EphA2 siRNA in Treating Patients With Advanced or Recurrent Solid Tumors
Last updated on April 2022Recruitment
- Recruitment Status
- Active, not recruiting
- Estimated Enrollment
- 40
Inclusion Criteria
- 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
- 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-computed tomography [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 Response Evaluation Criteria in Solid Tumors (RECIST); this may be one of the lesions mentioned above; tumors within a previously irradiated field will be designated as 'non-target' lesions
- All patients (dose escalation and dose expansion phases) must be willing to undergo pre- and post-treatment biopsies
- ...
- 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
- 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-computed tomography [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 Response Evaluation Criteria in Solid Tumors (RECIST); this may be one of the lesions mentioned above; tumors within a previously irradiated field will be designated as 'non-target' lesions
- All patients (dose escalation and dose expansion phases) must be willing to undergo pre- and post-treatment biopsies
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Total bilirubin less than or equal to 1.5
- Creatinine < 1.5 x ULN or creatinine clearance > 60 ml/min according to Cockcroft-Gault formula
- Resolution of any effects of prior therapy (except alopecia) to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade =< 1 and to baseline laboratory values as defined below
- All patients with histologic proof of advanced solid tumors, who are not candidates for known regimens or protocol treatments of higher efficacy or priority
- 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)
- Hemoglobin (HGB) >= 9 g/dL
- 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
- For dose expansion phase: patients must have EphA2 overexpression overall H-score of 3 or above in immunohistochemistry (IHC) evaluation; Clinical Laboratory Improvement Amendments (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
- Neuropathy (sensory and motor) =< to CTCAE grade 1
- Absolute neutrophil count (ANC) >= 1,500/mcL
- 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 gonadotropin-releasing hormone [GnRH] agonist), ovarian or breast cancer are not exclusionary
- Male subject agrees to use an acceptable method of contraception for the duration of the study
- Platelet (PLT) >= 100,000/mcL
- Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) < 2.5 x institutional upper limit of normal (ULN)
- For the dose escalation phase, the trial population will be limited to solid tumor types
- Patients should be free of active infection requiring intravenous antibiotics
- White blood cells (WBC) >= 3,000/mcL
- Prothrombin time (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 partial thromboplastin time (PTT) < 1.2 times control
Exclusion Criteria
- Pregnant or nursing women; extreme claustrophobia; weight near or greater than 350 pounds
- Pregnant or nursing women; extreme claustrophobia; weight near or greater than 350 pounds
Summary
- Conditions
- Advanced Malignant Solid Neoplasm
- Type
- Interventional
- Phase
- Phase 1
- Design
- Allocation: N/A
- Intervention Model: Single Group Assignment
- Masking: None (Open Label)
- Primary Purpose: Treatment
Participation Requirements
- Age
- Between 18 years and 125 years
- Gender
- Both males and females
Description
PRIMARY OBJECTIVES: I. To determine the safety and tolerability (toxicity profile) of EphA2-targeting DOPC-encapsulated siRNA (EphA2 siRNA) delivered via neutral liposome (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine or DOPC) administered intravenously in patients with advanced/recurrent malignanci...
PRIMARY OBJECTIVES: I. To determine the safety and tolerability (toxicity profile) of EphA2-targeting DOPC-encapsulated siRNA (EphA2 siRNA) delivered via neutral liposome (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine or DOPC) administered intravenously in patients with advanced/recurrent malignancies. II. To determine the maximal tolerated dose (MTD) or maximal administered dose (MAD) using a modified toxicity probability interval (mTPI) design. SECONDARY OBJECTIVES: I. To determine efficacy (EphA2 expression modulation) at the MTD or MAD. II. To evaluate the effect of EphA2 siRNA-DOPC on tumor and endothelial cell apoptosis. III. To record the clinical activity (objective response, duration of response, and time to treatment progression) of intravenous (IV) EphA2 siRNA -DOPC. IV. To describe the symptom burden of patients receiving siRNA-EphA2-DOPC treatment. EXPLORATORY OBJECTIVES: I. To determine the pharmacokinetic profile of siRNA-EphA2-DOPC in blood. II. To determine the effect of EphA2 siRNA-DOPC on tumor perfusion, apparent diffusion, and metabolism by radiographic imaging (dynamic contrast-enhanced-magnetic resonance imaging [DCE-MRI], diffusion weighted [DW]-MRI and fludeoxyglucose F-18-positron emission tomography [18FDG-PET]). III. To determine the impact of EphA2 siRNA-DOPC on surrogate biomarkers in blood (cell-free deoxyribonucleic acid [DNA], plasma/serum markers [vascular endothelial growth factor (VEGF), caveolin 1 (CAV1), soluble EphrinA1], and exosomes). OUTLINE: This is a dose-escalation study. Patients receive EphA2-targeting DOPC-encapsulated siRNA IV over 120 minutes on days 1 and 4. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.
Inclusion Criteria
- 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
- 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-computed tomography [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 Response Evaluation Criteria in Solid Tumors (RECIST); this may be one of the lesions mentioned above; tumors within a previously irradiated field will be designated as 'non-target' lesions
- All patients (dose escalation and dose expansion phases) must be willing to undergo pre- and post-treatment biopsies
- ...
- 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
- 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-computed tomography [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 Response Evaluation Criteria in Solid Tumors (RECIST); this may be one of the lesions mentioned above; tumors within a previously irradiated field will be designated as 'non-target' lesions
- All patients (dose escalation and dose expansion phases) must be willing to undergo pre- and post-treatment biopsies
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Total bilirubin less than or equal to 1.5
- Creatinine < 1.5 x ULN or creatinine clearance > 60 ml/min according to Cockcroft-Gault formula
- Resolution of any effects of prior therapy (except alopecia) to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade =< 1 and to baseline laboratory values as defined below
- All patients with histologic proof of advanced solid tumors, who are not candidates for known regimens or protocol treatments of higher efficacy or priority
- 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)
- Hemoglobin (HGB) >= 9 g/dL
- 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
- For dose expansion phase: patients must have EphA2 overexpression overall H-score of 3 or above in immunohistochemistry (IHC) evaluation; Clinical Laboratory Improvement Amendments (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
- Neuropathy (sensory and motor) =< to CTCAE grade 1
- Absolute neutrophil count (ANC) >= 1,500/mcL
- 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 gonadotropin-releasing hormone [GnRH] agonist), ovarian or breast cancer are not exclusionary
- Male subject agrees to use an acceptable method of contraception for the duration of the study
- Platelet (PLT) >= 100,000/mcL
- Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) < 2.5 x institutional upper limit of normal (ULN)
- For the dose escalation phase, the trial population will be limited to solid tumor types
- Patients should be free of active infection requiring intravenous antibiotics
- White blood cells (WBC) >= 3,000/mcL
- Prothrombin time (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 partial thromboplastin time (PTT) < 1.2 times control
Exclusion Criteria
- Pregnant or nursing women; extreme claustrophobia; weight near or greater than 350 pounds
- Pregnant or nursing women; extreme claustrophobia; weight near or greater than 350 pounds
Tracking Information
- NCT #
- NCT01591356
- Collaborators
- National Cancer Institute (NCI)
- Investigators
- Principal Investigator: Shannon Westin M.D. Anderson Cancer Center
- Shannon Westin M.D. Anderson Cancer Center