Randomized Phase II Trial of Timed Sequential Therapy (TST) With Alvocidib (Flavopiridol), Ara-C and Mitoxantrone (FLAM) vs. "7+3" for Adults Age 70 and Under With Newly Diagnosed Acute Myelogenous Leukemia (AML)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 172
- 试验地点
- 11
- 主要终点
- Complete Response Rate
研究概览
简要总结
This randomized phase II trial is studying how alvocidib, cytarabine, and mitoxantrone hydrochloride work compared to cytarabine and daunorubicin hydrochloride in treating patients with newly diagnosed acute myeloid leukemia. Alvocidib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine, mitoxantrone hydrochloride, and daunorubicin hydrochloride work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It is not yet known whether giving alvocidib, cytarabine, and mitoxantrone hydrochloride is more effective than giving cytarabine and daunorubicin hydrochloride in treating patients with acute myeloid leukemia.
详细描述
PRIMARY OBJECTIVES:
I. To compare the rate of complete remission (CR) after 1 course of induction therapy with the timed-sequential combination of alvocidib (flavopiridol), cytarabine (cytosine arabinoside [ara-C]), and mitoxantrone hydrochloride (FLAM) vs traditional "7+3" cytarabine and daunorubicin hydrochloride (ara-C + Daunorubicin) for adults (age 18 to 70) with newly diagnosed, previously untreated, intermediate-risk or poor-risk acute myelogenous leukemia (AML).
SECONDARY OBJECTIVES:
I. To evaluate and compare the toxicities of FLAM vs 7+3. II. To compare the 2-year disease-free survival (DFS) and overall survival (OS) in response to FLAM vs 7+3.
III. To detect and compare the presence of minimal-residual disease (MRD) remaining after FLAM vs 7+3.
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
- None
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
- •All adults with established, pathologically confirmed diagnoses of newly diagnosed AML and adults with newly diagnosed AML, excluding newly diagnosed core-binding factor (CBF) AMLs and acute progranulocytic leukemia (APL, M3), will be considered eligible for study
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-3
- •Patients >= 65 years of age must have ECOG PS =< 2 prior to developing leukemic symptoms
- •Serum creatinine ≤ 2.0 mg/dL
- •Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 5 times upper limit of normal (ULN) (unless leukemic infiltration)
- •Total bilirubin =< 2.0 mg/dL (unless Gilbert disease, hemolysis, or leukemia)
- •Left ventricular ejection fraction ≥ 45%
- •Newly diagnosed AML, subtypes M0, 1, 2, 4-7 but excluding M3 (APL), including those with the following poor risk features:
- •Antecedent hematologic disorder including myelodysplasia (MDS)-related AML (MDS/AML) and prior myeloproliferative disorder (MPD)
- •Treatment-related myeloid neoplasms (t-AML/t-MDS)
- •Myeloid sarcoma, myeloid proliferations related to Down Syndrome, and blastic plasmacytoid dendritic cell neoplasm
- •AML with multilineage dysplasia (AML-MLD)
- •Adverse cytogenetics (defined as -5/-5q; -7/-7q; abnormal 3q, 9q, 11q, 20q, 21q, or 17p; t(6;9); t(9;22); trisomy 8; trisomy 13; trisomy 21; and complex karyotypes (≥ 3 unrelated abnormalities)
- •Patients who have received hydroxyurea alone or have received non-cytotoxic therapies previously for myelodysplasia (MDS) or myeloproliferative disorder (MPD) (e.g., thalidomide or lenalidomide, interferon, cytokines, 5-azacytidine or decitabine, histone deacetylase inhibitors, low-dose cyclophosphamide [cytoxan], tyrosine kinase [TK] or dual TK/src inhibitors) will be eligible for this trial
- •At least 24 hours since prior leukopheresis or hydroxyurea for cytoreduction
排除标准
- •Any previous treatment with flavopiridol
- •Concomitant chemotherapy, radiation therapy, or immunotherapy
- •Hyperleukocytosis with >= 50,000 blasts/uL; leukopheresis or hydroxyurea may be used immediately prior to study drug administration for cytoreduction; must be stopped 24 hours before first dose of study chemotherapy
- •CBF AMLs associated with t(8;21) or M4eo subtype (inv[16] or t[16;16]), as diagnosed by morphologic criteria, flow cytometric characteristics, and rapid cytogenetics or FISH or molecular testing
- •Acute Progranulocytic Leukemia (APL, M3)
- •Active central nervous system (CNS) leukemia
- •Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible
- •Active, uncontrolled graft vs. host disease (GVHD) following allogeneic transplant for non-AML condition (e.g. MDS, lymphoid malignancy, aplastic anemia); patients with GVHD controlled on stable doses of immunosuppressants are eligible
- •Presence of other life-threatening illness
- •Patients with mental deficits and/or psychiatric history that preclude them form giving informed consent or from following protocol
- •Pregnant and nursing patients are excluded
研究组 & 干预措施
Arm I (alvocidib, cytarabine, mitoxantrone hydrochloride)
Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9. Patients who achieve complete or partial response to the first course (completion of all doses) may receive a second course of treatment or high-dose cytarabine after 21-63 days following blood count recovery, and/or undergo allogeneic bone marrow transplant.
干预措施: alvocidib (Drug)
Arm I (alvocidib, cytarabine, mitoxantrone hydrochloride)
Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9. Patients who achieve complete or partial response to the first course (completion of all doses) may receive a second course of treatment or high-dose cytarabine after 21-63 days following blood count recovery, and/or undergo allogeneic bone marrow transplant.
干预措施: mitoxantrone hydrochloride (Drug)
Arm I (alvocidib, cytarabine, mitoxantrone hydrochloride)
Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9. Patients who achieve complete or partial response to the first course (completion of all doses) may receive a second course of treatment or high-dose cytarabine after 21-63 days following blood count recovery, and/or undergo allogeneic bone marrow transplant.
干预措施: cytarabine (Drug)
Arm II (cytarabine, daunorubicin hydrochloride)
Patients receive cytarabine IV continuously on days 1-7 and daunorubicin hydrochloride IV on days 1-3. Patients who have residual disease on day 14 may receive additional cytarabine for 5 days and daunorubicin hydrochloride for 2 days.
干预措施: daunorubicin hydrochloride (Drug)
Arm II (cytarabine, daunorubicin hydrochloride)
Patients receive cytarabine IV continuously on days 1-7 and daunorubicin hydrochloride IV on days 1-3. Patients who have residual disease on day 14 may receive additional cytarabine for 5 days and daunorubicin hydrochloride for 2 days.
干预措施: cytarabine (Drug)
结局指标
主要结局
Complete Response Rate
时间窗: 3 years
Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an ANC of at least 1000/cu mm and a platelet count of 100,000/cu mm, absence of blast in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. These criteria are taken from Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010;115:453-474
次要结局
- Disease-free Survival(Time from randomization until death from any cause or relapse or recurrence, assessed up to 2 years)
- Incidence of Toxicities, Characterized by Number of Events by Treatment and Grade(Up to 14 days after completion of study treatment)
- Overall Survival(4 years)
- Progression-free Survival(4 years)
- Number of Patients With Minimal Residual Disease(From study start to 14 days after the start of treatment)