A Phase II Evaluation of MLN8237 (NSC #747888 IND #113149) in the Treatment of Recurrent or Persistent Leiomyosarcoma of the Uterus

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

- No patients with a history of central nervous system metastases and/or carcinomatous
meningitis

- 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])

- 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 (calculated or measured)

- Bilirubin ≤ ULN

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 times ULN

- Alkaline phosphatase ≤ 2.5 times ULN

- No patients who are pregnant or nursing

- Patients of childbearing potential must have a negative serum pregnancy test prior to
the study entry and be practicing an effective form of contraception

- 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

- 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

- No 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

- No patients who are known to be human immunodeficiency virus (HIV) positive

- No 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

- No requirement for supplemental oxygen

- No condition that could result in excessive toxicity associated with the
benzodiazepine-like effects of MLN8237

- No patients who are unable to swallow oral medication or any condition that would
modify small bowel absorption of oral medications, including malabsorption or
resection of pancreas or upper bowel

- No 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 must
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

- See Disease Characteristics

- Recovered from effects of recent surgery, radiotherapy, or chemotherapy

- 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

- 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

- 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

- No 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

- No 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 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

- No patients who have had prior allogeneic bone marrow or organ transplantation

- No patients who require constant administration of proton pump inhibitor, H2
antagonist, or pancreatic enzymes; intermittent uses of antacids or H2 antagonists
are allowed

- No patients who have had treatment with clinically significant enzyme inducers, such
as the enzyme-inducing antiepileptic drugs phenytoin, carbamazepine, oxcarbazepine,
primidone, phenobarbital, rifampin, rifabutin, rifapentine, or St. John wort within
14 days prior to the first dose of MLN8237 and during the study

Exclusion Criteria:

- Any prior radiation therapy must be discontinued at least four weeks prior to
registration