Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia

Blood

Volumn 113, Issue 12, 2009, Pages 2637-2645

  Phelps, Mitch A ^a   Lin, Thomas S ^b   Johnson, Amy J ^b   Hurh, Eunju ^c   Rozewski, Darlene M ^c   Farley, Katherine L ^a   Wu, Di ^c   Blum, Kristie A ^b   Fischer, Beth ^b   Mitchell, Sarah M ^b   Moran, Mollie E ^b   Brooker McEldowney, Michelle ^b   Heerema, Nyla A ^b   Jarjoura, David ^c   Schaaf, Larry J ^d   Byrd, John C ^b,c   Grever, Michael R ^b   Dalton, James T ^c  

^a OHIO STATE UNIVERSITY   (United States)

^b THE OHIO STATE UNIVERSITY WEXNER MEDICAL CENTER   (United States)

^c OHIO STATE UNIVERSITY   (United States)

^d THE OHIO STATE UNIVERSITY COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALLOPURINOL; CALCIUM; FLAVOPIRIDOL; FLUDARABINE; FUROSEMIDE; GLUCOSE; GLUCURONIDE; INSULIN; POLYSTYRENESULFONATE SODIUM; POTASSIUM; RASBURICASE; SALBUTAMOL;

ABDOMINAL CRAMP; ABDOMINAL PAIN; ADULT; AGED; AREA UNDER THE CURVE; ARTICLE; BLEEDING; CANCER SURVIVAL; CHROMOSOME 11Q; CHROMOSOME 14; CHROMOSOME 17P; CHROMOSOME 22; CHROMOSOME DELETION; CHROMOSOME DELETION 13; CHRONIC LYMPHATIC LEUKEMIA; CLINICAL ARTICLE; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; CYTOKINE RELEASE; DIARRHEA; DRUG DOSE ESCALATION; DRUG ELIMINATION; DYSPHAGIA; ERECTILE DYSFUNCTION; FATIGUE; FEBRILE NEUTROPENIA; FEMALE; HEART INFARCTION; HEART MUSCLE ISCHEMIA; HEART VENTRICLE ARRHYTHMIA; HUMAN; HYPERKALEMIA; HYPOTENSION; HYPOXIA; INFECTION; KIDNEY FAILURE; LEUKEMIA RELAPSE; LEUKOCYTE; MALE; METABOLITE; MULTIPLE CYCLE TREATMENT; MYALGIA; NAUSEA; NEUTROPENIA; PAIN; PHASE 1 CLINICAL TRIAL; POTASSIUM BLOOD LEVEL; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PRURITUS; SIDE EFFECT; TREATMENT RESPONSE; TUMOR CELL DESTRUCTION; TUMOR LYSIS SYNDROME;

EID: 63849246351     PISSN: 00064971     EISSN: 15280020     Source Type: Journal    
DOI: 10.1182/blood-2008-07-168583     Document Type: Article

References (32)

1. Carlson B, Lahusen T, Singh S, et al. Down- regulation of cyclin D1 by transcriptional repression in MCF-7 human breast carcinoma cells induced by flavopiridol. Cancer Res. 1999;59:4634-4641.
2. Lam LT, Pickeral OK, Peng AC, et al. Genomic- scale measurement of mRNA turnover and the mechanisms of action of the anti-cancer drug flavopiridol. Genome Biol. 2001;2: RESEARCH0041.
3. Senderowicz AM, Sausville EA. Preclinical and clinical development of cyclin-dependent kinase modulators. J Natl Cancer Inst. 2000;92:376-387.
4. Carlson BA, Dubay MM, Sausville EA, Brizuela L, Worland PJ. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res. 1996;56:2973-2978.
5. Worland PJ, Kaur G, Stetler-Stevenson M, Sebers S, Sartor O, Sausville EA. Alteration of the phosphorylation state of p34cdc2 kinase by the flavone L86-8275 in breast carcinoma cells: correlation with decreased H1 kinase activity. Biochem Pharmacol. 1993;46:1831-1840.
6. Decker RH, Dai Y, Grant S. The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in human leukemia cells (U937) through the mitochondrial rather than the receptor-mediated pathway. Cell Death Differ. 2001;8:715-724.
7. Gojo I, Zhang B, Fenton RG. The cyclindependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and down-regulation of Mcl-1. Clin Cancer Res. 2002;8:3527-3538.
8. Parker BW, Kaur G, Nieves-Neira W, et al. Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. Blood. 1998;91: 458-465.
9. Kitada S, Zapata JM, Andreeff M, Reed JC. Protein kinase inhibitors flavopiridol and 7-hydroxy- staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. Blood. 2000;96:393-397.
10. Wittmann S, Bali P, Donapaty S, et al. Flavopiridol down-regulates antiapoptotic proteins and sensitizes human breast cancer cells to epothilone B-induced apoptosis. Cancer Res. 2003;63: 93-99.
11. Byrd JC, Shinn C, Waselenko JK, et al. Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. Blood. 1998;92:3804-3816.
12. Cordone I, Masi S, Mauro FR, et al. p53 expression in B-cell chronic lymphocytic leukemia: a marker of disease progression and poor prognosis. Blood. 1998;91:4342-4349.
13. Dohner H, Fischer K, Bentz M, et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood. 1995;85:1580-1589.
14. Wattel E, Preudhomme C, Hecquet B, et al. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood. 1994;84:3148-3157.
15. Byrd JC, Peterson BL, Gabrilove J, et al. Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: results from Cancer and Leukemia Group B study 19805. Clin Cancer Res. 2005;11:4176-4181.
16. Lin TS, Howard OM, Neuberg DS, Kim HH, Shipp MA. Seventy-two hour continuous infusion flavopiridol in relapsed and refractory mantle cell lymphoma. Leuk Lymphoma. 2002;43:793-797.
17. Schwartz GK, Ilson D, Saltz L, et al. Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma. J Clin Oncol. 2001;19:1985-1992.
18. Schwartz GK, O'Reilly E, Ilson D, et al. Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors. J Clin Oncol. 2002; 20:2157-2170.
19. Shapiro GI, Supko JG, Patterson A, et al. A phase II trial of the cyclin-dependent kinase inhibitor flavopiridol in patients with previously untreated stage IV non-small cell lung cancer. Clin Cancer Res. 2001;7:1590-1599.
20. Stadler WM, Vogelzang NJ, Amato R, et al. Flavopiridol, a novel cyclin-dependent kinase inhibitor, in metastatic renal cancer: a University of Chicago Phase II Consortium study. J Clin Oncol. 2000;18:371-375.
21. Flinn IW, Byrd JC, Bartlett N, et al. Flavopiridol administered as a 24-hour continuous infusion in chronic lymphocytic leukemia lacks clinical activity. Leuk Res. 2005;29:1253-1257.
22. Byrd JC, Lin TS, Dalton JT, et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood. 2007;109:399-404.
23. Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. '996;87:4990-4997.
24. Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-'H) in patients who have failed fludarabine: results of a large international study. Blood. 2002;99:3554-356.
25. Phelps MA, Rozewski DM, Johnston JS, et al. Development and validation of a sensitive liquid chromatography/mass spectrometry method for quantitation of flavopiridol in plasma enables accurate estimation of pharmacokinetic parameters with a clinically active dosing schedule. J Chromatogr B Analyt Technol Biomed Life Sci. 2008; 868:110-115.
26. Karp JE, Passaniti A, Gojo I, et al. Phase I and pharmacokinetic study of flavopiridol followed by 1-beta-D-arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias. Clin Cancer Res. 2005; 11:8403-8412.
27. Innocenti F, Stadler WM, Iyer L, Ramirez J, Vokes EE, Ratain MJ. Flavopiridol metabolism in cancer patients is associated with the occurrence of diarrhea. Clin Cancer Res. 2000;6:3400-3405.
28. Jäger W, Gehring E, Hagenauer B, Aust S, Senderowicz A, Thalhammer T. The role of hepatic Mrp2 in the interaction of flavopiridol and bilirubin: impact on therapy. Int J Clin Pharmacol Ther. 2003;41:610-6.
29. Moreton P, Kennedy B, Lucas G, et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol. 2005;23:2971-2979.
30. Andritsos L, Fischer B, Lin T, et al. Low incidence of opportunistic infections in CLL patients treated with single agent flavopiridol. American Society of HematologyAnnual Meeting; Atlanta, GA, December '0, 2007:3128.
31. Lin T, Fischer B, Blum K, et al. Preliminary results of a phase II study of flavopiridol (Alvocidib) in relapsed chronic lymphocytic leukemia (CLL): confirmation of clinical activity in high- risk patients and achievement of complete responses (CR). Session Type: Poster Session, Board no. 323-III. American Society of Hematology Annual Meeting; Atlanta, GA, December 10, 2007:3104.
32. Rudek MA, Bauer KS Jr, Lush RM III, et al. Clinical pharmacology of flavopiridol following a 72hour continuous infusion. Ann Pharmacother. 2003;37:1369-1374.