Patients with Acute Myeloid Leukemia (AML) in complete remission will receive eltrombopag while undergoing consolidation chemotherapy with high-dose cytarabine. Eltrombopag may help increase the number of platelets during chemotherapy and may help prevent the risk of bleeding. Phase I will study the side effects, best dose and platelet effects of eltrombopag when given with consolidation chemotherapy. After the maximum safe and tolerated dose and schedule is found in Phase I, the study will proceed to Phase II. Phase II will confirm the dose and schedule of eltrombopag identified in Phase I that can increase platelet counts in patients receiving consolidation therapy.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
15
Cycle 1= Cytarabine 3 g/m² IV twice daily on Days 1, 3 and 5 (Patients \>60 years of age will receive cytarabine 1.5 g/m² IV per dose). Day 1 must start in AM. Eltrombopag (Open-Label) by mouth daily until platelet recovery or for 35 consecutive days, whichever occurs first. Phase I will determine the dose and schedule of Eltrombopag to be used in Phase II. One cycle of consolidation therapy with high-dose cytarabine and eltrombopag will be received on study. Additional chemotherapy may be administered at the investigators discretion without eltrombopag.
Cytarabine 3 g/m² IV twice daily on Days 1, 3 and 5 (Patients \>60 years of age will receive cytarabine 1.5 g/m² IV per dose). Day 1 must start in AM. Eltrombopag by mouth daily (dose and schedule as determined in Phase I) with 1st cycle of high-dose consolidation chemotherapy and placebo by mouth daily with 2nd cycle. Eltrombopag/placebo will continue until platelet recovery or for 35 consecutive days, whichever occurs first. Additional chemotherapy may be administered at the investigators discretion without eltrombopag.
Cytarabine 3 g/m² IV twice daily on Days 1, 3 and 5 (Patients \>60 years of age will receive cytarabine 1.5 g/m² IV per dose). Day 1 must start in AM. Placebo by mouth daily with 1st cycle of high-dose consolidation therapy and Eltrombopag by mouth daily (dose and schedule as determined in Phase I) with 2nd cycle. Eltrombopag/placebo will continue until platelet recovery or for 35 consecutive days, whichever occurs first. Additional chemotherapy may be administered at the investigators discretion without eltrombopag.
University of Massachusetts Worcester
Worcester, Massachusetts, United States
Mayo Clinic, Rochester
Rochester, Minnesota, United States
University Hospitals Case Medical Center
Cleveland, Ohio, United States
Penn State Hershey Cancer Institute
Hershey, Pennsylvania, United States
Vanderbilt University
Nashville, Tennessee, United States
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. The optimal dose was based on rules involving observation of Dose Limiting Toxicity (DLT events), defined as a CTCAE Version 4 non-hematologic adverse event of grade 3 or higher occurring within 30 days of the last dose of eltrombopag judged by the investigator to be at least possibly related to eltrombopag administration.
Time frame: 13 months
Phase I - Dose Level With Best Kinetics of Platelet Count Recovery
To describe the kinetics of platelet count recovery in acute myeloid leukemia patients in complete remission receiving intensive consolidation chemotherapy who will be receiving eltrombopag. This is assessed graphically by plotting platelet count vs. days relative to start of cytarabine for each patient.
Time frame: 13 months
Phase II- Assess if Platelet Count Recovery is Increased With Eltrombopag
To determine if platelet recovery following consolidation chemotherapy is accelerated with eltrombopag.
Time frame: 62 months
Phase I & Phase II- Pharmacokinetics of Eltrombopag
To determine the plasma concentrations of eltrombopag in acute myeloid leukemia patients in complete remission receiving intensive consolidation chemotherapy (selected dosing regimen only).
Time frame: 62 months
Phase II- Platelet Transfusion Requirements
To determine the impact of eltrombopag on platelet transfusion requirements in the setting of consolidation chemotherapy.
Time frame: 62 months
Phase II- Red Blood Cell Transfusion Requirements
To determine the impact of eltrombopag on red blood cell transfusion requirements.
Time frame: 62 months
Phase II- Bleeding Event Occurrence
To determine the impact of eltrombopag on occurrence of bleeding events.
Time frame: 62 months
Phase II- Time to Platelet Count Recovery
To determine the impact of eltrombopag on time to platelet recovery following consolidation chemotherapy.
Time frame: 62 months
Phase II- Depth of Platelet Nadir
To determine the impact of eltrombopag on the depth of platelet nadir following a cycle of consolidation chemotherapy.
Time frame: 62 months
Phase II- Duration of Platelet Nadir
To determine the duration of platelet nadir in the setting of eltrombopag exposure.
Time frame: 62 months
Phase II- Safety of Eltrombopag With Consolidation
To determine the safety and tolerability of eltrombopag when given at the optimal dose in the setting of consolidation chemotherapy.
Time frame: 62 months
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