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Phase I Study of Aurora A Kinase Inhibitor (MLN8237) Given in Combination With Selective VEGFR Inhibitor Pazopanib (Votrient) for Therapy in Solid Tumors

Phase 1
18 Years
Not Enrolling
Solid Tumor, Advanced Non-hematologic Solid Tumor

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Trial Information

Phase I Study of Aurora A Kinase Inhibitor (MLN8237) Given in Combination With Selective VEGFR Inhibitor Pazopanib (Votrient) for Therapy in Solid Tumors

Alisertib is taken orally twice a day for the 1st 7 days of a 21 day cycle. Pazopanib is
taken orally once a day continuously beginning on day 10 of cycle 1 to allow for alisertib
pharmacokinetics (PKs). Treatment continues until disease progression, unacceptable
toxicity, or patient refusal. PKs will be done on all patients in association with the last
dose of alisertib cycles 1 and 2.

Inclusion Criteria:

- Diagnosis of advanced non-hematologic solid tumor malignancy, including, but not
limited to breast, lung, colon, pancreatic, head and neck, kidney or sarcoma that has
failed or become intolerant to standard therapy and is no longer likely to respond to
such therapy. Note: The maximum tolerated dose (MTD) for pazopanib monotherapy in
patients with hepatocellular cancer was found to be 600 mg daily therefore enrollment
for these patients will be limited to pazopanib dose levels at or below 600 mg.

- Measurable or evaluable disease per Response Evaluation Criteria for Solid Tumors

- Age ≥ 18 years

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

- Prior systemic chemotherapy, immunotherapy, or biological therapy is allowed; however
prior use of either study drug alone or in combination is not allowed. Time since
prior therapy and the first dose of study drug

- At least 21 days since previous antineoplastic therapy

- At least 42 days since previous nitrosoureas or mitomycin-C

- At least 42 days since exposure to fully human monoclonal antibodies

- At least 28 days since previous chimeric monoclonal antibodies

- At least 14 days since noncytotoxic small molecule drugs (eg tyrosine kinase
inhibitors such as Tarceva® and hormonal agents such as Femara®)

- At least 21 days since previous radiation therapy

- At least 14 days since prior major surgery (defined as a surgery involving a
risk to the life of the patient; specifically: an operation upon an organ within
the cranium, chest, abdomen, or pelvic cavity)

- At least 3 months since prior autologous transplant

- Must have recovered from the reversible effects of previous anti-cancer treatment
prior to study registration

- Adequate organ function within 14 days of study registration

- Patient must be able to take oral medication and to maintain a fast as required for 2
hours before and 1 hour after alisertib administration

- Female patient is either post-menopausal or surgically sterilized or willing to use
an acceptable method of birth control (ie, a hormonal contraceptive, intra-uterine
device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
duration of the study.

- Male patient agrees to use an acceptable method for contraception during the entire
study treatment period through 4 months after the last dose of alisertib.

- Voluntary written consent before performance of any study-related procedure not part
of normal medical care, with the understanding that consent may be withdrawn by the
patient at any time without prejudice to future medical care.

Exclusion Criteria:

- Untreated or symptomatic central nervous system (CNS) metastases

- Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is
considered to be over 25%.

- Prior allogeneic bone marrow or organ transplantation

- >or = Grade 2 peripheral neuropathy within 14 days before enrollment

- 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.

- Requirement for constant administration of proton pump inhibitor, H2 antagonist, or
pancreatic enzymes. Intermittent uses of antacids or H2 antagonists are allowed.

- Systemic infection requiring intravenous (IV) antibiotic therapy within 14 days
preceding the first dose of study drug, or other severe infection.

- Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities. Prior to study entry, any ECG
abnormality at Screening has to be documented by the investigator as not medically

- Pregnant or breast-feeding. Pazopanib is Pregnancy Category D - known teratogenic
potential. Confirmation that the subject is not pregnant must be established by a
negative serum B-human chorionic gonadotropin (B-hCG) pregnancy test result obtained
during screening. Pregnancy testing is not required for post-menopausal or surgically
sterilized women.

- Patient has received other investigational drugs with 14 days before enrollment

- Serious medical or psychiatric illness in the opinion of the researcher that would
likely interfere with participation in this clinical study.

- Other severe acute or chronic medical or psychiatric condition, including
uncontrolled diabetes, malabsorption, resection of the pancreas or upper small bowel,
requirement for pancreatic enzymes, any condition that would modify small bowel
absorption of oral medications, or laboratory abnormality that may increase the risk
associated with study participation or investigational product administration or may
interfere with the interpretation of study results and, in the judgment of the
investigator, would make the patient inappropriate for enrollment in this study.

- Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

- Treatment with clinically significant enzyme inducers, such as the enzyme inducing
antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or rifampin,
rifabutin, rifapentine or St. John's wort within 14 days prior to the first dose of
alisertib and during the study.

- Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or
hepatitis C. Testing is not required in the absence of clinical findings or

- Recent (within 6 months) arterial thromboembolic events, including transient ischemic
attack (TIA), cerebrovascular accident (CVA), unstable angina, or myocardial
infarction (MI). Patients with clinically significant peripheral artery disease are

- History of thrombotic or hemorrhagic disorders, not receiving chronic daily treatment
with aspirin (>325 mg/day) or non-steroidal anti-inflammatory agents know to inhibit
platelet function. Treatment with dipyridamole (persantine), ticlopidine (Ticlid),
clopidogrel (Plavix) and/or cilostazol (Pletal).

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 28 days prior to beginning study treatment

- Clinically significant gastrointestinal abnormalities that may affect absorption of
investigational product including, but not limited to:

- Ongoing nausea or vomiting of any severity

- > grade 1 diarrhea

- Malabsorption syndrome

- Major resection of stomach or small bowel

- Inability to swallow oral medications or inability to take nothing by mouth except
water and prescribed medications for 2 hours before and 1 hour after each dose of

- Abnormalities on 12-lead electrocardiogram (ECG) considered by the investigator to be
clinical significant or baseline prolongation of the rate corrected QT interval
(e.g., repeated demonstration of QTc interval > 450 milliseconds)

- Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg
or diastolic blood pressure (DBP) of ≥ 90mmHg]. Note: Initiation or adjustment of
antihypertensive medication(s) is permitted prior to study entry. The mean SBP / DBP
values from each blood pressure assessment must be < 140/90mmHg in order for a
subject to be eligible for the study.

- History of cerebrovascular accident, pulmonary embolism or untreated deep venous
thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have
been treated with therapeutic anti-coagulating agents for at least 6 weeks are
eligible. Patients receiving Coumadin must be transition to low molecular weight
heparin and treated for at least 14 days prior to the first dose of study drug.

- Prior major surgery or trauma within 28 days prior to first dose of study drug and/or
presence of any non-healing wound, fracture, or ulcer (procedures such as catheter
placement not considered to be major)

- Evidence of active bleeding or bleeding diathesis

- Known endobronchial lesions or involvement of large pulmonary vessels by tumor or
centrally located pulmonary cavitating lesion

- Hemoptysis (> ½ teaspoon of bright red blood per episode) within 6 weeks of first
dose of study drug

- Unable or unwilling to discontinue use of prohibited medications for at least 14 days
prior to the first dose of study drug and for the duration of the study

- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to pazopanib or alisertib or drugs to formulate

Type of Study:


Study Design:

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

Outcome Measure:

Optimally Tolerated Dose

Outcome Description:

Complete all planned treatment for cycle 1 (defined as 14 doses of alisertib and daily pazopanib) without dose limiting toxicity and are able to start cycle 2 with no more than a 2 week delay.

Outcome Time Frame:

At end of Cycle 1 (approximately Day 21)

Safety Issue:


Principal Investigator

Arkadiusz Z. Dudek, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Illinois


United States: Food and Drug Administration

Study ID:




Start Date:

February 2013

Completion Date:

February 2016

Related Keywords:

  • Solid Tumor
  • Advanced Non-hematologic Solid Tumor
  • malignant solid tumor
  • Neoplasms



University of Illinois Cancer Center Chicago, Illinois  60612-7243