Phase 1b Study of Omacetaxine, Cytarabine and Idarubicin in Newly Diagnosed Acute Myelogenous Leukemia

The five year overall survival for patients under 65 with newly diagnosed acute myelogenous leukemia (AML) is 30%. Despite such dismal outcomes, few modifications have been made to the standard of care induction chemotherapy regimen “7+3” comprising of cytarabine and an anthracycline since the regimen was first introduced more than 30 years ago. Both preclinical and clinical data have demonstrated that omacetaxine has efficacy and works synergistically with cytarabine against AML. Combining omacetaxine with standard induction therapy may lead to increased complete response rates and increased overall survival. The specific aims of the proposed research are: (1) To determine the optimally tolerated and active dose (OTD) of omacetaxine, when combined with cytarabine and idarubicin in the induction therapy of AML using a phase I clinical trial design. (2) To determine the efficacy of omacetaxine in the induction therapy of AML. (3) To determine if a particular subgroup will benefit from the addition of omacetaxine to standard induction therapy. The study goal is to determine the role of omacetaxine in AML when combined with standard “7+3” induction chemotherapy. The patient population will be newly diagnosed, untreated patients, ages 18-70, with AML, diagnosed according to the World Health Organization (WHO) classification for AML. The study design will be a phase Ib to evaluate omacetaxine when given in combination with a standard induction regimen of “7+3” cytarabine for Days 1-7 and idarubicin for Days 1-3) in patients with newly diagnosed AML. The study will evaluate omacetaxine dose escalation using the Modified Toxicity Probability Interval (mPTI) design. If the toxicity level of the dose level is within the under dosing interval, the mTPI design will recommend escalating the dose level. For overdosing (toxicity), the mTPI will recommend de-escalating the dose level; for proper dosing, the mTPI will recommend continuing. Post induction therapy will consist of standard high dose cytarabine consolidation chemotherapy or allogeneic stem cell transplantation based on pretreatment cytogenetic risk assessment.