A phase I trial of flavopiridol in relapsed multiple myeloma
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Flavopiridol is primarily a cyclin-dependent kinase-9 inhibitor, and we performed a dose escalation trial to determine the maximum tolerated dose and safety and generate a pharmacokinetic (PK) profile.
Patients with a diagnosis of relapsed myeloma after at least two prior treatments were included. Flavopiridol was administered as a bolus and then continuous infusion weekly for 4 weeks in a 6-week cycle.
Fifteen patients were treated at three dose levels (30 mg/m2 bolus, 30 mg/m2 CIV to 50 mg/m2 bolus, and 50 mg/m2 CIV). Cytopenias were significant, and elevated transaminases (grade 4 in 3 patients, grade 3 in 4 patients, and grade 2 in 3 patients) were noted but were transient. Diarrhea (grade 3 in 6 patients and grade 2 in 5 patients) did not lead to hospital admission. There were no confirmed partial responses although one patient with t(4;14) had a decrease in his monoclonal protein >50 % that did not persist. PK properties were similar to prior publications, and immunohistochemical staining for cyclin D1 and phospho-retinoblastoma did not predict response.
Flavopiridol as a single agent given by bolus and then infusion caused significant diarrhea, cytopenias, and transaminase elevation but only achieved marginal responses in relapsed myeloma (ClinicalTrials.gov identifier NCT00112723).
KeywordsMultiple myeloma Flavopiridol Cyclin-dependent kinase inhibitor Pharmacokinetics Phase 1 clinical trial
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number U01CA076576 (PI Michael Grever). CCH was a Paul Calabresi scholar on K12CA133250 from the National Cancer Institute (PI John Byrd). The content is solely the responsibility of the authors and does not represent the official views of the National Cancer Institute or the National Institutes of Health.
Conflict of interest
None of the authors have a relevant conflict of interest to report.
- 2.Blum W, Phelps MA, Klisovic RB, Rozewski DM, Ni W, Albanese KA, Rovin B, Kefauver C, Devine SM, Lucas DM, Johnson A, Schaaf LJ, Byrd JC, Marcucci G, Grever MR (2010) Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias. Haematologica 95:1098–1105PubMedCrossRefGoogle Scholar
- 3.Byrd JC, Lin TS, Dalton JT, Wu D, Phelps MA, Fischer B, Moran M, Blum KA, Rovin B, Brooker-McEldowney M, Broering S, Schaaf LJ, Johnson AJ, Lucas DM, Heerema NA, Lozanski G, Young DC, Suarez JR, Colevas AD, Grever MR (2007) Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 109:399–404PubMedCrossRefGoogle Scholar
- 9.Dispenzieri A, Gertz MA, Lacy MQ, Geyer SM, Fitch TR, Fenton RG, Fonseca R, Isham CR, Ziesmer SC, Erlichman C, Bible KC (2006) Flavopiridol in patients with relapsed or refractory multiple myeloma: a phase 2 trial with clinical and pharmacodynamic end-points. Haematologica 91:390–393PubMedGoogle Scholar
- 10.Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV (2006) International uniform response criteria for multiple myeloma. Leukemia 20:1467–1473PubMedCrossRefGoogle Scholar
- 11.Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV (2006) International uniform response criteria for multiple myeloma. Leukemia 20:1467–1473PubMedCrossRefGoogle Scholar
- 13.Holkova B, Perkins EB, Ramakrishnan V, Tombes MB, Shrader E, Talreja N, Wellons MD, Hogan KT, Roodman GD, Coppola D, Kang L, Dawson J, Stuart RK, Peer C, Figg WD Sr, Kolla S, Doyle A, Wright J, Sullivan DM, Roberts JD, Grant S (2011) Phase I trial of bortezomib (PS-341; NSC 681239) and alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory B-cell neoplasms. Clin Cancer Res 17:3388–3397PubMedCentralPubMedCrossRefGoogle Scholar
- 14.Hussain SR, Lucas DM, Johnson AJ, Lin TS, Bakaletz AP, Dang VX, Viatchenko-Karpinski S, Ruppert AS, Byrd JC, Kuppusamy P, Crouser ED, Grever MR (2008) Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium. Blood 111:3190–3199PubMedCrossRefGoogle Scholar
- 17.Lopez-Girona A, Heintel D, Zhang LH, Mendy D, Gaidarova S, Brady H, Bartlett JB, Schafer PH, Schreder M, Bolomsky A, Hilgarth B, Zojer N, Gisslinger H, Ludwig H, Daniel T, Jager U, Chopra R (2011) Lenalidomide downregulates the cell survival factor, interferon regulatory factor-4, providing a potential mechanistic link for predicting response. Br J Haematol 154:325–336PubMedCrossRefGoogle Scholar
- 18.Mahoney E, Lucas DM, Gupta SV, Wagner AJ, Herman SEM, Smith LL, Yeh Y-Y, Andritsos L, Jones JA, Flynn JM, Blum KA, Zhang X, Lehman A, Kong H, Gurcan M, Grever MR, Johnson AJ, Byrd JC (2012) ER stress and autophagy: new players in the mechanism of action and drug resistance of the cyclin-dependent kinase inhibitor flavopiridol. Blood 120:1262–1273Google Scholar
- 20.McMillin DW, Delmore J, Negri J, Buon L, Jacobs HM, Laubach J, Jakubikova J, Ooi M, Hayden P, Schlossman R, Munshi NC, Lengauer C, Richardson PG, Anderson KC, Mitsiades CS (2011) Molecular and cellular effects of multi-targeted cyclin-dependent kinase inhibition in myeloma: biological and clinical implications. Br J Haematol 152:420–432PubMedCrossRefGoogle Scholar
- 21.Phelps MA, Lin TS, Johnson AJ, Hurh E, Rozewski DM, Farley KL, Wu D, Blum KA, Fischer B, Mitchell SM, Moran ME, Brooker-McEldowney M, Heerema NA, Jarjoura D, Schaaf LJ, Byrd JC, Grever MR, Dalton JT (2009) Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia. Blood 113:2637–2645PubMedCrossRefGoogle Scholar
- 22.Phelps MA, Rozewski DM, Johnston JS, Farley KL, Albanese KA, Byrd JC, Lin TS, Grever MR, Dalton JT (2008) 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 868:110–115PubMedCentralPubMedCrossRefGoogle Scholar
- 23.Santo L, Vallet S, Hideshima T, Cirstea D, Ikeda H, Pozzi S, Patel K, Okawa Y, Gorgun G, Perrone G, Calabrese E, Yule M, Squires M, Ladetto M, Boccadoro M, Richardson PG, Munshi NC, Anderson KC, Raje N (2010) AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3beta activation and RNA polymerase II inhibition. Oncogene 29:2325–2336PubMedCentralPubMedCrossRefGoogle Scholar
- 27.Shou Y, Martelli ML, Gabrea A, Qi Y, Brents LA, Roschke A, Dewald G, Kirsch IR, Bergsagel PL, Kuehl WM (2000) Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma. Proc Natl Acad Sci USA 97:228–233PubMedCrossRefGoogle Scholar
- 28.Takada Y, Aggarwal BB (2004) Flavopiridol inhibits NF-kappaB activation induced by various carcinogens and inflammatory agents through inhibition of IkappaBalpha kinase and p65 phosphorylation: abrogation of cyclin D1, cyclooxygenase-2, and matrix metalloprotease-9. J Biol Chem 279:4750–4759PubMedCrossRefGoogle Scholar
- 29.Tan AR, Yang X, Berman A, Zhai S, Sparreboom A, Parr AL, Chow C, Brahim JS, Steinberg SM, Figg WD, Swain SM (2004) Phase I trial of the cyclin-dependent kinase inhibitor flavopiridol in combination with docetaxel in patients with metastatic breast cancer. Clin Cancer Res 10:5038–5047PubMedCrossRefGoogle Scholar