Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias.

Flavopiridol is a protein bound, cytotoxic, cyclin-dependent kinase inhibitor. Flavopiridol given by 1-hour bolus at 50 mg/m(2) daily 3 times followed by cytosine arabinoside and mitoxantrone (FLAM) is active in adults with poor-risk acute leukemias. A pharmacologically derived "hybrid" schedule (30-minute bolus followed by 4-hour infusion) of flavopiridol was more effective than bolus administration in refractory chronic lymphocytic leukemia. Our phase 1 trial "hybrid FLAM" in 55 adults with relapsed/refractory acute leukemias began at a total flavopiridol dose of 50 mg/m(2) per day 3 times (20-mg/m(2) bolus, 30-mg/m(2) infusion). Dose-limiting toxicity occurred at level 6 (30-mg/m(2) bolus, 70-mg/m(2) infusion) with tumor lysis, hyperbilirubinemia, and mucositis. Death occurred in 5 patients (9%). Complete remission occurred in 22 (40%) across all doses. Overall and disease-free survivals for complete remission patients are more than 60% at more than 2 years. Pharmacokinetics demonstrated a dose-response for total and unbound plasma flavopiridol unrelated to total protein, albumin, peripheral blast count, or toxicity. Pharmacodynamically, flavopiridol inhibited mRNAs of multiple cell cycle regulators, but with uniform increases in bcl-2. "Hybrid FLAM" is active in relapsed/refractory acute leukemias, with a recommended "hybrid" dose of bolus 30 mg/m(2) followed by infusion of 60 mg/m(2) daily for 3 days. This clinical trial is registered at www.clinicaltrials.gov as #NCT00470197.

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.

BACKGROUND: Flavopiridol is a protein-bound, cytotoxic, cyclin dependent kinase inhibitor. A phase II trial of flavopiridol followed by ara-C and mitoxantrone with flavopiridol given by 1-h bolus for adults with newly-diagnosed, poor-risk acute myelogenous leukemia yielded 67% complete remission with median disease-free survival of 13.6 months. DESIGN AND METHODS: We compared bolus flavopiridol (50 mg/m(2)/day, Arm A) versus 'hybrid' flavopiridol (30 mg/m(2) over 30 min followed by 40 mg/m(2) over 4 h, Arm B) followed by ara-C and mitoxantrone in 78 patients (39 per arm) with newly diagnosed, poor-risk acute myelogenous leukemia. To mitigate imbalance, patients were stratified by presence or absence of secondary leukemia and therapy for antecedent disorder. RESULTS: Death at or before Day 60 occurred in 8% of patients per arm. Complete remission plus complete remission with incomplete recovery was 68% (Arm A, 62%; Arm B, 74%) overall, and 65% or over in both arms for patients with secondary leukemia and leukemia with adverse genetics. In Arm A 91% and in Arm B 86% of patients received chemotherapy and/or allogeneic transplantation in complete remission. Median overall survival for all remission patients has not been reached for either arm, with median disease free survival of 13.6 months for Arm A and of 12.0 months for Arm B. CONCLUSIONS: Both flavopiridol schedules produce comparably encouraging results in adults with poor-risk acute myelogenous leukemia. Given the greater ease of bolus administration, we are conducting a randomized phase II study of bolus flavopiridol followed by ara-c and mitoxantrone versus conventional induction therapy for patients aged 70 years and under with intermediate or poor-risk acute myelogenous leukemia. This study is registered at www.clinicaltrials.gov as #NCT 00407966.

Phase I and pharmacologic trial of cytosine arabinoside with the selective checkpoint 1 inhibitor Sch 900776 in refractory acute leukemias.

PURPOSE: Incorporation of cytarabine into DNA activates checkpoint kinase 1 (Chk1), which stabilizes stalled replication forks, induces S-phase slowing, and diminishes cytarabine cytotoxicity. The selective Chk1 inhibitor SCH 900776 abrogates cytarabine-induced S-phase arrest and enhances cytarabine cytotoxicity in acute leukemia cell lines and leukemic blasts in vitro. To extend these findings to the clinical setting, we have conducted a phase I study of cytarabine and SCH 900776. EXPERIMENTAL DESIGN: Twenty-four adults with relapsed and refractory acute leukemias received timed sequential, continuous infusion cytarabine 2 g/m(2) over 72 hours (667 mg/m(2)/24 hours) beginning on day 1 and again on day 10. SCH 900776 was administered as a 15- to 30-minute infusion on days 2, 3, 11, and 12. The starting dose of SCH 900776 was 10 mg/m(2)/dose. RESULTS: Dose-limiting toxicities consisting of corrected QT interval prolongation and grade 3 palmar-plantar erythrodysesthesia occurred at 140 mg flat dosing (dose level 5, equivalent to 80 mg/m(2)). Complete remissions occurred in 8 of 24 (33%) patients, with 7 of 8 at 40 mg/m(2) or higher. SCH 900776 did not accumulate at any dose level. Marrow blasts obtained pretreatment and during therapy showed increased phosphorylation of H2Ax after SCH 900776 beginning at 40 mg/m(2), consistent with unrepaired DNA damage. CONCLUSIONS: These data support a randomized phase II trial of cytarabine +/- SCH 900776 at a recommended flat dose of 100 mg (equivalent to 56 mg/m(2)) for adults with poor-risk leukemias. The trial (SP P05247) was registered at www.clinicaltrials.gov as NCT00907517.