Phase I/II multicenter study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD4877 in patients with refractory acute myeloid leukemia

Investigational New Drugs

Volumn 30, Issue 3, 2012, Pages 1107-1115

  Kantarjian, H M ^a   Padmanabhan, S ^b   Stock, W ^c   Tallman, M S ^e,g   Curt, G A ^d   Li, J ^d   Osmukhina, A ^d   Wu, K ^d,h   Huszar, D ^d   Borthukar, G ^a   Faderl, S ^a   Garcia Manero, G ^a   Kadia, T ^a   Sankhala, K ^b   Odenike, O ^c   Altman, J K ^e   Minden, M ^f  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^b University of Texas Health Science Center at San Antonio   (United States)

^c UNIVERSITY OF CHICAGO   (United States)

^d ASTRAZENECA   (United Kingdom)

^e NORTHWESTERN UNIVERSITY   (United States)

^f UNIVERSITY HEALTH NETWORK   (Canada)

^g MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^h R and D day   (United States)

Author keywords

AML; Eg5 inhibitor; MTD; Pharmacokinetics; Phase I II; Safety

Indexed keywords

ANTINEOPLASTIC AGENT; AZD 4877; UNCLASSIFIED DRUG;

ACUTE GRANULOCYTIC LEUKEMIA; ADULT; AGED; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; ARTICLE; BRAIN HEMORRHAGE; CANCER CHEMOTHERAPY; CANCER REGRESSION; CLINICAL EFFECTIVENESS; CONTINUOUS INFUSION; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DIARRHEA; DIVERTICULITIS; DOSE RESPONSE; DRUG DETERMINATION; DRUG EFFICACY; DRUG FATALITY; DRUG HALF LIFE; DRUG MECHANISM; DRUG RESEARCH; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DYSPHAGIA; FATIGUE; FEMALE; HAND FOOT SYNDROME; HEART ATRIUM FLUTTER; HUMAN; HYPERBILIRUBINEMIA; HYPERKALEMIA; HYPERMAGNESEMIA; HYPOALBUMINEMIA; HYPOCALCEMIA; HYPOKALEMIA; HYPOPHOSPHATEMIA; INFLAMMATION; LUNG MYCOSIS; MAJOR CLINICAL STUDY; MALE; MAXIMUM PLASMA CONCENTRATION; MUCOSAL DISEASE; MULTICENTER STUDY; NAUSEA; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; PNEUMONIA; PRIORITY JOURNAL; STEVENS JOHNSON SYNDROME; STOMATITIS;

ADULT; AGED; AGED, 80 AND OVER; ANTIMITOTIC AGENTS; BENZAMIDES; FEMALE; HUMANS; KINESIN; LEUKEMIA, MYELOID, ACUTE; MALE; MIDDLE AGED; PYRIMIDINONES; YOUNG ADULT;

EID: 84863439290     PISSN: 01676997     EISSN: 15730646     Source Type: Journal    
DOI: 10.1007/s10637-011-9660-2     Document Type: Article

References (32)

1. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277-300
2. Kantarjian H, O'Brien S, Cortes J, Giles F, Faderl S, Jabbour E, Garcia-Manero G, Wierda W, Pierce S, Shan J, Estey E (2006) Results ofintensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer 106:1090-1098
3. Kantarjian H, Ravandi F, O'Brien S, Cortes J, Faderl S, Garcia-Manero G, Jabbour E, Wierda W, Kadia T, Pierce S, Shan J, Keating M, Freireich EJ (2010) Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood 116:4422-4429
4. Sakowicz R, Finer JT, Beraud C, Crompton A, Lewis E, Fritsch A, Lee Y, Mak J, Moody R, Turincio R, Chabala JC, Gonzales P, Roth S, Weitman S, Wood KW (2004) Antitumor activity of a kinesin inhibitor. Cancer Res 64:3276-3280 (Pubitemid 38581433)
5. Hedge PS, Cogswell J, Carrick J, Jackson J, Wood KW, Eng WK, Brawner M, Huang PS, Bergsma D (2003) Differential gene expression analysis of kinesin spindle protein in human solid tumors. Proceedings of the American Society ofClinical Oncology 22:abst 535
6. Castillo A, Morse HC III, Godfrey VL, Naeem R, Justice MJ (2007) Overexpression of Eg5 causes genomic instability and tumor formation in mice. Cancer Res 67:10138-10147 (Pubitemid 350070785)
7. Blangy A, Lane HA, D'Herin P, Harper M, Kress M, Nigg EA (1995) Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 83:1159-1169
8. Masuda A, Maeno K, Nakagawa T, Saito H, Takahashi T (2003) Association between mitotic spindle checkpoint impairment and susceptibility to the induction of apoptosis by anti-microtubule agents in human lung cancers. Am J Pathol 163:1109-1116 (Pubitemid 37040146)
9. Taylor SS, McKeon F (1997) Kinetochore localization ofmurine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage. Cell 89:727-735 (Pubitemid 27516175)
10. Hayashi N, Koller E, Fazli L, Gleave ME (2008) Effects of Eg5 knockdown on human prostate cancer xenograft growth and chemosensitivity. Prostate 68:1283-1295
11. Kapoor TM, Mayer TU, Coughlin ML, Mitchison TJ (2000) Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5. J Cell Biol 150:975-988
12. Liu M, Yu H, Huo L, Liu J, Li M, Zhou J (2008) Validating the mitotic kinesin Eg5 as a therapeutic target in pancreatic cancer cells and tumor xenografts using a specific inhibitor. Biochem Pharmacol 76:169-178
13. Nakai R, Iida S, Takahashi T, Tsujita T, Okamoto S, Takada C, Akasaka K, Ichikawa S, Ishida H, Kusaka H, Akinaga S, Murakata C, Honda S, Nitta M, Saya H, Yamashita Y (2009) K858, a novel inhibitor of mitotic kinesin Eg5 and antitumor agent, induces cell death in cancer cells. Cancer Res 69:3901-3909
14. Zhang Y Xu W (2008) Progress on kinesin spindle protein inhibitors as anti-cancer agents. Anticancer Agents Med Chem 8:698-704
15. Carter BZ, Mak DH, Wassner R, Gross S, Schober WD, Estrov Z, Kantarjian H, Andreev E (2009) Inhibition of KSP by ARRY520 induces cell cycle block and cell death via the mitochondrial pathway in AML cells. Leukemia 23:1755-1762
16. Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB (2003) Mechanisms oftaxol resistance related to microtubules. Oncogene 22:7280-7295 (Pubitemid 37487160)
17. Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL, Mitchison TJ (1999) Small molecule inhibitor ofmitotic spindle bipolarity identified in a phenotype-based screen. Science 286:971-974
18. Pinzon-Ortiz MC, Cao A, Sheehy A, Pablo L, McEachern K, Hylander-Gans L, Wu K, Reimer C, Morosini D, McCoon P, Huszar D (2010) Characterization of the kinesin spindle protein inhibitor AZD4877. Proc Am Assoc Cancer Res 51:abst 4429
19. Borthakur G, Faderl S, Ravandi F, Padmanabhan S, Stock W, Wu K, Li J, Curt G, Tallman M, Minden M (2009) Clinical, pharmacokinetic (PK), and pharmacodynamic findings from a phase I trial of an Eg5 inhibitor (AZD4877) in patients with refractory acute myeloid leukemia (AML). J Clin Oncol 27(15S):abst 3580
20. World Medical Association (WMA). Declaration of Helsinki. Ethical principles for medical research involving human subjects. Adopted by the 18th WMA General Assembly, Helsinki, Finland, June. 1964. Available at: http://www.wma.net/en/30publications/10policies/b3/index.html
21. Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10 (Pubitemid 19099520)
22. Rowland M, Tozer TN (1995) Clinical pharmacokinetics: con-cepts and applications, 3 rdth edn. Williams & Wilkins, Lippincott
23. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD (2003) Revised recommendations of the international working group for diagnosis, standardization ofresponse criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 21:4642-4649 (Pubitemid 46594039)
24. Kantarjian HM, Gandhi V, Kozuch P, Faderl S, Giles F, Cortes J, O'Brien S, Ibrahim N, Khuri F, Du M, Rios MB, Jeha S, McLaughlin P, Plunkett W, Keating M (2003) Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. J Clin Oncol 21:1167-1173 (Pubitemid 46594149)
25. Infante JR, Spratlin JL, Kurzrock R, Eckhardt SG, Burris HA, Pulchalski TA, Li J, Wu K, Ochs J, Herbst RS (2008) Clinical, pharmacokinetic (PK), pharmacodynamic findings in a phase I trial of weekly (wkly) intravenous AZD4877 in patients with refractory solid tumors. J Clin Oncol 26(15S):abst 2501
26. Milionis HJ, Bourantas CL, Siamopoulos KC, Elisaf MS (1999) Acid-base and electrolyte abnormalities in patients with acute leukemia. Am J Hematol 62:201-207
27. Tang PA, Siu LL, Chen EX, Hotte SJ, Chia S, Schwarz JK, Pond GR, Johnson C, Colevas AD, Synold TW, Vasist LS (2008) Phase II study of ispinesib in recurrent or metastatic squamous cell carcinoma of the head and neck. Invest New Drugs 26:257-264
28. Knox JJ, Gill S, Synold T, Biagi JJ, Major P, Feld R, Cripps C, Wainman N, Eisenhauer E, Seymour L (2008) A phase II and pharmacokinetic study of SB-715992, in patients with metastatic hepatocellular carcinoma: a study of the National cancer institute of canada clinical trials group (NCIC CTG IND.168). Invest New Drugs 26:265-272
29. Lee CW, Belanger K, Rao SC, Petrella TM, Tozer RG, Wood L, Savage KJ, Eisenhauer EA, Synold TW, Wainman N (2008) A phase II study of ispinesib (SB-715992) in patients with metastatic or recurrent malignant melanoma: a National Cancer Institute of Canada Clinical Trials Group trial. Invest New Drugs 26:249-255 (Pubitemid 351579684)
30. Lee RT, Beekman KE, Hussain M, Davis NB, Clark JI, Thomas SP, Nichols KF, Stadler WM (2008) A University of Chicago consortium phase II trial of SB-715992 in advanced renal cell cancer. Clin Genitourin Cancer 6:21-24 (Pubitemid 351656239)
31. Beer TM, Goldman B, Synold TW, Ryan CW, Vasist LS, Van Veldhuizen P Jr, Dakhil SR, Lara PN Jr, Drelichman A, Hussain MH, Crawford ED (2008) Southwest Oncology Group phase II study of ispinesib in androgen-independent prostate cancer previously treated with taxanes. Clin Genitourin Cancer 6:103-109
32. Shahin MS, Braly P, Rose P, Malpass T, Bailey H, Alvarez RD, Hodge J, Bowen C, Buller R (2007) A Phase II, open-label study of ispinesib (SB-715992) in patients with platinum/taxane refractory or resistant relapsed ovarian cancer. J Clin Oncol 25(18S):abst 5562