A Phase II Pilot Study of Bortezomib (PS-341, Velcade) Combined With Reinduction Chemotherapy in Children and Young Adults With Recurrent, Refractory or Secondary Acute Myeloid Leukemia
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 52
- 试验地点
- 82
- 主要终点
- Dose Limiting Toxicity
研究概览
简要总结
This phase II trial is studying the side effects and best dose of bortezomib and to see how well it works when given together with combination chemotherapy in treating younger patients with recurrent, refractory, or secondary acute myeloid leukemia (AML). Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as idarubicin, cytarabine, 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) together with bortezomib may kill more cancer cells
详细描述
PRIMARY OBJECTIVES:
I. To determine the toxicities and tolerability of bortezomib in combination with standard-relapse AML therapy (idarubicin/cytarabine or etoposide/high-dose cytarabine) in pediatric and young adult patients with relapsed or primary-refractory or secondary AML.
II. To estimate the complete response rate to the Arm A and Arm B regimens.
SECONDARY OBJECTIVES:
I. To determine whether bortezomib inhibits proteasome activity, NF-kB activity and induces apoptosis pathway proteins in leukemia myeloblasts. II. To determine the feasibility of measuring AML stem cells in relapsed and recovering bone marrow.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of acute myeloid leukemia (AML) according to WHO classification
- •At least 5% blasts in the bone marrow
- •With or without extramedullary disease
- •To be eligible for the dose-finding phase (closed as of 10/10) :
- •Relapsed patients must meet the following criteria:
- •Must have had a prior diagnosis of AML, but may NOT have inv(16) or t(8;21) cytogenetics
- •May be in first or any subsequent relapse
- •If in first relapse, remission duration must be less than one year
- •Refractory patients must meet the following criteria:
- •Must have had a prior diagnosis of AML
- •May have received one or more attempt at remission induction
- •Patients with treatment-related AML may be previously treated or untreated for secondary AML
- •To be eligible for the efficacy phase:
- •Relapsed patients must meet the following criteria:
- •Must have had a prior diagnosis of AML, with no restriction on prior cytogenetics
- •Must be in first relapse
- •Must not have received prior reinduction therapy
- •Refractory patients must meet the following criteria:
- •Must have had a prior diagnosis of AML
- •Must not have received more than one attempt at remission induction (which may consist of up to two therapy courses)
- •Patients with treatment-related AML must be previously untreated for secondary AML
- •No juvenile myelomonocytic leukemia or acute promyelocytic leukemia (APL; FAB M3)
- •Patients with the following CNS status are eligible only in the absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy:
- •CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin preparation, regardless of the number of WBCs
- •CNS 2, defined as presence of < 5/μL WBCs in CSF and cytospin positive for blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm:
- •CNS 2a: < 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts
- •CNS 2b: ≥ 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts
- •CNS 2c: ≥ 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer algorithm
- •Patients with CNS3 disease (presence of ≥ 5/μL WBCs in CSF and cytospin positive for blasts [in the absence of a traumatic lumbar puncture] and/or clinical signs of CNS leukemia) are not eligible
- •CNS toxicity ≤ grade 2
- •Lansky (patients ≤ 16 years of age) or Karnofsky (patients > 16 years of age) performance status (PS) 50-100%
- •ECOG PS 0-2
- •No Down syndrome
- •No Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome
- •No evidence of active graft-vs-host disease
- •Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR serum creatinine based on age/gender as follows:
- •0.4 mg/dL for patients 1 month to < 6 months of age
- •0.5 mg/dL for patients 6 months to < 1 year of age
- •0.6 mg/dL for patients 1 to < 2 years of age
- •0.8 mg/dL for patients 2 to < 6 years of age
- •1 mg/dL for patients 6 to < 10 years of age
- •1.2 mg/dL for patients 10 to < 13 years of age
- •1.5 mg/dL (male) or 1.4 mg/dL (female) for patients 13 to < 16 years of age
- •1.7 mg/dL (male) or 1.4 mg/dL (female) for patients ≥ 16 years of age
- •Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age
- •ALT < 3.0 times ULN for age (unless elevation due to leukemia involvement)
- •Shortening fraction ≥ 27% by ECHO OR LVEF ≥ 50% by gated radionuclide
- •Normal respiratory rate and pulse oximetry > 94% on room air
- •FEV_1 ≥ 80% of predicted
- •FVC and DLCO > 50% (corrected for hemoglobin)
- 另有 31 项未显示
排除标准
- 未提供
研究组 & 干预措施
Bortezomib 1.3mg/m2-assess efficacy-low anthracycline exposure
Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old.
干预措施: idarubicin (Drug)
Bortezomib 1.3mg/m2-assess efficacy-low anthracycline exposure
Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old.
干预措施: cytarabine (Drug)
Bortezomib 1.3mg/m2-assess efficacy-low anthracycline exposure
Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old.
干预措施: bortezomib (Drug)
Bortezomib 1.3mg/m2-assess efficacy-low anthracycline exposure
Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old.
干预措施: laboratory biomarker analysis (Other)
Bortezomib 1.0mg/m2-assess feasibility high anthracycline exp
Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.
干预措施: cytarabine (Drug)
Bortezomib 1.0mg/m2-assess feasibility high anthracycline exp
Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.
干预措施: bortezomib (Drug)
Bortezomib 1.0mg/m2-assess feasibility high anthracycline exp
Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.
干预措施: etoposide (Drug)
Bortezomib 1.0mg/m2-assess feasibility high anthracycline exp
Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.
干预措施: laboratory biomarker analysis (Other)
Bortezomib 1.3 mg/m2-assess feasibility high anthracycline exp
Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10).
干预措施: cytarabine (Drug)
Bortezomib 1.3 mg/m2-assess feasibility high anthracycline exp
Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10).
干预措施: bortezomib (Drug)
Bortezomib 1.3 mg/m2-assess feasibility high anthracycline exp
Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10).
干预措施: etoposide (Drug)
Bortezomib 1.3 mg/m2-assess feasibility high anthracycline exp
Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10).
干预措施: laboratory biomarker analysis (Other)
Bortezomib 1.3 mg/m2-assess efficacy high anthracycline exp
Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity
干预措施: cytarabine (Drug)
Bortezomib 1.3 mg/m2-assess efficacy high anthracycline exp
Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity
干预措施: bortezomib (Drug)
Bortezomib 1.3 mg/m2-assess efficacy high anthracycline exp
Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity
干预措施: etoposide (Drug)
Bortezomib 1.3 mg/m2-assess efficacy high anthracycline exp
Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity
干预措施: laboratory biomarker analysis (Other)
结局指标
主要结局
Dose Limiting Toxicity
时间窗: During Course 1
Number of participants with dose limiting toxicity.
Overall Response (Complete Remission [CR] and CR With Partial Recovery [CRp]) During Course 1
时间窗: After course 1
Overall response (complete remission \[CR\] and CR with partial recovery \[CRp\]) during course 1.
次要结局
- NF-kB Activity by Enzyme-linked Immunosorbent Assay (ELISA)(At baseline, prior to and up to 24 hours after bortezomib treatment)
- Proteasome Inhibition Activity(At baseline)
- Protein Expression Assessed by Western Blot(At baseline, prior to and up to 24 hours after bortezomib treatment)
- Feasibility of Stem Cell Quantitation: Percentage of Leukemia Initiation Cells (LIC) Depletion(At baseline and after completion of course 1)