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

Abstract

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.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed by the other authors.

©2012 AACR.

Figures

Figure 1

Mean (±SD) plasma concentration profiles of SCH 900776 following 15- or 30-mintue intravenous infusions of 10 (○), 20 (▼), 40 (□) or 56 mg/m2 (▲) or 140 mg SCH 900776 (◊) in combination with cytarabine.

Figure 2

Assessment of H2Ax phosphorylation in sequential marrow samples from individual patients undergoing treatment with cytarabine and SCH 900776 at dose levels 2 to 5. Aliquots of whole-cell lysates containing protein from 5 × 105 marrow mononuclear cells (median 80% blasts; range, 64%–98%) were subjected to SDS-PAGE and immunoblotting for phosphorylated H2Ax or, as a loading control, c-Raf (lanes 4–18). Duplicate blots probed for lamin B1 and histone H1 yielded similar results. Each blot also contained whole-cell lysates from 3 × 105 HL-60 cells treated for 24 hours with diluent, 1 µmol/L cytarabine, or 1 µmol/L cytarabine + 1 µmol/L SCH 900776 (lanes 1–3, respectively). Dashed line indicates 2 different exposure times for the phospho-H2Ax blot from patients 406 and 505.