EphA2 siRNA in Treating Patients With Advanced or Recurrent Solid Tumors

Inclusion Criteria:

• All patients with histologic proof of advanced solid tumors, who are not candidatesfor known regimens or protocol treatments of higher efficacy or priority

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

• All patients (dose escalation and dose expansion phases) must be willing to undergopre- and post-treatment biopsies

• For the dose escalation phase, the trial population will be limited to solid tumortypes

• For dose expansion phase: patients must have EphA2 overexpression overall H-score of 3 or above in immunohistochemistry (IHC) evaluation; Clinical Laboratory ImprovementAmendments (CLIA) certified EphA2 IHC staining to be performed on formalin fixed,paraffin-embedded tissue sections using monoclonal EphA2 antibody; EphA2 expressionto be assessed through a combo of % of positive cells and staining intensity; the %of positive cells will be rated: 0 points (pts), 0 to 5%; 2 pts, 6 to 50%; 3 pts, 50%; the staining intensity will be rated as follows: 1 pt, weak intensity; 2 pts,moderate intensity; 3 pts, strong intensity; pts for expression and % of positivecells will be added; an overall score will be assigned; tumors to be categorizedinto 4 groups: negative (overall score 0), 5% cells stained, regardless ofintensity; weak expression (overall score 1), 1 - 2 pts; moderate expression (overall score 2), 3 - 4 pts; and strong expression (overall score 3), 5 - 6 pts;overall H-score of 3 or above will be defined as EphA2 overexpression in tumor cells

• Measurable disease is defined as at least one lesion that can be accurately measuredin at least one dimension; at least one biopsiable lesion must be available; whenimaging (DCE-MRI, DW-MRI and PET-computed tomography [CT] imaging) is beingperformed for secondary objectives (dose level III [or when the dose reaches atleast 1,500 ug/m^2] and during the expansion phase) at least one lesion (>= 2 cm)not adjacent to the diaphragm will be required when measured by conventionaltechniques, including palpation, plain x-ray, CT, and MRI; a second lesionaccessible for biopsy must also be present; patients must have at least one 'targetlesion' to be used to assess response on this protocol as defined by ResponseEvaluation Criteria in Solid Tumors (RECIST); this may be one of the lesionsmentioned above; tumors within a previously irradiated field will be designated as 'non-target' lesions

• Resolution of any effects of prior therapy (except alopecia) to National CancerInstitute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03grade =< 1 and to baseline laboratory values as defined below

• Hemoglobin (HGB) >= 9 g/dL

• White blood cells (WBC) >= 3,000/mcL

• Absolute neutrophil count (ANC) >= 1,500/mcL

• Platelet (PLT) >= 100,000/mcL

• Total bilirubin less than or equal to 1.5

• Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvatetransaminase (SGPT) < 2.5 x institutional upper limit of normal (ULN)

• Creatinine < 1.5 x ULN or creatinine clearance > 60 ml/min according toCockcroft-Gault formula

• Neuropathy (sensory and motor) =< to CTCAE grade 1

• Prothrombin time (PT) such that international normalized ratio (INR) is < 1.5 (or anin-range INR, usually between 2 and 3, if a patient is on a stable dose oftherapeutic warfarin or low molecular weight heparin) and a partial thromboplastintime (PTT) < 1.2 times control

• Patients should be free of active infection requiring intravenous antibiotics

• Any hormonal therapy directed at the malignant tumor must be discontinued at leastone week prior to registration (study enrollment); continuation of hormonereplacement therapy is permitted; stable regimens of hormonal therapy i.e. forprostate cancer (e.g. leuprolide, a gonadotropin-releasing hormone [GnRH] agonist),ovarian or breast cancer are not exclusionary

• Any other prior therapy directed at the malignant tumor, including immunologicagents, must be discontinued at least three weeks prior to first dose of study drug (6 weeks for nitrosoureas or mitomycin C)

• Female subject is either post-menopausal or surgically sterilized or willing to usean acceptable method of birth control (i.e., a hormonal contraceptive, intrauterinedevice, diaphragm with spermicide, condom with spermicide, or abstinence) for theduration of the study and for at least 3 months after completion of EphA2 siRNA-DOPCtherapy

• Male subject agrees to use an acceptable method of contraception for the duration ofthe study

• Patients must voluntarily sign an informed consent indicating that they are aware ofthe investigational nature of this study in keeping with the policies of thehospital

Exclusion Criteria:

• Patients may not be receiving any other investigational agents and/or other therapyfor their cancer

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to DOPC, Magnevist, or fluorodeoxyglucose (FDG)

• Patients with active bleeding or pathologic conditions that carry high risk ofbleeding, such as a known bleeding disorder, coagulopathy, or tumor involving majorvessels

• Patients with history or evidence upon physical examination of central nervoussystem (CNS) disease, including primary brain tumor, seizures not controlled withstandard medical therapy, any brain metastases

• Patients with history of cerebrovascular accident (CVA, stroke), transient ischemicattack (TIA) or subarachnoid hemorrhage within 6 months of the first date oftreatment on this study

• Patients with clinically significant cardiovascular disease; this includes:uncontrolled hypertension (greater than 140/90); myocardial infarction or unstableangina within 6 months prior to registration; New York Heart Association (NYHA)grade II or greater congestive heart failure; serious cardiac arrhythmia requiringmedication; grade II or greater peripheral vascular disease; patients withclinically significant peripheral artery disease, e.g., those with claudication,within 6 months of first date of treatment on this study

• Patients whose circumstances do not permit completion of the study or the requiredfollow-up

• Patients who are pregnant or nursing

• History of human immunodeficiency virus (HIV) or HIV-positive patients oncombination antiretroviral therapy are ineligible

• Patients whose tumor is not accessible for a core biopsy

• Exclusion criteria (MRI specific):

• Patients who are ineligible to undergo an MRI scan for reasons such asclaustrophobia or the presence of implanted devices or metallic foreign bodiesthat are not magnetic resonance (MR) compatible; patients with a known historyof allergic reaction to gadolinium contrast agents; patients with a history ofa glomerular filtration rate (GFR) of less than 60 or acute renal disease

• Exclusion criteria (PET specific):

• Pregnant or nursing women; extreme claustrophobia; weight near or greater than 350 pounds