Genetic testing was done to identify differences between HCC tumors and normal liver, and a
protein, PLVAP, was shown to be present on the blood vessels of HCC but not on the blood
vessels of normal liver. An antibody, CSR02, was made that recognizes PLVAP and then the Fab
portion of that antibody was combined with tissue factor, a normal human protein that
initiates the clotting cascade. The result is a manufactured (recombinant) protein called
CSR02-Fab-TF. Preclinical studies in a mouse model showed that infusion of an equivalent
mouse protein resulted in the necrosis (death) of a transplanted human HCC. The current study
is designed first, to identify a safe and optimal dose of CSR02-Fab-TF in patients , and then
second, to determine the response rate of HCC tumors to the IA administration of
CSR02-Fab-TF.
Inclusion Criteria:
- Age ≥ 18 years (US), Age ≥ 20 years (Taiwan)
- Diagnosis of HCC by at least one of the following criteria:
- Histological confirmation;
- Magnetic resonance imaging (MRI) or computerized tomography (CT) consistent with
liver cirrhosis AND at least one solid liver lesion > 2 cm with intense contrast
uptake during the arterial phase followed by contrast washout during the venous
phase regardless of alpha-fetal protein (AFP) level
- Barcelona Clinic Liver Cancer (BCLC) Intermediate Stage B or limited Advanced Stage C
(see Protocol Section 3.1). Patients with Stage C disease should have received or been
offered and chosen not to receive systemic therapy
- Inadequate response to prior liver-directed therapy (e.g., TACE, bland embolization,
Y90, ablation, radiation therapy) to the same targeted area or progressive disease
after prior liver-directed therapy) or to one or more systemic therapies
- Not a candidate for curative resection, liver transplantation, or percutaneous
ablation (See Protocol Appendix 3)
- Eastern Collective Oncology Group (ECOG) performance status ≤1 (See Protocol Appendix
5)
- Adequate laboratory parameters, including:
- Serum total bilirubin ≤ 2.0;
- Alkaline phosphatase, aspartate aminotransferase (AST) and aspartate
aminotransferase (ALT) < 5 x ULN;
- Serum creatinine ≤ 1.5 mg/dL;
- Prothrombin time (international normalized ratio; INR) ≤ 1.5;
- Absolute neutrophil count > 1000/μL;
- Platelet count > 75,000/μL;
- Hgb > 8 g/dL
- Acceptable pulmonary status, including room air O2 saturation > 90%
- Child-Pugh A-B7 without clinically significant ascites (See Protocol Appendix 4)
- Signed informed consent
- All subjects must be surgically sterile, at least two years post-menopausal (if
female), or agree to use adequate, effective contraception approved by the
Investigator until two (2) months after receiving a final dose of CSR02-Fab-TF
Exclusion Criteria:
- Eligible for transplantation by Milan criteria (Protocol Appendix 3) or potentially
eligible if successfully "down staged" by pre-transplant therapy
- Prior organ transplantation
- Any treatment for HCC (including TACE) or any investigational therapy within the
previous 60 days or treatment with Y90 within the previous 90 days
- Previously treated malignancies from which the subject has not been disease-free for
at least 2 years, except for adequately treated non-melanoma skin cancer, in situ
cancer, or low-grade prostate or bladder cancer
- Severe chronic obstructive or other pulmonary disease with hypoxemia that requires
supplementary oxygen or clinically significant pleural effusions
- New York Heart Association (NYHA) Class III or IV, cardiac disease, myocardial
infarction within 3 months prior to therapy, unstable arrhythmia, symptomatic
peripheral arterial vascular disease, or presence of an artificial or other vascular
device requiring chronic anticoagulation (See Protocol Appendix 6)
- Any of the following risks related to QT/QTc interval:
- Baseline prolongation of QT/QTc interval (repeated interval > 480 milliseconds
using Frederica's QT correction formula);
- History of additional risk factors for Torsades de Pointes (e.g. heart failure,
hypokalemia, family history of Long QT syndrome);
- Concomitant medications that have a known risk for prolongation of the QT/QTc
interval (see https://crediblemeds.org/new-drug-list/)
- Major surgery, vascular injury, or serious illness within the previous 60 days
- Known inherited thrombophilia (hypercoagulable state) or history of unprovoked venous
thrombosis
- Abnormal lupus anticoagulant
- Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic
therapy at screening. Subjects with prior HBV (positive HBSAg) must have HBV viral
load < 500 IU/mL. Subjects with HCV infection are eligible if other eligibility
criteria are met
- Females who are breast-feeding
- Allergy to iodinated contrast medium that is uncontrolled or refractory to medical
therapy
- Therapeutic anticoagulation that cannot be stopped 24-72 hours before treatment (per
Section 4.3) and reinstituted no sooner than 72 hours after therapy
- Any concomitant disease or condition that could interfere with the conduct of the
study, or that would, in the opinion of the Investigator, pose an unacceptable risk to
the subject in this study
- Unwillingness or inability to comply with the study protocol for any reason
