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

Autor: Katherine L. Farley, Larry J. Schaaf, Sarah M. Mitchell, Amy J. Johnson, Mitch A. Phelps, James T. Dalton, Eunju Hurh, David Jarjoura, Thomas S. Lin, Michael R. Grever, Beth Fischer, Nyla A. Heerema, Darlene M. Rozewski, Kristie A. Blum, Mollie E. Moran, Di Wu, Michelle Brooker-McEldowney, John C. Byrd
Rok vydání: 2008
Předmět:
Oncology
Male
Clinical Trials and Observations
Chronic lymphocytic leukemia
Salvage therapy
Pharmacology
Biochemistry
chemistry.chemical_compound
Piperidines
Recurrence
Infusions
Intravenous
Aged
80 and over
education.field_of_study
Cell Cycle
Hematology
Alvocidib
Middle Aged
Tumor lysis syndrome
Leukemia
Cytokine release syndrome
Treatment Outcome
Area Under Curve
Inactivation
Metabolic
Injections
Intravenous
Female
Vidarabine
Adult
medicine.medical_specialty
Immunology
Population
Antineoplastic Agents
Models
Biological
Disease-Free Survival
Pharmacokinetics
Internal medicine
medicine
Humans
education
Protein Kinase Inhibitors
Aged
Flavonoids
Salvage Therapy
business.industry
Cell Biology
medicine.disease
Leukemia
Lymphocytic
Chronic
B-Cell
chemistry
Drug Resistance
Neoplasm
Uridine Diphosphate Glucuronic Acid
business
Tumor Lysis Syndrome
Zdroj: Blood. 113(12)
ISSN: 1528-0020
Popis: 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.
Databáze: OpenAIRE
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