title: Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia.
abstract: We previously reported interim results of a phase 1 trial in patients with chronic lymphocytic leukemia (CLL) whereby flavopiridol was administered intravenously as a 30-minute bolus followed by 4-hour infusion. We now report full pharmacokinetic (PK) data, correlations of PK with clinical outcomes, and final response and progression-free survival (PFS). Twenty-one (40%) of 52 patients with relapsed CLL achieved a partial response (PR) with a median PFS of 12 months. Responders included 17 (40%) of 43 fludarabine refractory patients, 7 (39%) of 18 patients with del(17p13), and 14 (74%) of 19 patients with del(11q22). Six responders received repeat therapy at relapse, and 5 responded again with a second median PFS of 10 months. Noncompartmental analysis and nonlinear mixed effects modeling was used to estimate PK parameters and evaluate covariates. Two-compartment population parameter estimates were 31.4 L/h, 65.8 L, 8.49 L/h, and 157 L for CL, V1, Q, and V2, respectively. Flavopiridol area under the plasma concentration-time curve (AUC) correlated with clinical response and cytokine release syndrome, and glucuronide metabolite AUC correlated with tumor lysis syndrome. These composite results confirm high activity of this pharmacokinetically derived schedule in relapsed, genetically high-risk CLL. Furthermore, PK describes some, but not all, variability in response and toxicity.
authors.affiliation: Comprehensive Cancer Center, College of Pharmacy, Division of Pharmaceutics, The Ohio State University, Columbus, OH 43210, USA. mitch.phelps@osumc.edu
authors.forename: Mitch A
authors.initials: MA
authors.lastname: Phelps
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Lin
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: Eunju
authors.initials: E
authors.lastname: Hurh
authors.forename: Darlene M
authors.initials: DM
authors.lastname: Rozewski
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Farley
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.forename: Kristie A
authors.initials: KA
authors.lastname: Blum
authors.forename: Beth
authors.initials: B
authors.lastname: Fischer
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Mitchell
authors.forename: Mollie E
authors.initials: ME
authors.lastname: Moran
authors.forename: Michelle
authors.initials: M
authors.lastname: Brooker-McEldowney
authors.forename: Nyla A
authors.initials: NA
authors.lastname: Heerema
authors.forename: David
authors.initials: D
authors.lastname: Jarjoura
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Schaaf
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002453:Cell Cycle / Q000187:drug effects; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008658:Inactivation, Metabolic; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012008:Recurrence; D016879:Salvage Therapy; D016896:Treatment Outcome; D015275:Tumor Lysis Syndrome / Q000209:etiology; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D014535:Uridine Diphosphate Glucuronic Acid; C077990:alvocidib; D014740:Vidarabine; C024352:fludarabine