):1384-1394.
34. Fenaux P, Mufti GJ, Hellström-Lindberg E, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010;28(4):562-569.
35. Kantarjian HM, Thomas XG, Dmoszynska A, et al. 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;30(21):2670-2677.
36. Eisai Inc. FDA ODAC briefing document NDA 021790/S-010: Dacogen (decitabine). Indication: acute myeloid leukemia. February 9, 2012. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ Drugs/OncologicDrugsAdvisoryCommittee/UCM290512.pdf. Accessed April 7, 2014.