A Phase I Study of Azacitidine Combined With Mitoxantrone and Etoposide (A-NOVE) Chemotherapy for Patients' Age ≥ 60 With Poor Prognosis Acute Myeloid Leukemia (AML)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 13
- 试验地点
- 2
- 主要终点
- Maximum-tolerated dose of azacitidine that can be safely combined with mitoxantrone hydrochloride and etoposide chemotherapy
研究概览
简要总结
This phase I trial studies the best dose of azacitidine and to see how well it works with mitoxantrone hydrochloride and etoposide in treating older patients with acute myeloid leukemia that has a lower chance of responding to treatment or higher risk of returning (poor prognosis). Drugs used in chemotherapy, such as azacitidine, mitoxantrone hydrochloride, and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.
详细描述
PRIMARY OBJECTIVES:
I. To determine the highest tolerated dose of two dosing schedules of azacitidine when combined with mitoxantrone (mitoxantrone hydrochloride) and etoposide (A-NOVE) chemotherapy in poor prognosis older patients with acute myeloid leukemia (AML).
II. To evaluate the toxicity of this regimen.
SECONDARY OBJECTIVES:
I. To determine the complete response (CR) rate and using this regimen. II. To evaluate changes in topoisomerase II activity, deoxyribonucleic acid (DNA) methylation and DNA expression arrays in leukemia cells during azacitidine treatment, and to correlate these changes with responses to A-NOVE chemotherapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 60 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Acute myeloid leukemia (AML) as defined by World Health Organization (WHO) criteria, any subtype, de novo or secondary, except acute promyelocytic leukemia (APL)
- •One of the following:
- •Previously untreated, with adverse-risk cytogenetics, including any one of the following:
- •Complete or partial deletion of chromosome 7
- •Complete or partial deletion of chromosome 5
- •At least 3 numerical or structural abnormalities, other than t(15;17), t(8;21) or inv(16) or variant
- •11q23 abnormalities
- •Inv(3) or variant such as t(3:3)
- •Previously untreated, transformed from prior myelodysplastic syndrome (MDS) or myeloproliferative disorder (MPD) other than CML
- •Persistent leukemia following one cycle of 3+7 induction therapy (cytarabine plus either daunorubicin or idarubicin), any cytogenetic risk group
- •Left ventricular ejection fraction (LVEF) > 50% based on multi gated acquisition scan (MUGA) scan or 2-dimensional (2-D) echocardiogram
- •Serum creatinine =< 1.5 x upper limit of normal (ULN)
- •Serum bilirubin =< 1.5 x ULN
- •Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky >= 60%)
- •Patients with high initial white blood cell (WBC) should have the WBC reduced to below 50 x 10^9/L with hydroxyurea, to minimize the risk of leukostasis related-complications; hydroxyurea is permitted up to 24 hours prior to starting azacitidine
- •Men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; men should not father a child while participating in this study
- •Ability to understand and the willingness to sign a written informed consent document
排除标准
- •Patients who have had chemotherapy, radiotherapy or investigational agents within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
- •Patients who have received prior radiation greater than 3000 cGy to marrow producing areas
- •Patients may not be receiving any other investigational agents
- •Patients with active central nervous system (CNS) leukemia; prior CNS leukemia is permitted provided the cerebrospinal fluid has cleared and there is no other evidence of active CNS leukemia
- •Prior therapy for AML with decitabine, azacitidine, mitoxantrone, or etoposide
- •Prior therapy with azacitidine or decitabine for pre-existing MDS
- •History of allergic reactions attributed to decitabine, azacitidine, etoposide, mitoxantrone, or compounds of similar chemical or biologic composition
- •Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- •Human immunodeficiency virus (HIV)-positive patients with cluster of differentiation (CD) counts less than 500/mm^3 and/or a history of HIV/acquired immune deficiency syndrome (AIDS)-related complications will be excluded from the study
研究组 & 干预措施
Treatment (azacitidine, mitoxantrone hydrochloride, etoposide)
Patients receive induction therapy comprising azacitidine SC QD on days 1-7, mitoxantrone hydrochloride IV over 30 minutes, and etoposide IV over 1 hour on days 4-8. Patients may receive up to 2 additional courses of the same treatment as re-induction or consolidation therapy beginning 35-60 days from the start of the previous course.
干预措施: Azacitidine (Drug)
Treatment (azacitidine, mitoxantrone hydrochloride, etoposide)
Patients receive induction therapy comprising azacitidine SC QD on days 1-7, mitoxantrone hydrochloride IV over 30 minutes, and etoposide IV over 1 hour on days 4-8. Patients may receive up to 2 additional courses of the same treatment as re-induction or consolidation therapy beginning 35-60 days from the start of the previous course.
干预措施: Etoposide (Drug)
Treatment (azacitidine, mitoxantrone hydrochloride, etoposide)
Patients receive induction therapy comprising azacitidine SC QD on days 1-7, mitoxantrone hydrochloride IV over 30 minutes, and etoposide IV over 1 hour on days 4-8. Patients may receive up to 2 additional courses of the same treatment as re-induction or consolidation therapy beginning 35-60 days from the start of the previous course.
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (azacitidine, mitoxantrone hydrochloride, etoposide)
Patients receive induction therapy comprising azacitidine SC QD on days 1-7, mitoxantrone hydrochloride IV over 30 minutes, and etoposide IV over 1 hour on days 4-8. Patients may receive up to 2 additional courses of the same treatment as re-induction or consolidation therapy beginning 35-60 days from the start of the previous course.
干预措施: Mitoxantrone Hydrochloride (Drug)
结局指标
主要结局
Maximum-tolerated dose of azacitidine that can be safely combined with mitoxantrone hydrochloride and etoposide chemotherapy
时间窗: Up to 2 courses of treatment
The descriptions and grading scales found in the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.
次要结局
- Changes in DNA methylation(Baseline to day 4)
- Complete response rate(Up to 4 years)
- Overall survival(From the start of study treatment until death from any cause or last follow up, assessed up to 4 years)
- Relapse-free survival(From documentation of CR or MLFS to time of disease recurrence or last follow up, assessed up to 4 years)
- Changes in gene expression(Baseline to day 4)
- Changes in topoisomerase II levels(Baseline to day 4)