Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias

Abstract

BackgroundA pharmacokinetically derived schedule of flavopiridol administered as a 30 min intravenous bolus followed by 4-hour continuous intravenous infusion (IVB/CIVI) is active in fludarabinerefractory chronic lymphocytic leukemia, but no studies examining the feasibility and maximum tolerated dose of this schedule have been reported in acute leukemia. Design and MethodsWe conducted a phase I dose escalation trial of single-agent flavopiridol in adults with relapsed/refractory acute leukemias, utilizing a modification of the intravenous bolus/continuous intravenous infusion approach, intensifying treatment for administration on days 1, 2, and 3 of 21-day cycles. ResultsTwenty-four adults with relapsed/refractory acute myeloid leukemia (n=19) or acute lymphoblastic leukemia (n=5) were enrolled. The median age was 62 years (range, 23-78). The maximum tolerated dose of flavopiridol was 40mg/m 2 intravenous bolus plus 60mg/m 2 continuous intravenous infusion (40/60). The dose limiting toxicity was secretory diarrhea. Lifethreatening hyperacute tumor lysis syndrome requiring hemodialysis on day 1 was observed in one patient. Pharmacokinetics were dose-dependent with increased clearance observed at the two highest dose levels. Diarrhea occurrence and severity significantly correlated with flavopiridol concentrations at the end of the 4-hour infusion, volume of distribution, and elimination half-life. Modest anti-leukemic activity was observed, with most patients experiencing dramatic but transient reduction/clearance of circulating blasts lasting for 10-14 days. One refractory acute myeloid leukemia patient had short-lived complete remission with incomplete count recovery. ConclusionsFlavopiridol as a single agent given by intravenous bolus/continuous intravenous infusion causes marked, immediate cytoreduction in relapsed/refractory acute leukemias, but objective clinical responses were uncommon. With this schedule, the dose is limited by secretory diarrhea (ClinicalTrials.gov Identifier: NCT00101231).

Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription

“…10,35 While clinical studies have demonstrated the safety of using transcriptional repressors such as flavopiridol and SNS-032 that inhibit Cdks and block Mcl-1 expression, the limited clinical activity observed in patients with leukemias suggests that targeting Mcl-1 alone may only be effective in a subset of AML cases. 45,46 Our findings show that dual targeting of both PI3K and transcriptional kinases by PIK-75 demonstrates antileukemic activity in primary human AML cells without impacting on the survival, colonyforming potential, or engraftment capacity of nontransformed hematopoietic BM progenitors ( Figure 6). Thus, while PIK-75 targets 2 fundamental cell survival pathways, our data indicate that there is a therapeutic window that permits selective targeting of AML cells.…”

Randomized phase II study of two schedules of flavopiridol given as timed sequential therapy with cytosine arabinoside and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia

“…In our phase I trial of FLAM with escalating doses of 'hybrid' flavopiridol for adults with relapsed and refractory acute leukemias, 19 the maximal tolerated dose was 90 mg/m 2 (30 mg/m 2 bolus followed by 60 mg/m 2 infusion) daily for three days, which represents a 28% increase over the 70 mg/m 2 total dose daily for three days used in the present study. However, pharmacokinetic studies of haematologica | 2012; 97(11) flavopiridol given by bolus, 16,23,25 infusional, 23,24,34 or 'hybrid' 19,[26][27][28][29] schedules display significant inter-individual variability. This variability occurs for both total and unbound drug concentrations and, in the context of the 'hybrid' schedule, is independent of total serum protein, albumin, WBC or occurrence of flavopiridol-related toxicities.…”

“…19 In order to mitigate imbalance in randomization, patients were stratified by presence or absence of secondary AML, antecedent MDS or MPD six months or more prior to AML transformation, and therapy for antecedent disorder. 29,30 As in previous FLAM trials, [16][17][18][19] a 72-h continuous infusion of ara-C 2 gms/m 2 (667 mg/m 2 /24 h) began Day 6 and mitoxantrone 40 mg/m 2 was administered as an intravenous bolus over 60-120 min on Day 9, 12 h after completing ara-C. Patients who achieved CR after cycle 1 were eligible to receive a second cycle of FLAM beginning 21±7 days following hospital discharge from the first cycle.…”

The CDK inhibitors in cancer research and therapy

“…The combinations of Xavopiridol with gemcitabine and irinotecan (Fekrazad et al 2010), vorinostat (Dickson et al 2010), oxaliplatin and Xuorouracil/leucovorin (Rathkopf et al 2009), paclitaxel and carboplatin (George et al 2008), cisplatin and carboplatin ) and irinotecan (Shah et al 2005) were also assessed in various solid tumors in phase I clinical trials. In leukemias, Xavopiridol both as single agent Blum et al 2010) and in combinations with 1-beta-D-arabinofuranosylcytosine and mitoxantrone (Karp et al 2005) and cytosine arabinoside and mitoxantrone (Karp et al 2011) showed a promise in phase I clinical trials.…”