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

PRIMARY OBJECTIVE:

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.

SECONDARY OBJECTIVES:

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).

ARM I (NEUROBLASTOMA- MEASURABLE): 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.

ARM II (NEUROBLASTOMA-MIBG EVALUABLE): 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.

ARM III (RHABDOMYOSARCOMA): 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.

ARM IV (OSTEOSARCOMA): 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.

ARM V (EWING SARCOMA/ PERIPHERAL PNET): 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.

ARM VI (NON-RMS SOFT TISSUE SARCOMA): 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.

ARM VII (HEPATOBLASTOMA): 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.

ARM VIII (MALIGNANT GERM CELL TUMOR): 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.

ARM IX (WILMS TUMOR): 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.

ARM X (ACUTE LYMPHOBLASTIC LEUKEMIA): 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.

ARM XI (ACUTE MYELOGENOUS LEUKEMIA): 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.

ARM XII (RHABDOID MALIGNANCY): 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.

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.

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