Alisertib in Treating Patients With Recurrent or Persistent Leiomyosarcoma of the Uterus

PRIMARY OBJECTIVES:

I. To assess the clinical activity of MLN8237 (alisertib) in patients with recurrent or
persistent leiomyosarcoma of the uterus who have received one or two prior cytotoxic
therapies and the frequency of patients who survive progression-free for at least 6 months
after initiating therapy or have objective tumor response.

SECONDARY OBJECTIVES:

I. To determine the frequency and severity of adverse events as assessed by Common
Terminology Criteria for Adverse Events version 4 (CTCAE v4) among women with leiomyosarcoma
treated with MLN8237.

II. To determine the distribution of progression-free survival (PFS) and overall survival
(OS).

TERTIARY OBJECTIVES:

I. To determine the relationship of Aurora A Kinase expression, measured by
immunohistochemistry, with objective response, PFS at 6 months, survival, and
progression-free survival.

OUTLINE:

Patients receive alisertib orally (PO) twice daily (BID) on days 1-7. Courses repeat every 21
days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.

Inclusion Criteria:

- Patients must have incurable recurrent or persistent uterine leiomyosarcoma;
histologic confirmation of the original primary tumor is required

- Patients must have measurable disease; measurable disease is defined by Response
Evaluation Criteria in Solid Tumors (RECIST) (version 1.1); measurable disease is
defined as at least one lesion that can be accurately measured in at least one
dimension (longest diameter to be recorded); each lesion must be >= 10 mm when
measured by computed tomography (CT), magnetic resonance imaging (MRI), or caliper
measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes
must be >= 15 mm in short axis when measured by CT or MRI

- Patients must have at least one "target lesion" to be used to assess response on this
protocol as defined by RECIST version 1.1; tumors within a previously irradiated field
will be designated as "non-target" lesions unless progression is documented or a
biopsy is obtained to confirm persistence at least 90 days following completion of
radiation therapy

- Patients must not be eligible for a higher priority Gynecologic Oncology Group (GOG)
protocol, if one exists; in general, this would refer to any active GOG phase III
protocol for the same patient population (12/10/2012)

- Patients who have received one prior regimen must have a GOG performance status of 0,
1, or 2; patients who have received two prior regimens must have a GOG performance
status of 0 or 1

- Patients should be free of active infection requiring antibiotics (with the exception
of uncomplicated urinary tract infection [UTI])

- Any hormonal therapy directed at the malignant tumor must be discontinued at least one
week prior to registration

- Any other prior therapy directed at the malignant tumor, including chemotherapy and
immunologic agents, must be discontinued at least three weeks prior to registration
(12/10/2012)

- Any prior radiation therapy must be discontinued at least four weeks prior to
registration (12/10/2012)

- Patients must have had at least one prior chemotherapeutic regimen for management of
leiomyosarcoma

- Patients are allowed to receive, but are not required to receive, one additional
cytotoxic regimen for management of recurrent or persistent disease (12/10/2012)

- Patients must NOT have received any prior therapy directed at Aurora kinase for
management of recurrent or persistent disease; patients who were treated on GOG-0250
(gemcitabine + docetaxel plus bevacizumab vs placebo) are eligible; treatment on
GOG-0250 would count as ONE prior regimen

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Serum creatinine =< institutional upper limit of normal (ULN) OR creatinine clearance
>= 60 mL/min/1.73m^2 (calculated or measured)

- Bilirubin =< ULN

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN

- Alkaline phosphatase =< 2.5 x ULN

- Patients must have signed an approved informed consent and authorization permitting
release of personal health information

- Patients of childbearing potential must have a negative serum pregnancy test prior to
the study entry and be practicing an effective form of contraception; pregnant women
are excluded from this study

- Patients must be able to take oral medication and to maintain a fast for 2 hours
before and 1 hour after MLN8237 administration

- Patient must not have taken agents that effect gastric pH within 4 days (any proton
pump inhibitor), or 1 day (any histamine-2 antagonist) of the planned start of
therapy; patients must be able to avoid all other types of antacids for 2 hours before
and 2 hours after each dose of MLN8237

Exclusion Criteria:

- Patients who have had prior therapy with MLN8237 or taken part in a study of an
investigational compound or device within 4 weeks of entering this study

- Patients who have had surgery (excluding biopsy), radiotherapy, or chemotherapy within
4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to the planned start of
protocol treatment or those who have not recovered from adverse events due to agents
administered more than 4 weeks earlier; patients who have had hormonal agents within 1
week of the planned start of protocol treatment

- Patients with other invasive malignancies, with the exception of non-melanoma skin
cancer, carcinoma in situ of the cervix, or ductal carcinoma in situ of the breast,
are excluded if there is any evidence of other malignancy being present within the
last three years

- Patients who have received prior radiotherapy to any portion of the abdominal cavity
or pelvis OTHER THAN for the treatment of uterine leiomyosarcoma within the last three
years are excluded; thus, patients with a history of prior pelvic radiation for
uterine leiomyosarcoma are eligible; prior radiation for localized cancer of the
breast, head and neck, or skin is permitted, provided that it was completed more than
three years prior to registration, and the patient remains free of recurrent or
metastatic disease

- Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER
THAN for the treatment of uterine leiomyosarcoma within the last three years are
excluded; patients may have received prior adjuvant chemotherapy for localized breast
cancer, provided that it was completed more than three years prior to registration,
and that the patient remains free of recurrent or metastatic disease

- Patients who are nursing because there is an unknown but potential risk for adverse
events in nursing infants from MLN8237

- Patients with a history of central nervous system metastases and/or carcinomatous
meningitis

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to MLN8237, including but not limited to established
allergic reaction to benzodiazepines

- Patients who are known to be human immunodeficiency virus (HIV) positive

- Patients who have had prior allogeneic bone marrow or organ transplantation

- Patients with a known history of uncontrolled sleep apnea syndrome and other
conditions that could result in excessive daytime sleepiness, such as severe chronic
obstructive pulmonary disease; requirement for supplemental oxygen; or any conditions
that could result in excessive toxicity associated with the benzodiazepine-like
effects of MLN8237

- Patients who require constant administration of proton pump inhibitor, H2 antagonist,
or pancreatic enzymes; intermittent uses of antacids or H2 antagonists are allowed

- Patients who are unable to swallow oral medication or to maintain a fast as required
for 2 hours before and 1 hour after MLN8237 administration or any condition that would
modify small bowel absorption of oral medications, including malabsorption, or
resection of pancreas or upper bowel

- Patients who have had treatment with clinically significant enzyme inducers, such as
the enzyme-inducing antiepileptic drugs phenytoin, carbamazepine, oxcarbazepine,
primidone or phenobarbital, or rifampin, rifabutin, rifapentine, or St. John's wort
within 14 days prior to the first dose of MLN8237 and during the study

- Patients who have had a myocardial infarction within 6 months prior to enrollment or
have New York Heart Association (NYHA) class III (marked limitation of physical
activity, comfortable at rest, but less than ordinary activity causes fatigue,
palpitation, or dyspnea) or IV (unable to carry out any physical activity without
discomfort, symptoms of cardiac insufficiency at rest, if any physical activity is
undertaken, discomfort is increased) heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities; prior to study entry, any
electrocardiogram (ECG) abnormality at screening has to be documented by the
investigator as not medically relevant

- Patients must limit alcohol consumption to no more than 1 standard unit of alcohol (12
oz beer [350 mL], 1.5 oz [45 mL] of 80-proof alcohol, or one 6-oz [175 mL] glass of
wine) per day during the study and for 30 days from the last dose of MLN8237; patients
who are unable to comply with these restrictions are not eligible