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

Sponsor

Koo Foundation Sun Yat-Sen Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04601428

Collaborator

(none)

Enrollment

Locations

Arm

20.1

Anticipated Duration (Months)

6.1

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma (HCC)	Biological: IA therapy of HCC with CSR02-Fab-TF	Early Phase 1

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

43 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

The dose escalation phase of the study will begin with 3 single cohort subjects and then proceed to a traditional 3 +3 study design until a Maximum Tolerated Dose (MTD) or an active dose (i.e., a dose at which subjects achieve a complete response in the liver or complete elimination of tumor blood flow) is identified. Once an appropriate dose in established, an expansion phase will administer CSR02-Fab-TF to 16 additional subjects to estimate the response proportion in subjects with refractory HCC.The dose escalation phase of the study will begin with 3 single cohort subjects and then proceed to a traditional 3 +3 study design until a Maximum Tolerated Dose (MTD) or an active dose (i.e., a dose at which subjects achieve a complete response in the liver or complete elimination of tumor blood flow) is identified. Once an appropriate dose in established, an expansion phase will administer CSR02-Fab-TF to 16 additional subjects to estimate the response proportion in subjects with refractory HCC.

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jan 26, 2021

Anticipated Primary Completion Date :

Oct 1, 2022

Anticipated Study Completion Date :

Oct 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Investigational Arm	Biological: IA therapy of HCC with CSR02-Fab-TF Intra-Arterial Infusion of CSR02-Fab-TF

Arm

Intervention/Treatment

Experimental: Investigational Arm

Biological: IA therapy of HCC with CSR02-Fab-TF

Intra-Arterial Infusion of CSR02-Fab-TF

Outcome Measures

Primary Outcome Measures

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 [Infusion to Day 50]
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
HCC blood flow [MRI on Day 4]
HCC blood flow will be assessed by magnetic resonance imaging (MRI) on day 4 after infusion of CSR02-FabTF.

Secondary Outcome Measures

Determine tumor response to intra-arterial infusion of CSR02-Fab-TF [by MRI on Day 50 and then every 3 months for an average of one year.]
Measured by radiographic response using acceptable imaging modalities used for assessment of tumor vasculature and blood flow (MRI or CT) based on mRECIST.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine, Mallinckrodt Institute of Radiology	Saint Louis	Missouri	United States	63110
2	UT Southwestern Medical Center	Dallas	Texas	United States	75390
3	University of Washington	Seattle	Washington	United States	98115
4	National Cheng Kung University Hospital (NCKUH)	Tainan City	North Dist.	Taiwan	70403
5	Koo Foundation Sun Yat-Sen Cancer Center (KFSYSCC)	Taipei	Pei-Tou Dist.	Taiwan	11259
6	National Taiwan University Hospital (NTUH)	Taipei city	Zhongzheng Dist.	Taiwan	100225
7	KFSYSCC	Taipei		Taiwan	112