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

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.