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MLN8237 in Young Patients With Relapsed or Refractory Solid Tumors or Acute Lymphoblastic Leukemia
This study is currently recruiting participants.
Verified by National Cancer Institute (NCI), October 2008
First Received: August 20, 2008   Last Updated: August 6, 2009   History of Changes
Sponsors and Collaborators: Children's Oncology Group
National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00739427
  Purpose

RATIONALE: MLN8237 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I/II trial is studying the side effects and best dose of MLN8237 and to see how well it works in treating young patients with relapsed or refractory solid tumors or acute lymphoblastic leukemia.


Condition Intervention Phase
Leukemia
Neuroblastoma
Unspecified Childhood Solid Tumor, Protocol Specific
Drug: Aurora A kinase inhibitor MLN8237
Genetic: fluorescence in situ hybridization
Genetic: gene expression analysis
Genetic: polymerase chain reaction
Genetic: polymorphism analysis
Other: immunohistochemistry staining method
Other: pharmacological study
Phase I
Phase II

Study Type: Interventional
Study Design: Treatment
Official Title: A Phase I Study of MLN8237, an Oral Selective Small Molecule Inhibitor of Aurora A Kinase, in Pediatric Patients With Relapsed/Refractory Solid Tumors and Leukemia

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose and recommended phase II dose of Aurora A kinase inhibitor MLN8237 administered once daily or twice daily (Phase I) [ Designated as safety issue: Yes ]
  • Toxicity (Phase I) [ Designated as safety issue: Yes ]
  • Pharmacokinetics [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Antitumor activity (Phase I) [ Designated as safety issue: No ]
  • Efficacy (Phase II) [ Designated as safety issue: No ]
  • Relationship between polymorphic variations in UGT1A1 and exposure to drug [ Designated as safety issue: No ]
  • Influence of common polymorphic variants Phe31Ile and Val57Ile on tumorigenesis [ Designated as safety issue: No ]
  • Relationship between Aurora A expression status and response to Aurora A inhibition [ Designated as safety issue: No ]

Estimated Enrollment: 102
Study Start Date: September 2008
Estimated Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)
Detailed Description:

OBJECTIVES:

Primary

  • To estimate the maximum tolerated dose and recommended phase II dose of Aurora A kinase inhibitor MLN8237 administered once daily or twice daily in pediatric patients with relapsed or refractory solid tumors (except CNS tumors) or acute lymphoblastic leukemia.
  • To evaluate the toxicity of this drug in these patients.
  • To characterize the pharmacokinetics of this drug in these patients.

Secondary

  • To determine the antitumor activity of this drug in these patients. (Phase I)
  • To determine the efficacy of this drug, using the twice daily dosing schedule, in these patients. (Phase II)
  • To explore the relationship between polymorphic variations in the UDPglucuronyltransferase gene UGT1A1 and exposure to MLN8237.
  • To assess two common polymorphic variants in the Aurora A kinase gene (Phe31Ile and Val57Ile) thought to potentially influence tumorigenesis.
  • To examine the relationship between Aurora A expression status and response to Aurora A inhibition.

OUTLINE: This is a multicenter phase I, dose escalation followed by a phase II study. Patients are stratified according to diagnosis (solid tumors vs neuroblastoma vs acute lymphoblastic leukemia).

Patients receive oral Aurora A kinase inhibitor MLN8237 once or twice daily on days 1-7. Courses repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

Whole blood samples are collected from all patients for genotyping for polymorphisms in UGT1A1 enzymes and polymorphisms in the Aurora A kinase gene. For patients in the phase II portion of the study, previously preserved tumor tissue blocks and bone marrow or peripheral blasts are evaluated for Aurora A kinase protein using IHC, mRNA expression, and gene amplification using FISH or quantitative PCR. Blood samples are also collected periodically during the first course of therapy for pharmacokinetics studies.

  Eligibility

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

DISEASE CHARACTERISTICS:

  • Histologically confirmed solid tumor (phase I, stratum A), neuroblastoma (phase II, stratum B), or relapsed/refractory acute lymphoblastic leukemia (ALL) (phase II, stratum C)

    • Relapsed or refractory disease

      • Patients with leukemia who relapse during standard maintenance therapy are eligible at time of relapse
  • Meets the following criteria for measurable or evaluable disease as defined below by stratum:

    • Stratum A: measurable or evaluable disease
    • Stratum B: meets 1 of the following criteria:

      • Measurable tumor on MRI, CT scan, or x-ray obtained within 4 weeks prior to study entry
      • Evaluable tumor by MIBG scan or bone marrow involvement with tumor cells seen on routine morphology
    • Stratum C: must have M3 bone marrow
  • No existing curative therapy for the disease or therapy proven to prolong survival with an acceptable quality of life
  • No CNS tumors or known CNS metastatic disease

PATIENT CHARACTERISTICS:

  • Karnofsky performance status (PS) 50-100% (patients > 16 years of age) OR Lansky PS 50-100% (patients ≤ 16 years of age)
  • Patients with solid tumors (phase I, stratum A) must meet the following hematopoietic criteria:

    • ANC ≥ 1,000/μL
    • Platelet count ≥ 100,000/μL (no platelet transfusions within 7 days prior to enrollment)
    • Hemoglobin ≥ 8.0 g/dL (transfusion allowed)
  • Patients in phase II portion of the study (stratum B & C) must meet the following hematopoietic criteria:

    • ANC ≥ 750/μL
    • Platelet count ≥ 50,000/μL (transfusion allowed)*
    • Hemoglobin ≥ 8.0 g/dL (transfusion allowed)* NOTE: * Patients with leukemia must not be refractory to red blood cell or platelet transfusions
  • Creatinine clearance or radioisotope glomerular filtration rate ≥ 70ml/min OR serum creatinine based on age/gender (male [M], female [F]) as follows (in mg/dL):

    • 0.6(M), 0.6(F) (for patients 1 to < 2 years of age)
    • 0.8(M), 0.8(F) (for patients 2 to < 6 years of age)
    • 1(M), 1(F) (for patients 6 to < 10 years of age)
    • 1.2(M), 1.2(F) (for patients 10 to < 13 years of age)
    • 1.5(M), 1.4(F) for patients 13 to < 16 years of age)
    • 1.7(M), 1.4(F) (for patients 16 years of age and over)
  • Bilirubin ≤ 1.5 times upper limit of normal for age
  • ALT ≤ 110/µL
  • Serum albumin ≥ 2 g/dL.
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No uncontrolled infection
  • Patients must be able to swallow capsules
  • No patients who are unable to comply with the safety monitoring requirements of the study, in the opinion of the investigator

PRIOR CONCURRENT THERAPY:

  • Recovered from prior chemotherapy, immunotherapy, or radiotherapy for patients who relapsed when not receiving standard ALL maintenance therapy
  • More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea) (stratum A)
  • At least 14 days since prior cytotoxic therapy
  • At least 24 hours since cytoreduction with hydroxyurea
  • At least 7 days since prior hematopoietic growth factor therapy
  • At least 7 days since prior biological therapy (anti-neoplastic agent)
  • At least 2 weeks since prior local palliative external radiotherapy (XRT) (small port)
  • At least 6 weeks since prior treatment with therapeutic doses of iodine I 131 metaiodobenzylguanidine
  • At least 6 months since prior total-body irradiation (TBI), craniospinal XRT, or radiation to more than 50% of pelvis
  • At least 6 weeks since prior other substantial bone marrow radiation
  • At least 3 months since prior stem cell transplant or rescue without TBI AND no evidence of active graft vs host disease
  • More than 7 days since prior growth factors that support platelet or white cell number or function
  • Concurrent corticosteroids allowed provided patient is on a stable or decreasing dose of corticosteroid for

    • 7 days prior to study enrollment
  • No other concurrent investigational drug
  • No other concurrent anticancer therapy, including chemotherapy, radiotherapy, immunotherapy, or biological therapy

    • Concurrent intrathecal methotrexate allowed for patients with ALL at the discretion of the treating investigator
  • No concurrent chronic benzodiazepines
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00739427

Locations
United States, Alabama
UAB Comprehensive Cancer Center Recruiting
Birmingham, Alabama, United States, 35294
Contact: Clinical Trials Office - UAB Comprehensive Cancer Center     205-934-0309        
United States, California
Children's Hospital of Orange County Recruiting
Orange, California, United States, 92868
Contact: Violet Shen     714-532-8636        
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, District of Columbia, United States, 20010-2970
Contact: Clinical Trials Office - Children's National Medical Center     202-884-2549        
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229-3039
Contact: Clinical Trials Office - Cincinnati Children's Hospital Medica     513-636-2799        
Sponsors and Collaborators
Children's Oncology Group
Investigators
Study Chair: Yael P. Mosse, MD Children's Hospital of Philadelphia
  More Information

Additional Information:
No publications provided

Responsible Party: Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital ( Susan M. Blaney )
Study ID Numbers: CDR0000610257, COG-ADVL0812
Study First Received: August 20, 2008
Last Updated: August 6, 2009
ClinicalTrials.gov Identifier: NCT00739427     History of Changes
Health Authority: Unspecified

Keywords provided by National Cancer Institute (NCI):
unspecified childhood solid tumor, protocol specific
recurrent neuroblastoma
recurrent childhood acute lymphoblastic leukemia

Study placed in the following topic categories:
Acute Lymphoblastic Leukemia, Childhood
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immunoproliferative Disorders
Neuroectodermal Tumors, Primitive
Neuroblastoma
Recurrence
Leukemia
Lymphatic Diseases
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neuroepithelioma
Lymphoproliferative Disorders
Lymphoma
Acute Lymphoblastic Leukemia
Neuroectodermal Tumors, Primitive, Peripheral
Neoplasms, Glandular and Epithelial

Additional relevant MeSH terms:
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Immunoproliferative Disorders
Neuroectodermal Tumors, Primitive
Immune System Diseases
Neoplasms, Nerve Tissue
Neuroblastoma
Neuroectodermal Tumors
Leukemia
Lymphatic Diseases
Neoplasms
Neoplasms, Germ Cell and Embryonal
Lymphoproliferative Disorders
Neoplasms, Neuroepithelial
Neuroectodermal Tumors, Primitive, Peripheral
Neoplasms, Glandular and Epithelial

ClinicalTrials.gov processed this record on September 11, 2009