Horowitz, Jo Ann

Abstract Abstract 1531 Checkpoint kinase (Chk1) is a serine-threonine kinase that is activated via phosphorylation in response to DNA damage and is critical to the regulation of cell cycle progression. Ara-C triggers sequential activation of ATR kinase and Chk1 ex vivo to induce the S phase slowing that accompanies Ara-C treatment. Inhibition of Chk1 may abrogate S phase slowing, thereby preventing repair of Ara-C-induced DNA damage and potentiating the antitumor activity of Ara-C. The Hsp90 inhibitor tanespimycin (17-AAG) has been shown to enhance the cytotoxicity of Ara-C in part through Chk1 downregulation (RA Mesa et al., Blood 2005). While a phase I trial of Ara-C plus 17-AAG resulted in decreased blast cell Chk1 phosphorylation, drug toxicities precluded the clinical use of tanespimycin (SH Kaufmann et al., Haematologica, in press 2011). We have now tested the selective Chk1 inhibitor SCH 900776 (SCH 776) in combination with Ara-C in a Phase I dose-escalation trial in 24 adult patients with relapsed and refractory acute leukemias. AML (21) ALL (2) CML-BC (1) Male/Female 9/12 1/1 1/0 Age (range) 57 (23–73) 30, 63 36 Previous Ara-C 19 0 1 Relapsed 8 1 0 No. Prior CRs 2 (1–3) 2 0 Prior Stem Cell Transplant 6 0 0 Refractory 13 1 1 No. Prior Regimens 2 (1–4) 3 3 Prior Stem Cell Transplant 1 0 0 Secondary AML 8 0 0 MDS/MPD 6 0 0 Treatment-Related 2 0 0 Adverse Genetics 13 1 1 Single cytogenetics 3 1 0 Complex cytogenetics 11 0 1 Patients received Ara-C 667 mg/m2 on days 1–3 and 10–12 via 72-hour IV infusion along with SCH 776 on days 2, 3, 11, and 12 over 15 min IV starting at 10 mg/m2 (n=3) escalated to 20 mg/m2 (n=3), 40 mg/m2 (n=6), 56 mg/m2 (n=6), and flat dose of 140 mg (n=6) administered over 30 min IV. Maximal administered dose was achieved at 140 mg due to grade 3 prolonged QTc interval (n=1) and grade 3 hand-foot skin reaction (n=1). None of the expected mucosal or marrow toxicities of timed sequential Ara-C were exacerbated by SCH 776. Complete tumor clearance from day 14 bone marrow was detected in 13/24 (54%). CR plus CRi occurred in 7 patients (29%), with 6 of those CRs occurring at 40 mg/m2 or higher (response rate 40% for ≥ dose level 3). Examination of sequential samples of marrow blasts harvested pretreatment (day 0), 24 hours after initial Ara-C infusion prior to SCH 776 (day 2), and 2 hours after the second SCH 776 administration (day 3) demonstrated increased phosphorylation of Chk1 at Ser317 or Ser345 beginning at 40 mg/m2 consistent with the presence of unrepaired damage and further ATR activation. Pharmacokinetic (PK) data in each cohort showed lack of significant accumulation of SCH 776 in plasma. We plan for a randomized Phase II trial with 100 mg flat dose (or equivalent of 56 mg/m2) of SCH 900776 to assess any contributions to net Ara-C cytotoxicity and efficacy in relapsed and refractory acute leukemias. Disclosures: Gore: Celgene: Consultancy, Equity Ownership, Research Funding. Loechner:Merck Research Laboratories: Employment. Horowitz:Merck Research Labs: Employment, stock. Karp:Schering Merck: Research Funding.

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/m2 over 72 hours (667 mg/m2/24 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/m2/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/m2). Complete remissions occurred in 8 of 24 (33%) patients, with 7 of 8 at 40 mg/m2 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/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 NCT00907517. Clin Cancer Res; 18(24); 6723–31. ©2012 AACR.