Trial of Eltrombopag During Consolidation Therapy in Adults With AML in Complete Remission
NCT ID: NCT01656252
Last Updated: 2020-11-03
Study Results
Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.
View full resultsBasic Information
Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.
TERMINATED
PHASE1/PHASE2
15 participants
INTERVENTIONAL
2012-07-31
2016-03-31
Brief Summary
Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.
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.
Detailed Description
Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.
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.
Conditions
See the medical conditions and disease areas that this research is targeting or investigating.
Study Design
Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.
RANDOMIZED
PARALLEL
TREATMENT
TRIPLE
Study Groups
Review each arm or cohort in the study, along with the interventions and objectives associated with them.
Phase I- Cytarabine & Eltrombopag
Cycle 1= Cytarabine twice daily on Days 1, 3 and 5 and Eltrombopag (Open-Label) 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.
Phase I- Cytarabine & Eltrombopag
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.
Phase II- Sequence A
Cytarabine twice daily on Days 1, 3 and 5. Eltrombopag(dose and schedule as determined in Phase I) with 1st cycle of high-dose consolidation chemotherapy and placebo with 2nd cycle. Treatment sequence will be blinded to the patient and all study/sponsor personnel.
Phase II- Sequence A
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.
Phase II- Sequence B
Cytarabine twice daily on Days 1, 3 and 5. Placebo with 1st cycle of high-dose consolidation therapy and Eltrombopag(dose and schedule as determined in Phase I) with 2nd cycle. Treatment sequence will be blinded to the patient and all study/sponsor personnel.
Phase II- Sequence B
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.
Interventions
Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.
Phase I- Cytarabine & Eltrombopag
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.
Phase II- Sequence A
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.
Phase II- Sequence B
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.
Other Intervention Names
Discover alternative or legacy names that may be used to describe the listed interventions across different sources.
Eligibility Criteria
Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.
Inclusion Criteria
Phase I Enrollment:
* Must be in first or second complete remission, e.g., no evidence of active disease in blood, bone marrow (\<5% blasts), or other tissues.
* For each remission, may have received no more than 2 cycles of induction treatment (any type).
* May have received no more than one course of consolidation for the current remission prior to enrollment (any type)
Phase II Enrollment:
* Must be in first complete remission, e.g., no evidence of active disease in blood, bone marrow (\<5% blasts), or other tissues.
* May have received no more than 2 cycles of induction treatment (any type).
Enrollment in Either Phase:
* Remission status must be documented by a bone marrow examination up to 28 days prior to study registration.
* Have recovered from induction and first consolidation (if applicable) therapy side effects (or ≤grade 1).
* ≥18 years of age and ≤70 years of age.
* ECOG performance status 0, 1, 2.
* Have not received cytotoxic drug therapy within 21 days of registration.
* Have not received hematopoietic colony stimulating growth factors within 14 days of registration.
* Have not received packed red blood cells or platelets within 7 days of registration.
* Have not received investigational agents within 30 days of registration and will not receive any investigational agents other than eltrombopag/placebo during study.
* Signed IRB-approved informed consent.
* Willing to provide blood samples for research purposes.
* Adequate organ function obtained within 28 days prior to registration:
* Absolute neutrophil count \>1 x 10⁹/L
* Platelet count \>100 x 10⁹/L
* Total direct serum bilirubin ≤1.5x upper limit of normal (ULN)
* ALT and AST ≤3x ULN
* BUN and serum creatinine \<2x ULN
* Albumin ≥2.5 g/dL
* PT and PTT 80-120% of institutional normal range
* Women of childbearing potential must have a negative serum pregnancy test within 14 days of registration.
* Not pregnant nor breast feeding.
* Women of childbearing potential and sexually active males must use an accepted and effective method of contraception.
* Patients of known East Asian ancestry (Chinese, Japanese, Taiwanese, and Korean) are excluded from protocol participation for safety and efficacy reasons.
* Able to swallow and retain orally administered medication.
* No clinically significant gastrointestinal abnormalities such as malabsorption syndrome or major resection of the stomach or bowels.
* No clinical evidence of hepatomegaly or splenomegaly.
* No known risk for Torsades de Pointes. (Eltrombopag use has not been shown to be associated with Torsades de Pointes.)
* No active or unresolved infection and must be off all antibiotics for at least 7 days prior to registration.
* No current evidence of invasive fungal infection.
* No known Hepatitis B, Hepatitis C active disease.
* No known Human Immunodeficiency Virus (HIV) seropositivity. The risk for potential toxicities secondary to HIV (e.g., increased risk for fatal opportunistic infection) may confound the toxicity profile of eltrombopag.
* Patients with a history of Central Nervous System (CNS) leukemia are eligible if there is documentation of no current CNS involvement on cerebrospinal fluid (CSF) examination (e.g., negative CSF by lumbar puncture) within 28 days of registration.
* No prior or concomitant malignancy in the past 5 years which is currently active and likely to interfere with the patient's treatment for AML or which is likely to increase the patient's morbidity or mortality. No prior chemotherapy or radiation therapy allowed (unless related to AML treatment).
* No concurrent organ damage or medical problems that would prohibit therapy.
18 Years
70 Years
ALL
No
Sponsors
Meet the organizations funding or collaborating on the study and learn about their roles.
GlaxoSmithKline
INDUSTRY
Novartis
INDUSTRY
PrECOG, LLC.
OTHER
Responsible Party
Identify the individual or organization who holds primary responsibility for the study information submitted to regulators.
Principal Investigators
Learn about the lead researchers overseeing the trial and their institutional affiliations.
Hillard M Lazarus, MD
Role: STUDY_CHAIR
University Hospitals Cleveland Medical Center
Locations
Explore where the study is taking place and check the recruitment status at each participating site.
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
Countries
Review the countries where the study has at least one active or historical site.
References
Explore related publications, articles, or registry entries linked to this study.
Mavroudi I, Pyrovolaki K, Pavlaki K, Kozana A, Psyllaki M, Kalpadakis C, Pontikoglou C, Papadaki HA. Effect of the nonpeptide thrombopoietin receptor agonist eltrombopag on megakaryopoiesis of patients with lower risk myelodysplastic syndrome. Leuk Res. 2011 Mar;35(3):323-8. doi: 10.1016/j.leukres.2010.06.029. Epub 2010 Aug 4.
Will B, Kawahara M, Luciano JP, Bruns I, Parekh S, Erickson-Miller CL, Aivado MA, Verma A, Steidl U. Effect of the nonpeptide thrombopoietin receptor agonist Eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome. Blood. 2009 Oct 29;114(18):3899-908. doi: 10.1182/blood-2009-04-219493. Epub 2009 Aug 26.
Kellum A, Jagiello-Gruszfeld A, Bondarenko IN, Patwardhan R, Messam C, Mostafa Kamel Y. A randomized, double-blind, placebo-controlled, dose ranging study to assess the efficacy and safety of eltrombopag in patients receiving carboplatin/paclitaxel for advanced solid tumors. Curr Med Res Opin. 2010 Oct;26(10):2339-46. doi: 10.1185/03007995.2010.510051.
Vadhan-Raj S. Management of chemotherapy-induced thrombocytopenia: current status of thrombopoietic agents. Semin Hematol. 2009 Jan;46(1 Suppl 2):S26-32. doi: 10.1053/j.seminhematol.2008.12.007.
Strickland SA, Wang XV, Cerny J, Rowe JM, Rybka W, Tallman MS, Litzow M, Lazarus HM. A novel PrECOG (PrE0901) dose-escalation trial using eltrombopag: enhanced platelet recovery during consolidation therapy in acute myeloid leukemia. Leuk Lymphoma. 2020 Sep;61(9):2191-2199. doi: 10.1080/10428194.2020.1762878. Epub 2020 May 30.
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
ELT114465
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
PrE0901
Identifier Type: -
Identifier Source: org_study_id