Phase I and Pharmacological Trial of Cystosine Arabinoside with the Selective Checkpoint 1 Inhibitor SCH 900776 in Refractory Acute Leukemias
Mené sur 24 patients adultes atteints d'une leucémie aiguë récidivante ou réfractaire, cet essai de phase I évalue la toxicité d'un traitement combinant la cytarabine avec un composé appelé SCH 900776, un inhibiteur de Chk1
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. Methods. 24 adults with relapsed and refractory acute leukemias received timed sequential, continuous infusion cytarabine 2 gm/m2 over 72 hrs (667 mg/m2/24 hrs) 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/m2/dose. Results. Dose limiting toxicities consisting of QTc prolongation and grade 3 palmar-plantar erythrodysesthesia occurred at 140 mg flat dosing (dose level 5, equivalent to 80 mg/m2). Complete remissions occurred in 8/24 (33%) patients, with 7/8 at 40 mg/m2 or higher. SCH 900776 did not accumulate at any dose level. Marrow blasts obtained pretreatment and during therapy demonstrated increased phosphorylation of H2Ax after SCH 900776 beginning at 40 mg/m2, 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/m2) for adults with poor-risk leukemias. The trial (SP P05247) was registered at www.clinicaltrials.gov as NCT #00907517.