This is a phase I/II open label study being conducted to evaluate the overall safety and initial effectiveness of an investigational drug, Eltrombopag in patients who are 60 years of age and older and who have Acute Myelogenous Leukemia (AML). Eltrombopag is an investigational drug, which means it has not been approved by the U.S. Food and Drug Administration (FDA) for use in this type of disease. Approximately 35 people will be enrolled on this study at the University of Pennsylvania
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
44
Oral formulation taken daily
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, Pennsylvania, United States
Maximally Tolerated Dose of Eltrombopag for Elderly Subjects With AML in Phase 1 Group
The maximal tolerated dose of eltrombopag for elderly subjects with AML will be defined as the number of dose limiting toxicities per dosing level.
Time frame: The time from first day of therapy until subject is off study treatment, an average of 10 weeks.
Tolerability of Maximum Dose in Phase II Cohort
The tolerability of eltrombopag in elderly patients with AML at the maximally tolerated starting dose determined in Phase I portion of study will be assessed by the number of dose limiting toxicities in the Phase II dosing cohort. 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).
Time frame: The time from first day of therapy to the first four weeks of therapy.
The Safety of Eltrombopag for Elderly Subjects With AML in Phase 1 Group
Safety of eltrombopag will be measured as the number of Grade 3 or higher adverse events per dosing level in Phase 1 group related to Eltrombopag. Relatedness is defined as event being assessed as unlikely, possibly, probably and definitely related to Eltrombopag. All events meeting these assessment categories will be considered related, and those assessed as Grade 3 or higher are reported for each dose level.
Time frame: First day of study treatment to 30 days after last study treatment, an average of 10 weeks.
Safety of Eltrombopag in Patients With AML in Phase II Cohort.
Safety of eltrombopag will be measured as the number of Serious Adverse Events in Phase II group related to Eltrombopag. Relatedness is defined as event being assessed as unlikely, possibly, probably and definitely related to Eltrombopag. All Serious Adverse Events meeting these assessment categories will be considered related and are reported for the Phase II cohort.
Time frame: First day of study treatment to 30 days after last study treatment, an average of 7 weeks.
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Number of Participants With Peripheral Platelet Count Response in Phase I Cohort
Peripheral platelet count response is defined by number of participants in each dosing cohort exhibiting a peripheral platelet count response using the IWG modified Hematologic Improvement response criteria: For patients with counts less than 100,000/ul: 1) For patients with baseline platelet of \> 20,000/ul, absolute increase of platelet count by at least 30,000 /ul 2) For patients with baseline platelets \< 20,000/ul, an increase to \> 20,000/ul and by at least 100%.
Time frame: First day of study treatment to 30 days after last study treatment, an average of 10 weeks.
Overall Response Rate (Phase I and Phase II)
This will include subjects who achieve a complete remission (CR) based on definitions by the International Working Group (IWG). CR is defined as the participant have a neutrophil Count\>1000/ul, platelet count of \>100,000/ul, bone Marrow Blasts \< 5% and having no evidence of extramedullary disease.
Time frame: The time from first day of therapy to time when subject achieves a complete remission (CR), based on the definition of the International Working Group (IWG), approximately 30 days.