Alisertib in Treating Young Patients With Recurrent or Refractory Solid Tumors or Leukemia

This study has been completed.
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group Identifier:
First received: June 30, 2010
Last updated: August 31, 2015
Last verified: March 2014
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.

Condition Intervention Phase
Childhood Hepatoblastoma
Previously Treated Childhood Rhabdomyosarcoma
Recurrent Childhood Acute Lymphoblastic Leukemia
Recurrent Childhood Acute Myeloid Leukemia
Recurrent Childhood Malignant Germ Cell Tumor
Recurrent Childhood Rhabdomyosarcoma
Recurrent Childhood Soft Tissue Sarcoma
Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
Recurrent Neuroblastoma
Recurrent Osteosarcoma
Recurrent Wilms Tumor and Other Childhood Kidney Tumors
Drug: alisertib
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of MLN8237 (IND# 102984), a Selective Aurora A Kinase Inhibitor in Children With Recurrent/Refractory Solid Tumors and Leukemias

Resource links provided by NLM:

Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • Objective response rate [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed accounting for the two-stage design.

Secondary Outcome Measures:
  • Incidence of adverse events graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Toxicity tables constructed to summarize the observed incidence in each reporting period by type of toxicity and grade. Relative frequency of each type of toxicity quantified as the number of toxicity-evaluable cycles in which the AE was noted at >= grade 3 considered by the treating physician to be possibly, probably or definitely related to alisertib divided by the number toxicity-evaluable cycles administered to patients enrolled on the trial. In addition to the tabular presentation of the data, any adverse experience that results in the filing of an AdEERS report will be identified.

  • Pharmacokinetic parameters of alisertib, including systemic exposure, drug clearance, and other pharmacokinetic parameters [ Time Frame: During the first cycle prior to drug administration and on days 1, 4, and 7 ] [ Designated as safety issue: No ]
    The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).

Enrollment: 228
Study Start Date: February 2011
Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (alisertib)
Patients 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.
Drug: alisertib
Given orally
Other Names:
  • Aurora A kinase inhibitor MLN8237
  • MLN8237
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:


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.


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.

III. To evaluate aurora A kinase expression using immunohistochemistry in solid tumors and leukemic blasts from tissue obtained at diagnosis and, if available, at relapse.

IV. To explore the relationship between polymorphic variations in the UDP-glucuronosyltransferase gene UGT1A1 and exposure to MLN8237, and to assess 2 common polymorphic variants in the aurora A kinase gene, Phe31Ile and Val57Ile.

OUTLINE: This is a multicenter study. Patients are stratified according to type of tumor (measurable neuroblastoma vs neuroblastoma with metaiodobenzylguanidine [MIBG]-positive lesions vs osteosarcoma vs Ewing sarcoma/primitive neuroectodermal tumor [PNET] vs rhabdosarcoma vs non-rhabdomyosarcoma [RMS] soft tissue sarcoma vs hepatoblastoma vs malignant germ cell tumor vs Wilms tumor vs acute myeloid leukemia [AML] vs acute lymphoblastic leukemia [ALL] vs rhabdoid tumors).

Patients receive alisertib orally (PO) once daily (QD) on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

Plasma samples are collected from all patients at baseline and periodically during course 1 for pharmacokinetic and other studies.

After completion of study therapy, patients are followed up for 5 years.


Ages Eligible for Study:   1 Year to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 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
    • Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment)
    • Hemoglobin > 8.0 g/dL (may receive red blood cell [RBC] transfusions)
  • For patients with solid tumors and known bone marrow metastatic disease:

    • Peripheral absolute neutrophil count (ANC) ≥ 750/mm^3
    • Platelet count ≥ 50,000/mm^3
    • Hemoglobin ≥ 8.0 g/dL
    • Transfusions are permitted to meet both the platelet and hemoglobin criteria; patients must not be known to be refractory to red blood cell or platelet transfusions
  • Patients with leukemia must not be known to be refractory to red blood cell or platelet transfusions
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

    • 1 to < 2 years: 0.6
    • 2 to < 6 years: 0.8
    • 6 to < 10 years: 1
    • 10 to < 13 years: 1.2
    • 13 to < 16 years: 1.5 (male), 1.4 (female)
    • >= 16 years: 1.7 (male), 1.4 (female)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
  • Serum glutamic pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) ≤ 5.0 x ULN for age (≤ 225 U/L); for the purpose of this study, the ULN for SGPT is 45 U/L
  • Serum albumin ≥ 2 g/dL
  • All patients and/or their parents or legal guardians must sign a written informed consent

Exclusion Criteria:

  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01154816

  Show 104 Study Locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Principal Investigator: Yael Mosse Children's Oncology Group
  More Information

Responsible Party: Children's Oncology Group Identifier: NCT01154816     History of Changes
Other Study ID Numbers: ADVL0921  NCI-2011-02051  CDR0000680512  U10CA098543  COG-ADVL0921 
Study First Received: June 30, 2010
Last Updated: August 31, 2015
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Kidney Neoplasms
Leukemia, Lymphoid
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms, Germ Cell and Embryonal
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Neuroectodermal Tumors, Primitive, Peripheral
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Rhabdomyosarcoma, Embryonal
Sarcoma, Ewing
Wilms Tumor
Genetic Diseases, Inborn
Immune System Diseases
Immunoproliferative Disorders
Kidney Diseases
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Bone Tissue
Neoplasms, Complex and Mixed processed this record on May 24, 2016