MLN8237 in Young Patients With Relapsed or Refractory Solid Tumors or Acute Lymphoblastic Leukemia

• 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 ]

• Maximum tolerated dose (Phase I) [ Designated as safety issue: Yes ]
• Toxicity (Phase I) [ Designated as safety issue: Yes ]
• Pharmacokinetics [ Designated as safety issue: No ]

• 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 ]

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 (acute lymphoblastic leukemia closed to accrual as of 02/18/10).

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 (ALL). (ALL closed to accrual as of 02/18/10)
• 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 once 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). (Acute lymphoblastic leukemia closed to accrual as of 02/18/10)

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. Bone marrow is also obtained for FAB morphology, immunophenotyping, and cytogenetics. Blood samples are also collected periodically during the first course of therapy for pharmacokinetics studies.

• Leukemia
• Neuroblastoma
• Unspecified Childhood Solid Tumor, Protocol Specific

• Drug: alisertib
• Genetic: cytogenetic analysis
• Genetic: fluorescence in situ hybridization
• Genetic: gene expression analysis
• Genetic: polymerase chain reaction
• Genetic: polymorphism analysis
• Other: immunohistochemistry staining method
• Other: pharmacological study

• Mossé YP, Lipsitz E, Fox E, Teachey DT, Maris JM, Weigel B, Adamson PC, Ingle MA, Ahern CH, Blaney SM. Pediatric Phase I Trial and Pharmacokinetic Study of MLN8237, an Investigational Oral Selective Small-Molecule Inhibitor of Aurora Kinase A: A Children's Oncology Group Phase I Consortium Study. Clin Cancer Res. 2012 Oct 11. [Epub ahead of print]
• Lipsitz E, Moorthy G, Mosse Y, Fox E, Adamson PC. A sensitive and selective liquid chromatography/tandem mass spectrometry method for determination of MLN8237 in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Jul 3; [Epub ahead of print]

DISEASE CHARACTERISTICS:

• Histologically confirmed solid tumor (phase I, stratum A1 or A2) or neuroblastoma (phase II, stratum B) or relapsed/refractory acute lymphoblastic leukemia (ALL) (phase II, stratum C) (ALL closed to accrual as of 02/18/10)

  • Relapsed or refractory

    • Patients with leukemia who relapse during standard maintenance therapy are eligible at time of relapse (closed to accrual as of 02/18/10)

• Meets the following criteria for measurable or evaluable disease as defined below by stratum:

  • Stratum A1 or A2: 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 (closed to accrual as of 02/18/10)
• No existing curative therapy for the disease or therapy proven to prolong survival with an acceptable quality of life
• No CNS tumors, known CNS metastatic disease, or known CNS leukemia

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 A1 or A2) 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: (stratum C closed to accrual as of 02/18/10)

  • 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 (closed to accrual as of 02/18/10)

• 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 (ULN) for age
• ALT ≤ 5.0 times ULN for age
• 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
• More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea) (stratum A1 or A2)
• 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
• At least 3 half-lives since prior therapy that includes a monoclonal antibody
• 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 P-gp substrates (i.e., digoxin, cyclosporine, tacrolimus, or sirolimus)
• No concurrent chronic benzodiazepines