MLN8237 and Pazopanib in Combination for Solid Tumors

This phase I dose escalation study will evaluate alisertib, an Aurora A kinase inhibitor, when given in combination with the selective vascular endothelial growth factor receptor (VEGFR) inhibitor pazopanib in patients with advanced, previously treated non-hematologic 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.

• Solid Tumor
• Advanced Non-hematologic Solid Tumor

• Drug: Alisertib
  Alisertib at the assigned (10, 20, 40 or 50 mg) dose by mouth (PO) twice a day for 7 days beginning on day 1 of a 21 day cycle.
• Drug: Pazopanib
  Pazopanib at the assigned dose (400, 600 or 800 mg) by mouth (PO) once a day beginning on day 10 of the 1st cycle and continuing daily for the duration of study treatment.

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 (RECIST)
• 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 relevant.
• 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 suspicion.
• 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 ineligible.
• 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 alisertib.
• 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