Phase I Dose Finding/Phase II Placebo-Controlled Trial of Eltrombopag During Consolidation Therapy in Adults With Acute Myeloid Leukemia (AML) in Complete Remission
Consolidation chemotherapy with high dose cytarabine usually causes myelosuppression for 14
to 21 days after each treatment. Patients have low blood counts for days or weeks before the
bone marrow resumes function. This may result in e.g., hospitalization, treatment with
antibiotics, and transfusions with blood and/or platelets. In addition, this may cause a
delay in treatment and reduction in dose. To achieve the best outcome from treatment, dose
reductions and delays in treatment must be avoided.
The incidence and duration of decreased white blood cells (neutropenia) and neutropenic
complications have been reduced by the use of growth colony stimulating factors.
Additionally, the use of erythropoietin-stimulating factors has reduced anemia and the need
for red blood cell transfusions. Thrombocytopenia remains an important limiting factor in
administration of chemotherapy and maintaining dose intensity in some patients.
Additionally, the risk of bleeding secondary to low platelet counts may increase sickness or
even death in patients undergoing cancer treatment.
Thrombopoietin (TPO) is the principal cytokine involved in the regulation of
megakaryopoiesis and platelet production. Eltrombopag is an orally bioavailable, small
molecule, TPO-receptor agonist that stimulates platelet production by a similar, but not
identical, mechanism to endogenous TPO. Eltrombopag has been approved in the U.S. for the
treatment of chronic Idiopathic Thrombocytopenic Purpura. Eltrombopag is also under
development for other indications such as Hepatitis C Virus-associated thrombocytopenia,
Myelodysplastic Syndrome/AML, and oncology related thrombocytopenias. This agent appears to
possess many of the desirable properties for a treatment for chemotherapy induced
thrombocytopenia, including oral administration.
The Phase I portion of this study will be conducted using a dose escalation/de-escalation
strategy for patients in either the first or second complete remission. Dose escalations are
planned in the form of both acceleration of date of initiation of eltrombopag relative to
the start of consolidation chemotherapy as well as increasing daily dosing.
The Phase II portion will be conducted using the dose and schedule selected from the Phase I
portion of the study for those patients in first complete remission. Patients will be used
as their own controls, e.g., a two-period two-treatment cross-over design. Patients will be
randomly allocated 1:1 to one of two sequences. Patients randomized to Sequence A will
receive eltrombopag with their first cycle of consolidation and placebo with Cycle 2.
Patients randomized to Sequence B will receive placebo with their first cycle of
consolidation and eltrombopag with Cycle 2. The treatment assignment will be blinded to the
patient and all study/sponsor personnel.
Patients will undergo blood sample collection for Thrombopoietin(TPO)/ Erythropoietin(EPO)
and pharmacokinetic analysis of eltrombopag in Phase I and pharmacokinetic analysis of
eltrombopag in the Phase II portion of the study.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
Phase I- Optimal tolerated dose of eltrombopag
To determine the safety, tolerability and optimal dose of eltrombopag in acute myeloid leukemia patients in complete remission receiving intensive consolidation chemotherapy.
Hillard M Lazarus, MD
University Hospital Case Medical Center
United States: Food and Drug Administration
|Abramson Cancer Center of the University of Pennsylvania||Philadelphia, Pennsylvania 19104-4283|
|Vanderbilt University||Nashville, Tennessee 37232-6305|
|University Hospitals Case Medical Center||Cleveland, Ohio 44106|
|Penn State Hershey Cancer Institute||Hershey, Pennsylvania 17033|