Eltrombopag in Elderly Acute Myelogenous Leukemia (AML)

• Phase I Portion [ Designated as safety issue: No ]
  The maximally tolerated initial starting dose of eltrombopag for elderly subjects with AML. Clinical assessment and laboratory evaluation of Adverse Events and DLTs will be done according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 of the National Cancer Institute (NCI) Cancer Therapy Evaluation Program(CTEP).
  
  
• Phase II portion: [ Designated as safety issue: No ]
  The safety and tolerability of eltrombopag in elderly patients with AML at the maximally tolerated starting dose determined in Phase I portion of study. Clinical assessment and laboratory evaluation of Adverse Events and DLTs will be done according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 of the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP).
  
  

• Overall response rate (Phase I and Phase II) [ Designated as safety issue: No ]
  This will include subjects who achieve a complete remission (CR), CR with incomplete count recovery, partial response (PR), and hematologic improvement (HI) based on definitions by the International Working Group (IWG) Of note: subjects who only have HI-platelet (HIp) will not be considered to have had a disease response as this may be due to direct stimulation of meagkaryocytes and not cytotoxic effect
  
  
• Survival, Response and Progression [ Designated as safety issue: No ]

  Overall survival (OS) is defined as the time from first day of therapy to death due to any cause or last patient contact.

  Progression-free survival (PFS) is defined as the time from first day of therapy to disease progression, death due to any cause, or last patient contact.

  PFS is defined for all patients entered on the study, following an intent-to-treat analysis plan.

  Relapse free survival (RFS) Time from complete remission to disease relapse. The time to response is defined as the time from the first day of therapy until the time that measurement criteria are met for response.

  
  

Primary Objectives (Phase I Portion): 1). To determine the safety and tolerability of eltrombopag in elderly subjects with AML 2). To determine the maximally tolerated initial starting dose of eltrombopag for elderly subjects with AML Primary Objectives (Phase II portion): 1). To better define the safety and tolerability of eltrombopag in elderly patients with AML at the maximally tolerated starting dose Page 9 of 18 determined in Phase I portion of study. 2). To determine the incidence of peripheral platelet count improvement (using baseline and response parameters as defined below) for subjects with disease related thrombocytopenia. Secondary Objectives (Phase I and II): 1). To preliminarily determine the efficacy (using AML response criteria as defined below) of eltrombopag in elderly subjects with AML.

2). To perform ex-vivo analyses using subject AML samples and stock eltrombopag to 1) assess leukemic proliferative capacity and 2) investigate potential eltrombopag induced cytoxic mechanisms for leukemic cell death. 3). To perform pharmacodynamic assessments of drug activity in leukemic cells using subject samples collected at various time points before and during drug exposure. 4). To preliminarily correlate pharmacodynamic findings with clinical response.