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Clinical Trial
. 2012 Dec 15;18(24):6723-31.
doi: 10.1158/1078-0432.CCR-12-2442. Epub 2012 Oct 23.

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

Judith E Karp  1 , Brian M Thomas, Jacqueline M Greer, Christopher Sorge, Steven D Gore, Keith W Pratz, B Douglas Smith, Karen S Flatten, Kevin Peterson, Paula Schneider, Karen Mackey, Tomoko Freshwater, Mark J Levis, Michael A McDevitt, Hetty E Carraway, Douglas E Gladstone, Margaret M Showel, Sabine Loechner, David A Parry, Jo Ann Horowitz, Randi Isaacs, Scott H Kaufmann
Affiliations
Clinical Trial

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

Judith E Karp et al. Clin Cancer Res. .

"V体育2025版" 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 VSports手机版. .

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 V体育安卓版. 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 V体育ios版. 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 VSports最新版本. .

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VSports app下载 - Conflict of interest statement

Disclosure of Potential Conflicts of Interest

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

Figures

Figure 1
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
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.
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References

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