Clinical Trials /

Hepatic IA Therapy in Stage B or Limited Stage C Hepatoma (HCC)

NCT04601428

Description:

Intra-arterial (IA) therapy is generally used to treat HCC tumors that are too extensive to excise or treat with potentially curative local therapy. IA therapy takes advantage of the fact that the blood supply of HCC comes predominantly from the hepatic artery compared with the surrounding normal liver which is predominantly supplied by portal venous blood. The intent is to deprive the HCC of its blood supply, leading to the death of the tumor. Traditionally, various methods have been used to block the HCC blood supply, but improvements are needed. This study will investigate a new agent designed in the laboratory to block only tumor blood vessels, not blood vessels in the normal liver.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Hepatic IA Therapy in Stage B or Limited Stage C Hepatoma (HCC)
  • Official Title: CSR02-Fab-TF as Hepatic Intra-arterial Therapy in Intermediate Stage B or Limited Advanced Stage C Hepatocellular Carcinoma (HCC): Dose-Escalation Study to Assess Safety and Tolerability

Clinical Trial IDs

  • ORG STUDY ID: KF-CSR02-001
  • NCT ID: NCT04601428

Conditions

  • Hepatocellular Carcinoma (HCC)

Interventions

DrugSynonymsArms
IA therapy of HCC with CSR02-Fab-TFInvestigational Arm

Purpose

Intra-arterial (IA) therapy is generally used to treat HCC tumors that are too extensive to excise or treat with potentially curative local therapy. IA therapy takes advantage of the fact that the blood supply of HCC comes predominantly from the hepatic artery compared with the surrounding normal liver which is predominantly supplied by portal venous blood. The intent is to deprive the HCC of its blood supply, leading to the death of the tumor. Traditionally, various methods have been used to block the HCC blood supply, but improvements are needed. This study will investigate a new agent designed in the laboratory to block only tumor blood vessels, not blood vessels in the normal liver.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Investigational ArmExperimental
  • IA therapy of HCC with CSR02-Fab-TF

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence and severity of adverse events from intra-arterial infusion of CSR02-Fab-TF in patients with hepatoma only or largely confined to the liver, and resistant/recurrent after prior therapy [Time Frame: Through Day 28 after infusion of CSR-Fab-TF]
Time Frame:Infusion to Day 50
Safety Issue:
Description:Measured by the number of treatment-emergent adverse events and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0

Secondary Outcome Measures

Measure:Determine tumor response to intra-arterial infusion of CSR02-Fab-TF [ Time Frame: Response will be evaluated ~7 weeks following the last administration of CSR02-Fab-TF ]
Time Frame:by MRI on Day 50 and then every 3 months for an average of one year.
Safety Issue:
Description:Measured by radiographic response using acceptable imaging modalities used for assessment of tumor vasculature and blood flow (MRI or CT) based on mRECIST.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Koo Foundation Sun Yat-Sen Cancer Center

Trial Keywords

  • Hepatocellular carcinoma
  • HCC
  • hepatoma
  • IA (intra-arterial) therapy
  • PLVAP
  • CSR02-Fab-TF

Last Updated

October 19, 2020