A Phase II Study of MLN8237, a Selective Aurora A Kinase Inhibitor in Children With Recurrent/Refractory Solid Tumors and Leukemias
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 118
- 试验地点
- 105
- 主要终点
- Number of Participants With Overall Response
研究概览
简要总结
This phase II trial is studying the side effects of and how well alisertib works in treating young patients with relapsed or refractory solid tumors or leukemia. Alisertib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
详细描述
PRIMARY OBJECTIVE:
I. To determine the objective response rate to MLN8237 (alisertib) in children with relapsed or refractory solid tumors and leukemias, administered once daily for 7 days every 21 days.
SECONDARY OBJECTIVES:
I. To further define and describe the toxicities of MLN8237 administered on this schedule.
II. To further characterize the pharmacokinetics of MLN8237 in children with refractory cancer.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 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
- •Patients must have had histologic verification of malignancy at original diagnosis or at relapse, to include any of the following malignancies (no other histology is eligible):
- •Neuroblastoma- measurable
- •Neuroblastoma- MIBG evaluable
- •Rhabdomyosarcoma
- •Osteosarcoma
- •Ewing sarcoma/Peripheral PNET
- •Non-RMS soft tissue sarcoma
- •Hepatoblastoma
- •Malignant germ cell tumor
- •Wilms tumor
- •Acute lymphoblastic leukemia
- •Acute myelogenous leukemia
- •Rhabdoid malignancy
- •Disease status for solid tumor patients:
- •Patients must have radiographically measurable disease (with the exception of neuroblastoma)
- •Measurable disease is defined as the presence of at least one lesion on magnetic resonance imaging (MRI) or computed tomography (CT) scan that can be accurately measured with the longest diameter a minimum of 20 mm in at least one dimension; for spiral CT, measurable disease is defined as a minimum diameter of 10 mm in at least one dimension
- •Note: The following do not qualify as measurable disease:
- •Malignant fluid collections (e.g., ascites, pleural effusions)
- •Bone marrow infiltration
- •Lesions detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans)
- •Elevated tumor markers in plasma or cerebrospinal fluid (CSF)
- •Previously irradiated lesions that have not demonstrated clear progression post radiation
- •Patients with neuroblastoma who do not have measurable disease but have MIBG+ evaluable disease are eligible
- •Disease status for leukemia patients:
- •Patients with leukemia must be recurrent or refractory to at least two prior induction or treatment regimens, in addition to the following criteria:
- •Acute lymphoid leukemia:
- •25% blasts in the bone marrow (M3 bone marrow), excluding patients with known central nervous system (CNS) disease
- •Acute myeloid leukemia according to FAB classification
- •≥ 5 % blasts in the bone marrow (M2/M3 bone marrow); excluding patients with known CNS disease
- •Rhabdoid tumors:
- •To be eligible for enrollment in the rhabdoid tumors stratum, the patient must have a solid tumor where the institutional pathological evaluation of the tumor at initial diagnosis or relapse has confirmed:
- •Morphology and immunophenotypic panel consistent with rhabdoid tumor (required)
- •Loss of SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1 (INI1) confirmed by immunohistochemistry, or
- •Molecular confirmation of tumor-specific bi-allelic INI1 loss/mutation if INI1 immunohistochemistry is not available; note that molecular confirmation of tumor-specific bi-allelic INI1 loss/mutation is encouraged in cases where INI1 immunohistochemistry is equivocal
- •Patients must have a Lansky or Karnofsky performance status score of ≥ 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age; Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
- •Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study enrollment
- •Myelosuppressive chemotherapy:
- •Solid tumors:
- •Patients with solid tumors must not have received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (6 weeks if prior nitrosourea)
- •Leukemia:
- •Patients with leukemia who relapse while receiving standard maintenance therapy will not be required to have a waiting period before enrollment onto this study
- •Patients who relapse while they are not receiving standard maintenance therapy must have completely recovered from all acute toxic effects of chemotherapy, immunotherapy or radiotherapy prior to study enrollment; at least 14 days must have elapsed since the completion of cytotoxic therapy, with the exception of hydroxyurea
- •Note: cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of MLN8237
- •At least 7 days must have elapsed since the completion of therapy with a growth factor; at least 14 days must have elapsed after receiving pegfilgrastim
- •At least 7 days must have elapsed since completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur
- •At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody
- •≥ 2 weeks must have elapsed since local palliative radiation therapy (XRT) (small port); ≥ 6 weeks must have elapsed since treatment with therapeutic doses of MIBG; ≥ 6 months must have elapsed if prior craniospinal XRT was received, if ≥ 50% of the pelvis was irradiated, or if total body irradiation (TBI) was received; ≥ 6 weeks must have elapsed if other substantial bone marrow irradiation was given
- •No evidence of active graft vs. host disease and ≥ 3 months must have elapsed since transplant
- •For patients with solid tumors without bone marrow involvement:
- •Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
- 另有 19 项未显示
排除标准
- •Patients who are pregnant or breast-feeding are not eligible for this study; negative pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study therapy; breastfeeding women are excluded
- •Growth factors that support platelet or white cell number or function must not have been administered within the 7 days prior to enrollment (14 days if pegfilgrastim)
- •Patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 7 days prior to enrollment are not eligible
- •Patients who are currently receiving another investigational drug are not eligible
- •Patients who are currently receiving other anti-cancer agents are not eligible
- •Use of daily benzodiazepine therapy excludes a patient from being eligible because of the potential benzodiazepine-like effects of MLN8237
- •Patients who are currently receiving digoxin, cyclosporine, tacrolimus, or sirolimus are not eligible
- •Patients who are unable to swallow tablets are not eligible
- •Patients who have an uncontrolled infection are not eligible
- •Leukemia patients with CNS disease are not eligible
- •Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
研究组 & 干预措施
Arm I (neuroblastoma- measurable)
Patients with measurable neuroblastoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Alisertib (Drug)
Arm I (neuroblastoma- measurable)
Patients with measurable neuroblastoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Arm I (neuroblastoma- measurable)
Patients with measurable neuroblastoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Arm II (Neuroblastoma- MIBG evaluable)
Patients MIBG evaluable neuroblastoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Alisertib (Drug)
Arm II (Neuroblastoma- MIBG evaluable)
Patients MIBG evaluable neuroblastoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Arm II (Neuroblastoma- MIBG evaluable)
Patients MIBG evaluable neuroblastoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Arm III (rhabdomyosarcoma)
Patients with rhabdomyosarcoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Alisertib (Drug)
Arm III (rhabdomyosarcoma)
Patients with rhabdomyosarcoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Arm III (rhabdomyosarcoma)
Patients with rhabdomyosarcoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Arm IV (osteosarcoma)
Patients with osteosarcoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Alisertib (Drug)
Arm IV (osteosarcoma)
Patients with osteosarcoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Arm IV (osteosarcoma)
Patients with osteosarcoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Arm V (Ewing sarcoma/peripheral PNET)
Patients with Ewing sarcoma/peripheral PNET receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Alisertib (Drug)
Arm V (Ewing sarcoma/peripheral PNET)
Patients with Ewing sarcoma/peripheral PNET receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Arm V (Ewing sarcoma/peripheral PNET)
Patients with Ewing sarcoma/peripheral PNET receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Arm VI (non-RMS soft tissue sarcoma)
Patients with non-RMS soft tissue sarcoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Alisertib (Drug)
Arm VI (non-RMS soft tissue sarcoma)
Patients with non-RMS soft tissue sarcoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Arm VI (non-RMS soft tissue sarcoma)
Patients with non-RMS soft tissue sarcoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Arm VII (hepatoblastoma)
Patients hepatoblastoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Alisertib (Drug)
Arm VII (hepatoblastoma)
Patients hepatoblastoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Arm VII (hepatoblastoma)
Patients hepatoblastoma receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Arm VIII (malignant germ cell tumor)
Patients with malignant germ cell tumor receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Alisertib (Drug)
Arm VIII (malignant germ cell tumor)
Patients with malignant germ cell tumor receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Arm VIII (malignant germ cell tumor)
Patients with malignant germ cell tumor receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Arm IX (Wilms tumor)
Patients with Wilms tumor receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Alisertib (Drug)
Arm IX (Wilms tumor)
Patients with Wilms tumor receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Arm IX (Wilms tumor)
Patients with Wilms tumor receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Arm X (acute lymphoblastic leukemia)
Patients with acute lymphoblastic leukemia receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Alisertib (Drug)
Arm X (acute lymphoblastic leukemia)
Patients with acute lymphoblastic leukemia receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Arm X (acute lymphoblastic leukemia)
Patients with acute lymphoblastic leukemia receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Arm XI (acute myelogenous leukemia)
Patients acute myelogenous leukemia receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Alisertib (Drug)
Arm XI (acute myelogenous leukemia)
Patients acute myelogenous leukemia receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Arm XI (acute myelogenous leukemia)
Patients acute myelogenous leukemia receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Arm XII (rhabdoid malignancy)
Patients with rhabdoid malignancy receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Alisertib (Drug)
Arm XII (rhabdoid malignancy)
Patients with rhabdoid malignancy receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Arm XII (rhabdoid malignancy)
Patients with rhabdoid malignancy receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
结局指标
主要结局
Number of Participants With Overall Response
时间窗: From first dose of alisertib through 6 cycles of protocol therapy or until removal from protocol therapy whichever occurred first.
For patients with recurrent solid tumors a patient who experienced a complete or partial response according to RECIST version 1.1 criteria is considered a responder. For patients with recurrent acute lymphoblastic leukemia a patient who experiences a bone marrow evaluation with \< 5% blast cells on morphological evaluation of bone marrow will be considered a responder. For patients with recurrent acute myelogenous leukemia a patient who experiences a complete remission or complete remission with partial recovery of platelet count according to the AML International Working Group Criteria will be considered a responder.
次要结局
- Number of Patients Cycles With Grade 3 or Higher Adverse Event(Up to 24 months)
- Serum Concentration of Alisertib on the First Day of Administration Six Hours After Administration(day 1 of protocol therapy)
- Serum Concentration of Alisertib on the Fourth Day of Administration Prior to the Administration of the Day 4 Dose(day 4 of protocol therapy)
- Serum Concentration of Alisertib on the First Day of Administration One Hour After Administration(day 1 of protocol therapy)
- Serum Concentration of Alisertib on the Seventh Day of Administration Prior to the Administration of the Day 7 Dose.(day 7 of protocol therapy)
- Serum Concentration of Alisertib Prior to the First Day of Administration(day 1 of protocol therapy)
- Serum Concentration of Alisertib on the First Day of Administration Three Hours After Administration(day 1 of protocol therapy)