Randomized Phase II Trial of Timed Sequential Cytosine Arabinoside (ara-C) with and without the Checkpoint Kinase 1 (CHK1) Inhibitor MK-8776 in Adults with Relapsed
B Douglas Smith
1.1 Primary Objective To compare the rates of complete remission (CR) plus CR with incomplete recovery (CRi) achieved with cytosine arabinoside (ara-C) plus the checkpoint kinase 1 (CHK1) inhibitor MK-8776 vs. ara-C alone for adults (ages 18-75) with relapsed acute myelogenous leukemia (AML). 1.2 Secondary Objectives 1.2.1 To evaluate and compare the toxicities of ara-C + MK-8776 vs. ara-C alone 1.2.2 To determine the impact of MK-8776 on AML blast cell DNA repair protein expression profiles and correlate the expression profiles with CR/CRi in response to ara-C + MK-8776 vs. ara-C alone. 1.2.3 To evaluate and compare the amount of DNA damage induced in AML blasts by ara-C + MK-8776 vs. ara-C.
Tumor Types: Adults age 18 to 75 yrs with relapsed Acute Myelogenous Leukemia (AML). Performance Status: ECOG 0-2 Abnormal Function Permitted: Multilineage bone marrow failure Serum creatinine less than 2.0 mg/dl Hepatic enzymes (AST, ALT) less than 5x upper limit of normal (ULN) Bilirubin less than 2.0 mg/dl unless Gilbertâ??s, hemolysis, or leukemic infiltration Left ventricular ejection fraction greater than 45% Baseline QTc less than 480 msec Allowed Prior Therapy: No more than 2 prior cytotoxic therapies (induction+consolidation or induction+transplant considered as 1 therapy) Previous allogeneic or autologous stem cell transplant permitted greater than 2 weeks from prior cytotoxic therapy greater than 2 weeks off biologic therapies including hematopoietic growth factors If using Hydroxyurea, steroids, tyrosine kinase/src inhibitors (including FLT 3 inhibitors), , interferon, or leukopheresis for count control, must be off therapy for greater than 24 hours prior to beginning therapy with ara-C +/- MK-8776.
Phase of Study: Randomized Phase II Treatment Plan: â?¢Arm A: ara-C 2 gm/m2 continuous intravenous infusion (CIVI) over 72 hours (0.667 gm/m2/24 hours) beginning days 1 and 10 plus MK-8776 100 mg/dose given by 30 minute IV infusion days 2,3 and 11,12 â?¢Arm B: ara-C 2 gm/m2 CIVI over 72 hours (0.667 gm/m2/24 hours) beginning days 1 and 10 Patients who achieve CR,CRi or PR may receive up to 1 additional cycles of therapy, provided that hematologic recovery occurs within 42 days of cycle completion and no dose-limiting non-hematologic toxicity occurs.
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