Phase I Dose-Escalation Study of SCH 900776 in Combination with Cytarabine (Ara-C) in Patients with Acute Leukemia

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.

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.