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

Abstract

Purpose 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 acute leukemia patients. The hybrid schedule was devised to be pharmacologically superior in chronic leukemia based on unbound exposure. Experimental Design Data from 129 patients in 3 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 non-linear mixed-effect population pharmacokinetic methodologies. Exposure-response relationships using unbound flavopiridol AUC were explored using recursive partitioning. Results 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 ≥ 1690 h*ng/mL for relapsed/refractory patients. Higher exposures were not associated with increases in severe adverse events (≥ grade 3). Conclusions Pharmacokinetic modeling showed no difference in flavopiridol plasma protein binding for bolus versus hybrid dosing. Further trials in newly diagnosed acute leukemia patients should utilize the bolus FLAM regimen at the maximum tolerated dose (MTD) of 50 mg/m2/day. Trials in relapsed/refractory patients should use the hybrid dosing schedule at the MTD (30/60 mg/m2/day) in order to achieve the higher exposures required for maximal efficacy in this population.

Cyclin-dependent kinases-based synthetic lethality: Evidence, concept, and strategy

“…Alvocidib, also known as flavopiridol, is a traditional CDK1/2/4/9 inhibitor that shows limited antitumor activity when used alone. Alvocidib in combination with cytarabine and mitoxantrone is an emerging treatment for CLL and AML and shows encouraging effects in clinical trials 99 , 100 , 101 . In addition, a combination scheme of alvocidib and BCL-2 inhibitors is undergoing phase I clinical trials and may be a potential synthetic lethality strategy for AML ( Table 2 ).…”

Protein kinase inhibitors for acute leukemia

“…Alvocidib, also known as flavopiridol or HMR-1275, is a multi-serine threonine cyclin-dependent kinase inhibitor and mainly downregulates CDK7 and CDK9 to inhibit c-MYC, cyclin D1, and MCL-1. Alvocidib has currently been examined in a phase II study for the treatment of intermediate- and high-risk AML combined with othet effective agents [ 62 ].…”