EphA2 Gene Targeting using Neutral Liposomal Small Interfering RNA Delivery (IND# 72924): A Phase I Clinical Trial
The goal of this clinical research study is to learn about the safety of siRNA-EphA2-DOPC when given to patients with advanced, recurrent cancer. Researchers also want to learn the highest tolerable dose of this drug that can be given. siRNA-EphA2-DOPC is designed to shut down the activity of a genetic biomarker called EphA2. Biomarkers are found in the blood and tissue and may be related to your reaction to the study drug. You are being asked to take part in this study because you have advanced cancer that is recurrent (has come back).
Disease Group: Advanced Cancers,Phase I Studies
Treatment Agent: siRNA-EphA2-DOPC
Treatment Location: Only at MDACC
Primary Objectives: To determine the safety and tolerability (toxicity profile) of EphA2 siRNA delivered via neutral liposome (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine or DOPC) administered intravenously in patients with advanced/recurrent malignancies To determine the maximal tolerated dose (MTD) or maximal administered dose (MAD) using a modified toxicity probability interval (mTPI) design Exploratory Objectives To determine the pharmacokinetic profile of siRNA-EphA2-DOPC in blood To determine the effect of EphA2 siRNA-DOPC on tumor perfusion, apparent diffusion, and metabolism by radiographic imaging (DCE-MRI, DW-MRI and 18FDG-PET) To determine the impact of EphA2 siRNA-DOPC on surrogate biomarkers in blood (cell-free DNA, plasma/serum markers [VEGF, CAV1, soluble EphrinA1] and exosomes) Secondary Objectives: To determine efficacy (EphA2s897 expression modulation) at the MTD or MAD To evaluate the effect of EphA2 siRNA-DOPC on tumor and endothelial cell apoptosis To record the clinical activity (objective response, duration of response, and time to treatment progression) of IV EphA2 siRNA -DOPC
IRB Review and Approval Date: 07/01/2015
Recruitment Status: Open
Projected Accrual: 40
1) All patients with histologic proof of advanced solid tumors, who are
not candidates for known regimens or protocol treatments of higher
efficacy or priority.
2) Subject/patient must be 18 years or older (no dosing or adverse event data are currently available on the use of EphA2 siRNA-DOPC in patients < 18 years of age).
3) ECOG performance status </=2.
4) All patients (dose escalation and dose expansion phases) must be willing to undergo pre- and post-treatment biopsies.
5) For the dose escalation phase, the trial population will be limited to solid tumor types
6) For dose expansion phase: patients must have EphA2 overexpression overall H-score of 3 or above in IHC evaluation.CLIA certified EphA2 IHC staining to be performed on formalin fixed, paraffin-embedded tissue sections using monoclonal EphA2 antibody. EphA2 expression to 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 positive cells will be added; an overall score will be assigned. Tumors to be categorized into 4 groups: negative (overall score 0), 5% cells stained, regardless of intensity; 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.
7) Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension. At least one biopsiable lesion must be available. When imaging (DCE-MRI, DW-MRI and PET-CT imaging) is being performed for Secondary Objectives (Dose Level III [or when the dose reaches at least 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 conventional techniques, including palpation, plain x-ray, CT, and MRI. A second lesion accessible for biopsy must also be present. Patients must have at least one 'target lesion' to be used to assess response on this protocol as defined by RECIST. This may be one of the lesions mentioned above. Tumors within a previously irradiated field will be designated as 'non-target' lesions.
8) Resolution of any effects of prior therapy (except alopecia) to NCI CTCAE Version 4.03 grade </= 1 and to baseline laboratory values as defined in inclusion criteria 7.
9) Patients must have adequate: Bone marrow function: HGB >/= 9 g/dL, WBC >/= 3,000/mcL, ANC >/= 1,500/mcL, PLT >/= 100,000/mcL; Hepatic function: Total bilirubin less than or equal to 1.5, SGOT and SGPT < 2.5 X institutional ULN; Renal function: Creatinine < 1.5 x ULN or creatinine clearance > 60ml/min according to Cockroft-Gault formula; Neurologic function: Neuropathy (sensory and motor) </= to CTCAE grade 1; Blood coagulation parameters: PT such that international normalized ratio (INR) is < 1.5 (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin or low molecular weight heparin) and a PTT < 1.2 times control.
10) Patients should be free of active infection requiring intravenous antibiotics.
11) Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration (study enrollment). Continuation of hormone replacement therapy is permitted.Stable regimens of hormonal therapy i.e. for prostate cancer (e.g. leuprolide, a GnRH agonist), ovarian or breast cancer are not exclusionary.
12) Any other prior therapy directed at the malignant tumor, including immunologic agents, must be discontinued at least three weeks prior to first dose of study drug (6 weeks for nitrosoureas or mitomycin C).
13) Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study and for at least 3 months after completion of EphA2 siRNA-DOPC therapy.
14) Male subject agrees to use an acceptable method of contraception for the duration of the study.
15) Patients must voluntarily sign an informed consent indicating that they are aware of the investigational nature of this study in keeping with the policies of the hospital.
1) Patients may not be receiving any other investigational agents and/or
other therapy for their cancer.
2) History of allergic reactions attributed to compounds of similar chemical or biologic composition to DOPC, Magnevist, or FDG.
3) Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as a known bleeding disorder, coagulopathy, or tumor involving major vessels.
4) Patients with history or evidence upon physical examination of CNS disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases.
5) Patients with history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within 6 months of the first date of treatment on this study.
6) Patients with clinically significant cardiovascular disease; this includes: Uncontrolled hypertension (greater than 140/90); Myocardial infarction or unstable angina within 6 months prior to registration; New York Heart Association (NYHA) Grade II or greater congestive heart failure; Serious cardiac arrhythmia requiring medication; Grade II or greater peripheral vascular disease; Patients with clinically significant peripheral artery disease, e.g., those with claudication, within 6 months of first date of treatment on this study.
7) Patients whose circumstances do not permit completion of the study or the required follow-up.
8) Patients who are pregnant or nursing. To date, no fetal studies in animals or humans have been performed with this agent.
9) History of HIV or HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with EphA2 siRNA-DOPC.
10) Patients whose tumor is not accessible for a core biopsy.
11) Exclusion criteria (MRI specific): Patients who are ineligible to undergo an MRI scan for reasons such as claustrophobia or the presence of implanted devices or metallic foreign bodies that are not MR compatible. Patients with a known history of allergic reaction to gadolinium contrast agents. Patients with a history of a GFR of less than 60 or acute renal disease.
12) Exclusion criteria (PET specific): Pregnant or nursing women. Extreme claustrophobia. Weight near or greater than 350 pounds
Information and next steps
Advanced Cancers,Phase I Studies
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