Pemetrexed Disodium and Sorafenib Tosylate in Treating Patients With Advanced Solid Tumors

PRIMARY OBJECTIVES:

I. To determine doses for the combination of pemetrexed (pemetrexed disodium) with sorafenib (sorafenib tosylate) appropriate for Phase II study.

SECONDARY OBJECTIVES:

I. To evaluate the safety, tolerance, and toxicity of the combination of pemetrexed and sorafenib.

II. To observe antitumor effects of the combination.

OUTLINE: This is a dose-escalation study of pemetrexed disodium and sorafenib tosylate.

Patients receive pemetrexed disodium intravenously (IV) on day 1 every 2 weeks and sorafenib tosylate orally (PO) twice daily (BID) on days 1-5. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion criteria

• Advanced solid tumor malignancy for which there is no potentially curative treatment; there is no limit to the number of prior lines of therapy
• Performance status Eastern Cooperative Oncology Group (ECOG) equal or less than 1
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 3 x upper institutional limit (ULN)
• Total bilirubin =< 1.5 ULN
• Creatinine clearance (CrCl) >= 45 mL/min as measured by the standard Cockcroft-Gault equation
• International normalized ratio (INR) =< 1.5 (if not due to anticoagulants)
• White blood cell count (WBC) >= 3,000 cells/mm3
• Absolute neutrophil count (ANC) >= 1,500 cells/mm3
• Platelets >= 100,000 cells/mm3
• Hemoglobin (Hgb) >= 8.5 g/dL
• Prior toxicities are allowed as long as they are stable and would not interfere with study drug toxicity assessment
• Measurable or evaluable disease by Response Evaluation Criteria In Solid Tumors (RECIST) (v 1.1)
• Ability to understand and the willingness to sign a written informed consent document; a signed informed consent must be obtained prior to any study specific procedures
• Women of childbearing potential must have a negative pregnancy test performed within 7 days prior to the start of treatment; women of childbearing potential and men must agree to use a medically accepted form of birth control for the duration of study participation; men must agree to use a medically accepted form of birth control for 2 months following completion of study treatment

Exclusion criteria

• Any investigational agent within 4 weeks of first dose of study treatment
• Unwillingness or inability to take folic acid, vitamin B12, or dexamethasone
• Known or presumed intolerance of pemetrexed or sorafenib; unable to swallow medication; suspected malabsorption
• Active illicit substance or alcohol abuse
• Contraindication to antiangiogenic agents, including:
• Pulmonary hemorrhage/bleeding event >= Grade 2 within 4 weeks or less prior to the first dose of study drug
• Any other hemorrhage/bleeding event >= Grade 3 within 4 weeks or less prior to the first dose of study drug
• Serious non-healing wound, ulcer, or bone fracture
• Thrombolic or embolic events such as a myocardial infarction, cerebrovascular accident including transient ischemic attacks within the past 6 months
• Major cardiac dysfunction, such as uncontrolled angina, congestive heart failure with New York Heart Association (NYHA) class III or higher, ventricular arrhythmias requiring anti-arrhythmic therapy
• Systolic blood pressure > 160 mmHg or diastolic pressure > 100 mmHg despite optimal medical management
• Inability to interrupt aspirin or other nonsteroidal anti-inflammatory agents for a 5 day period
• Serious uncontrolled infection > Common Terminology Criteria for Adverse Events (CTCAE) (v 4) grade 2
• Peripheral motor or sensory neuropathy>CTCAE (v4) grade 2
• Uncontrolled metastatic brain disease
• Serum B12 or folate levels below the institution's lower limit of normal. Patients may begin B12/folic acid supplementation and can be reconsidered for study once levels meet the eligibility requirements
• Administration of non-steroidal anti-inflammatory drugs (NSAIDs) within 5 days prior to pemetrexed dosing (note: if a candidate routinely takes NSAIDs prior to enrollment, consider transition to alternate non-NSAID for duration of study treatment, if possible).
• Other condition(s) that in the opinion of the investigator might compromise the objectives of the study