Phase I and Pharmacokinetic Study of Flavopiridol followed by 1-β-d-Arabinofuranosylcytosine and Mitoxantrone in Relapsed and Refractory Adult Acute Leukemias

Abstract

Purpose: The serine/threonine kinase inhibitor flavopiridol targets multiple cyclin-dependent kinases, induces checkpoint arrest, and interrupts transcriptional elongation.We designed a phase I clinical trial using a timed sequential therapy approach where flavopiridol was given for the dual purpose of initial cytoreduction and enhancing cell cycle progression of the remaining leukemia cell cohort followed by cycle-dependent drugs 1-h-D-arabinofuranosylcytosine (ara-C) and mitoxantrone. Experimental Design: Flavopiridol was given by1-hour infusion daily for 3 days beginning day1 followed by 2 g/m 2 /72 h ara-C beginning day 6 and 40 mg/m 2 mitoxantrone beginning day 9. In vivo correlates included pharmacokinetics, modulation of blast cycle regulators, and serum and marrow supernatant vascular endothelial growth factor levels. Results: Of 34 adults receiving induction therapy, 16 (47%) evinced direct leukemia cytotoxicity with z50 % drop in peripheral blast counts and tumor lysis in 9 (26 %). Four (12 %) died during therapy (two fungal infections and two sudden death). Dose-limiting toxicity occurred at 60 mg/m 2 /d with profound neutropenia >40 days duration, and maximal tolerated dose was 50 mg/m 2 /d. Overall response rate was 31% in 26 acute myelogenous leukemia and 12.5% in acute lymphoblastic leukemia. Pharmacokinetics showed that a linear two-compartment model with first-order elimination provided the best fit of the observed concentration versus time data. Flavopiridol down-regulated one or more target proteins in marrow blasts in vivo.Vascular endothelial growth factor was detected in sera and marrow supernatant pretreatment, and sera obtained on day 3 inhibited bovine aortic endothelial cell proliferation by a mean of 32% (range, 10-80%). Conclusions: Our data suggest that flavopiridol is cytotoxic to leukemic cells and, when followed by ara-C and mitoxantrone, exerts biological and clinical effects in patients with relapsed and refractory acute leukemias. These findings warrant continuing development of flavopiridol at 50 mg/m 2 /d  3 days in combination with cytotoxic and biological agents for acute leukemias.

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

“…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.…”

“…[5][6][7][8][9][10][11][12][13][14][15] We have conducted longitudinal clinical-laboratory studies of flavopiridol followed in a timed sequential manner by ara-C and mitoxantrone (FLAM). [16][17][18][19] The hypothesis-driven design of FLAM was generated in an in vitro model where flavopiridol followed by ara-C enhanced ara-C related apoptosis in marrow leukemic blasts. 20,21 Serial trials of FLAM in poor-risk AML [16][17][18] have documented reproducible and durable CRs and low morbidity and mortality.…”

“…[16][17][18][19] The hypothesis-driven design of FLAM was generated in an in vitro model where flavopiridol followed by ara-C enhanced ara-C related apoptosis in marrow leukemic blasts. 20,21 Serial trials of FLAM in poor-risk AML [16][17][18] have documented reproducible and durable CRs and low morbidity and mortality. For newly diagnosed, poor-risk patients, 67% achieved CR, 9% died in the first 60 days, and median overall survival (OS) and disease-free survival (DFS) for patients achieving CR were 12.6 and 13.3 months, respectively.…”

“…The 'hybrid' schedule yielded dramatic responses in more than 50% of refractory chronic lymphocytic leukemia (CLL) patients, accompanied by severe tumor lysis syndrome. [26][27][28] Based on our phase II data using 1-h bolus flavopiridol in FLAM, [16][17][18] and the results of single-agent hybrid flavopiridol in CLL, we conducted a phase I trial of 'hybrid FLAM' built on the template of previous trials. 19 Dose-limiting toxicity occurred with 100 mg/m 2 (30 mg/m 2 bolus, 70 mg/m 2 infusion), with tumor lysis, hyperbilirubinemia and mucositis.…”

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.…”