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Phase II Study of MLN8237 in Advanced / Metastatic Sarcoma

Phase 2
18 Years
Open (Enrolling)
Adult Alveolar Soft-part Sarcoma, Adult Angiosarcoma, Adult Epithelioid Sarcoma, Adult Extraskeletal Chondrosarcoma, Adult Fibrosarcoma, Adult Leiomyosarcoma, Adult Liposarcoma, Adult Neurofibrosarcoma, Chondrosarcoma, Endometrial Stromal Sarcoma, Mast Cell Sarcoma, Metastatic Adult Malignant Fibrous Histiocytoma of Bone, Ovarian Carcinosarcoma, Ovarian Sarcoma, Recurrent Adult Malignant Fibrous Histiocytoma of Bone, Recurrent Adult Soft Tissue Sarcoma, Small Intestine Leiomyosarcoma, Stage III Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma

Thank you

Trial Information

Phase II Study of MLN8237 in Advanced / Metastatic Sarcoma


I. To determine the response rate (complete response [CR] + partial response [PR]) assessed
for patients within each cohort: liposarcoma (cohort 1); leiomyosarcoma (non-uterine)
(cohort 2); undifferentiated sarcoma (including pleomorphic undifferentiated sarcoma,
formerly known as malignant fibrous histiocytoma, and myxofibrosarcoma) (cohort 3);
malignant peripheral nerve sheath tumor (cohort 4); and other sarcomas (cohort 5).


I. To estimate the progression-free survival (PFS) and overall survival (OS) for patients
treated with alisertib (MLN8237) in each cohort.

II. To assess the adverse events associated with patients treated with MLN8237 in each


I. To correlate potential clinical benefit with markers of aurora kinase inhibition in pre-
and post-treatment tumor biopsies.

II. To correlate clinical outcome with change in fluorine F 18 fluorothymidine
(FLT)-positron emission tomography (PET) uptake at baseline versus after one week of
treatment (i.e., week 2 of cycle 1).


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 for up to 18 months.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed sarcoma that is
metastatic and/or locally advanced or locally recurrent and unresectable

- Patients will been rolled on one of five cohorts of the study:

- Cohort 1: Liposarcoma

- Cohort 2: Leiomyosarcoma (non-uterine)

- Cohort 3: Undifferentiated sarcoma (including malignant fibrous
histiocytoma and myxofibrosarcoma)

- Cohort 4: Malignant peripheral nerve sheath tumor

- Cohort 5: Other sarcomas

- Patients must have measurable disease per Response Evaluation Criteria in Solid
Tumors(RECIST) 1.1, defined as at least one lesion that can be accurately measured in
at least one dimension (longest diameter to be recorded for non-nodal lesions and
short axis for nodal lesions) as ≥ 2 cm with conventional techniques or as ≥ 1 cm
with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or
calipers by clinical exam

- Any number of prior therapies is permitted

- The last dose of systemic therapy (including tyrosine kinase inhibitors) must
have been given ≥ 4 weeks prior to initiation of study therapy

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelet count >= 100,000/mcL

- Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
serum glutamic pyruvate transaminase (alanine aminotransferase [AST]) < 3 times ULN
if no liver metastases or < 5 times ULN if liver metastases present

- Creatinine =< 1.5 times ULN OR creatinine clearance >= 60 mL/min/1.73m^2 for patients
with creatinine levels above institutional normal

- Women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation; men treated or enrolled on this protocol
must also agree to use adequate contraception prior to the study, for the duration of
study participation, and 4 months after completion of MLN8237 administration

- Ability to understand and the willingness to sign a written informed consent document

- According to current guidelines, patients must be able to take oral medication and to
maintain a fast as required for approximately one hour before and two hours after
MLN8237 administration

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- No patients who have had radiation therapy to more than 25% of the bone marrow
(whole pelvic radiation is considered to be over 25%)

- Patients who are receiving any other investigational agents

- Patients with known brain metastases

- 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

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, New York Heart Association (NYHA) class II-IV heart failure, unstable
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements

- Pregnant women; women of child-bearing potential must have a negative serum or urine
pregnancy test within 7 days prior to registration; breastfeeding should be
discontinued if the mother is treated with MLN8237; these potential risks may also
apply to other agents used in this study

- Leiomyosarcoma of the uterus

- Patients known to be human immunodeficiency virus (HIV)-positive on antiretroviral

- Prior allogeneic bone marrow or organ transplantation

- 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

- Requirement for constant administration of proton pump inhibitor, histamine-2 (H2)
antagonist, or pancreatic enzymes

- Intermittent uses of antacids or H2 antagonists are allowed

- Inability to swallow oral medication or to maintain a required fast for approximately
one hour before and two hours after MLN8237 administration or any condition that
would modify small bowel absorption of oral medications, including malabsorption or
resection of pancreas or upper bowel

- 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. Johns wort within 14 days
prior to the first dose of MLN8237 and during the study

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The confirmed response rate (CR/PR)

Outcome Description:

The overall response rate (CR + PR) will be estimated and a 90% confidence interval provided.

Outcome Time Frame:

Up to 18 months

Safety Issue:


Principal Investigator

Mark Dickson

Investigator Role:

Principal Investigator

Investigator Affiliation:

Cancer and Leukemia Group B


United States: Food and Drug Administration

Study ID:




Start Date:

August 2012

Completion Date:

Related Keywords:

  • Adult Alveolar Soft-part Sarcoma
  • Adult Angiosarcoma
  • Adult Epithelioid Sarcoma
  • Adult Extraskeletal Chondrosarcoma
  • Adult Fibrosarcoma
  • Adult Leiomyosarcoma
  • Adult Liposarcoma
  • Adult Neurofibrosarcoma
  • Chondrosarcoma
  • Endometrial Stromal Sarcoma
  • Mast Cell Sarcoma
  • Metastatic Adult Malignant Fibrous Histiocytoma of Bone
  • Ovarian Carcinosarcoma
  • Ovarian Sarcoma
  • Recurrent Adult Malignant Fibrous Histiocytoma of Bone
  • Recurrent Adult Soft Tissue Sarcoma
  • Small Intestine Leiomyosarcoma
  • Stage III Adult Soft Tissue Sarcoma
  • Stage IV Adult Soft Tissue Sarcoma
  • Histiocytoma
  • Histiocytoma, Benign Fibrous
  • Carcinosarcoma
  • Mixed Tumor, Mullerian
  • Chondrosarcoma
  • Fibrosarcoma
  • Fibrosis
  • Hemangiosarcoma
  • Leiomyosarcoma
  • Liposarcoma
  • Mast-Cell Sarcoma
  • Sarcoma
  • Sarcoma, Endometrial Stromal
  • Sarcoma, Alveolar Soft Part
  • Neurofibrosarcoma
  • Neurilemmoma
  • Adenoma
  • Histiocytoma, Malignant Fibrous
  • Ovarian Neoplasms



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