Exposure-Response Analysis of Alvocidib (Flavopiridol) Treatment by Bolus or Hybrid Administration in Newly Diagnosed or Relapsed/Refractory Acute Leukemia Patients

• Published in: Clinical cancer research Vol. 23; no. 14; pp. 3592 - 3600
• Main Authors: LaCerte, Carl, Ivaturi, Vijay, Gobburu, Joga, Greer, Jacqueline M, Doyle, L Austin, Wright, John J, Karp, Judith E, Rudek, Michelle A
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 15-07-2017
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - blood; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Biomarkers, Pharmacological - blood; Cancer; Clinical trials; Cytarabine; Cytarabine - administration & dosage; Cytarabine - blood; Cytarabine - pharmacokinetics; Cytosine; Dosage; Drug Administration Schedule; Experimental design; Exposure; Female; Flavonoids - administration & dosage; Flavonoids - blood; Flavonoids - pharmacokinetics; Flavopiridol; Humans; Leukemia; Leukemia, Myeloid, Acute - blood; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - pathology; Male; Maximum Tolerated Dose; Middle Aged; Mitoxantrone; Mitoxantrone - administration & dosage; Mitoxantrone - blood; Mitoxantrone - pharmacokinetics; Modelling; Parameter estimation; Parameter identification; Partitioning; Patients; Pharmacodynamics; Pharmacology; Piperidines - administration & dosage; Piperidines - blood; Piperidines - pharmacokinetics; Schedules; Vidarabine - administration & dosage; Vidarabine - analogs & derivatives; Vidarabine - blood; Vidarabine - pharmacokinetics
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-2629

To elucidate any differences in the exposure-response of alvocidib (flavopiridol) given by 1-hour bolus or a hybrid schedule (30-minute bolus followed by a 4-hour infusion) using a flavopiridol/cytosine arabinoside/mitoxantrone sequential protocol (FLAM) in patients with acute leukemia. The hybrid schedule was devised to be pharmacologically superior in chronic leukemia based on unbound exposure.
Data from 129 patients in three FLAM studies were used for pharmacokinetic/pharmacodynamic modeling. Newly diagnosed (62%) or relapsed/refractory (38%) patients were treated by bolus (43%) or hybrid schedule (57%). Total and unbound flavopiridol concentrations were fit using nonlinear mixed-effect population pharmacokinetic methodologies. Exposure-response relationships using unbound flavopiridol AUC were explored using recursive partitioning.
Flavopiridol pharmacokinetic parameters were estimated using a two-compartment model. No pharmacokinetic covariates were identified. Flavopiridol fraction unbound was 10.9% and not different between schedules. Partitioning found no association between dosing schedule and clinical response. Clinical response was associated with AUC ≥ 780 h*ng/mL for newly diagnosed patients and AUC ≥ 1,690 h*ng/mL for relapsed/refractory patients. Higher exposures were not associated with increases in severe adverse events (≥ grade 3).
Pharmacokinetic modeling showed no difference in flavopiridol plasma protein binding for bolus versus hybrid dosing. Further trials in newly diagnosed patients with acute leukemia should utilize the bolus FLAM regimen at the MTD of 50 mg/m
/day. Trials in relapsed/refractory patients should use the hybrid dosing schedule at the MTD (30/60 mg/m
/day) to achieve the higher exposures required for maximal efficacy in this population.
.