Phase I Dose Finding/Phase II Placebo-Controlled Trial of Eltrombopag During Consolidation Therapy in Adults With Acute Myeloid Leukemia (AML) in Complete Remission
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- PrECOG, LLC.
- 入组人数
- 15
- 试验地点
- 5
- 主要终点
- Phase II- Assess if Platelet Count Recovery is Increased With Eltrombopag
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Cytomorphologically documented diagnosis of acute myeloid leukemia (AML). Acute promyelocytic leukemia patients will be excluded (FAB M3). FAB classification, cytogenetics and molecular markers (if applicable) must be available at registration.
- •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,
- •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.
排除标准
- 未提供
研究组 & 干预措施
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.
干预措施: Phase I- Cytarabine & Eltrombopag (Drug)
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.
干预措施: Phase II- Sequence A (Drug)
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.
干预措施: Phase II- Sequence B (Drug)
结局指标
主要结局
Phase II- Assess if Platelet Count Recovery is Increased With Eltrombopag
时间窗: 62 months
To determine if platelet recovery following consolidation chemotherapy is accelerated with eltrombopag.
Phase I- Optimal Tolerated Dose of Eltrombopag
时间窗: 13 months
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.
Phase I - Dose Level With Best Kinetics of Platelet Count Recovery
时间窗: 13 months
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.
次要结局
- Phase II- Safety of Eltrombopag With Consolidation(62 months)
- Phase II- Red Blood Cell Transfusion Requirements(62 months)
- Phase II- Bleeding Event Occurrence(62 months)
- Phase I & Phase II- Pharmacokinetics of Eltrombopag(62 months)
- Phase II- Platelet Transfusion Requirements(62 months)
- Phase II- Time to Platelet Count Recovery(62 months)
- Phase II- Depth of Platelet Nadir(62 months)
- Phase II- Duration of Platelet Nadir(62 months)