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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01154816
First Posted: July 1, 2010
Last Update Posted: October 23, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group
  Purpose
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
Hepatoblastoma Previously Treated Childhood Rhabdomyosarcoma Recurrent Childhood Acute Lymphoblastic Leukemia Recurrent Childhood Acute Myeloid Leukemia Recurrent Childhood Kidney Neoplasm 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 Drug: Alisertib Other: Laboratory Biomarker Analysis Other: Pharmacological Study Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of MLN8237, 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:
  • Number of Participants With Overall Response [ Time Frame: 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.


Secondary Outcome Measures:
  • Number of Patients Cycles With Grade 3 or Higher Adverse Event [ Time Frame: Up to 24 months ]
    The number of patient-cycles in which the adverse event considered grade 3 or higher AE according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 considered by the treating physician to be possibly, probably or definitely related to alisertib.

  • Serum Concentration of Alisertib Prior to the First Day of Administration [ Time Frame: day 1 of protocol therapy ]
    Serum concentration of alisertib prior to the first day of administration in nanograms/milliliter.

  • Serum Concentration of Alisertib on the First Day of Administration One Hour After Administration [ Time Frame: day 1 of protocol therapy ]
    Serum concentration of alisertib on the first day of administration one hour after administration in nanograms/milliliter.

  • Serum Concentration of Alisertib on the First Day of Administration Three Hours After Administration [ Time Frame: day 1 of protocol therapy ]
    Serum concentration of alisertib on the first day of administration three hours after administration in nanograms/milliliter.

  • Serum Concentration of Alisertib on the First Day of Administration Six Hours After Administration [ Time Frame: day 1 of protocol therapy ]
    Serum concentration of alisertib on the first day of administration six hours after administration in nanograms/milliliter.

  • Serum Concentration of Alisertib on the Fourth Day of Administration Prior to the Administration of the Day 4 Dose [ Time Frame: day 4 of protocol therapy ]
    Serum concentration of alisertib on the fourth day of administration prior to the administration of the day 4 dose in nanograms/milliliter.

  • Serum Concentration of Alisertib on the Seventh Day of Administration Prior to the Administration of the Day 7 Dose. [ Time Frame: day 7 of protocol therapy ]
    Serum concentration of alisertib on the seventh day of administration prior to the administration of the day 7 dose in nanograms/milliliter.


Enrollment: 118
Study Start Date: February 2011
Primary Completion Date: December 31, 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: Alisertib
Given orally
Other Names:
  • Aurora A Kinase Inhibitor MLN8237
  • MLN-8237
  • MLN8237
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Experimental: 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.
Drug: Alisertib
Given orally
Other Names:
  • Aurora A Kinase Inhibitor MLN8237
  • MLN-8237
  • MLN8237
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Experimental: 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.
Drug: Alisertib
Given orally
Other Names:
  • Aurora A Kinase Inhibitor MLN8237
  • MLN-8237
  • MLN8237
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Experimental: 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.
Drug: Alisertib
Given orally
Other Names:
  • Aurora A Kinase Inhibitor MLN8237
  • MLN-8237
  • MLN8237
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Experimental: 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.
Drug: Alisertib
Given orally
Other Names:
  • Aurora A Kinase Inhibitor MLN8237
  • MLN-8237
  • MLN8237
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Experimental: 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.
Drug: Alisertib
Given orally
Other Names:
  • Aurora A Kinase Inhibitor MLN8237
  • MLN-8237
  • MLN8237
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Experimental: 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.
Drug: Alisertib
Given orally
Other Names:
  • Aurora A Kinase Inhibitor MLN8237
  • MLN-8237
  • MLN8237
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Experimental: 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.
Drug: Alisertib
Given orally
Other Names:
  • Aurora A Kinase Inhibitor MLN8237
  • MLN-8237
  • MLN8237
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Experimental: 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.
Drug: Alisertib
Given orally
Other Names:
  • Aurora A Kinase Inhibitor MLN8237
  • MLN-8237
  • MLN8237
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Experimental: 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.
Drug: Alisertib
Given orally
Other Names:
  • Aurora A Kinase Inhibitor MLN8237
  • MLN-8237
  • MLN8237
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Experimental: 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.
Drug: Alisertib
Given orally
Other Names:
  • Aurora A Kinase Inhibitor MLN8237
  • MLN-8237
  • MLN8237
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Experimental: 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.
Drug: Alisertib
Given orally
Other Names:
  • Aurora A Kinase Inhibitor MLN8237
  • MLN-8237
  • MLN8237
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01154816


  Show 105 Study Locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
Principal Investigator: Yael Mosse Children's Oncology Group
  More Information

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT01154816     History of Changes
Other Study ID Numbers: ADVL0921
NCI-2011-02051 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000680512
ADVL0921 ( Other Identifier: Childrens Oncology Group )
ADVL0921 ( Other Identifier: CTEP )
U10CA098543 ( U.S. NIH Grant/Contract )
First Submitted: June 30, 2010
First Posted: July 1, 2010
Results First Submitted: July 28, 2016
Results First Posted: June 5, 2017
Last Update Posted: October 23, 2017
Last Verified: September 2017

Additional relevant MeSH terms:
Leukemia
Neoplasms
Leukemia, Myeloid, Acute
Sarcoma
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neuroblastoma
Neoplasms, Germ Cell and Embryonal
Osteosarcoma
Rhabdomyosarcoma
Leukemia, Myeloid
Sarcoma, Ewing
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Rhabdomyosarcoma, Embryonal
Neuroectodermal Tumors, Primitive, Peripheral
Kidney Neoplasms
Hepatoblastoma
Neoplasms by Histologic Type
Neoplasms, Connective and Soft Tissue
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Neuroepithelial
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Myosarcoma