Sequential TACE and SBRT Followed by ImmunoTherapy for Downstaging HCC for Hepatectomy

Study Overview
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Brief Summary
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This study is a prospective phase II, single arm clinical study conducted in Queen Mary Hospital (Hong Kong) assessing the efficacy and safety of the sequential administration of trans-arterial chemo-embolization (TACE) and stereotactic body radiotherapy (SBRT) with an immune checkpoint inhibitor in hepatocellular carcinoma (HCC) patients.

Detailed Description
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All the patients must be registered with the Investigator(s) prior to initiation of treatment. The registration desk will confirm all eligibility criteria and obtain essential information (including patient number). TACE should start within 28 days of study registration and its procedure will be standardised. SBRT screening and planning will be performed by radiation therapists, medical physicists, and oncologists.

Official Title
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Sequential TransArterial Chemoembolization and Stereotactic RadioTherapy Followed by ImmunoTherapy for Downstaging Hepatocellular Carcinoma for Hepatectomy (START-FIT)

Conditions
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HCC

Intervention / Treatment
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* Procedure: TACE
* Radiation: SBRT
* Drug: Immune Checkpoint Inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of HCC confirmed pathologically or made according to American Association for the Study of Liver Diseases (AASLD) practice guideline 2010: patients with cirrhosis of any etiology and patients with chronic hepatitis B (HBV) who may not have fully developed cirrhosis, the presence of liver nodule >1cm and demonstrated in a single contrast-enhanced dynamic imaging [magnetic resonance imaging (MRI)] of intense arterial uptake and washout in portal venous and delayed phases. Male or female subjects with age: 18-75 years old Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 Tumor size 5-15cm or number of lesions ≤3 or segmental portal vein involvement Child-Pugh liver function class A-B7 Liver volume minus intrahepatic GTV >700 cc. Minimal distance from GTV to stomach, duodenum, small or large bowel >1 cm. No prior systemic therapy nor immunotherapy No prior trans-arterial chemo-embolization (TACE) No prior radiotherapy to the liver or selective internal radiation (SIRT) Written informed consent obtained for clinical trial participation and providing archival tumor tissue, if available. Subjects with confirmed concomitant HBV infection (defined as HBsAg positive or HBV DNA detectable) that are eligible for inclusion must be treated with antiviral therapy (per local institutional practice) prior to enrollment to ensure adequate viral suppression (HBV DNA <2000 IU/mL), must remain on antiviral therapy for the study duration, and continue therapy for 6 months after the last dose of investigational product(s) At least one measurable lesion according to RECIST v1.1. Adequate organ and marrow function, as defined below: Hemoglobin ≥9 g/dL Absolute neutrophil count ≥1,500/μL Platelet count ≥100,000/μL Total bilirubin ≤2.0 × ULN ALT ≤3 × ULN Albumin ≥2.8 g/dL INR ≤1.6 Calculated creatinine clearance ≥45 mL/minute as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine clearance Females of childbearing potential or non-sterilized male who are sexually active must use a highly effective method of contraception Females of childbearing potential must have negative serum or urine pregnancy test Exclusion Criteria: Prior invasive malignancy within 2 years except for noninvasive malignancies such as cervical carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma of the skin, lobular or ductal carcinoma in situ of the breast that has been surgically cured Contraindicated of SBRT: Any one hepatocellular carcinoma >15 cm; Total maximal sum of hepatocellular carcinoma >20 cm; More than 3 discrete hepatic nodule; Direct tumor extension into the stomach, duodenum, small bowel, large bowel, common or main branch of biliary tree Severe, active co-morbidity Presence of extra-hepatic metastases (M1) Left portal vein, right portal vein, main portal vein or inferior vena cava (IVC) thrombosis or involvement Presence of clinically meaningful ascites as ascites requiring non pharmacologic intervention (eg, paracentesis) or escalation in pharmacologic intervention to maintain symptomatic control Hepatic encephalopathy Active or untreated gastrointestinal varices Untreated central nervous system (CNS) metastatic disease, lepto-meningeal disease, or cord compression Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke ( <6 months prior to enrollment), myocardial infarction ( <6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication. Prior treatment with any immune checkpoint inhibitors or an antibody targeting immuno-regulatory receptors or mechanisms Irritable bowel syndrome or other serious gastrointestinal chronic conditions associated with diarrhea within the past 3 years prior to the start of treatment Known history of testing positive for HIV or known acquired immunodeficiency syndrome. On chronic systemic steroid or any other forms of immunosuppressive medication within 14 days prior to the treatment. Except: intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); Systemic corticosteroids at physiologic doses <=10 mg/day of prednisone or equivalent; Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication). Active or prior documented autoimmune or inflammatory disorders in the past 2 years, except diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment History of primary immunodeficiency or solid organ transplantation Receipt of live, attenuated vaccine within 28 days prior to the study treatment Active infection requiring systemic therapy Severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb) Females who are pregnant, lactating, or intend to become pregnant during their participation in the study Psychiatric disorders and substance (drug/alcohol) abuse

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: START-FIT<br>Single group assignment combining TACE and SBRT with immune checkpoint inhibitor as treatment in HCC patients. Procedure of TACE will be standardized. SBRT screening and planning will be performed by radiation therapists, medical physicists, and oncologists. An immune checkpoint inhibitor may be administered up to 3 days before or after the scheduled day of administration of each cycle due to administrative reasons. | Procedure: TACE<br>* Procedure of TACE will be standardized.<br>Radiation: SBRT<br>* SBRT screening and planning will be performed by radiation therapists, medical physicists, and oncologists.<br>Drug: Immune Checkpoint Inhibitor<br>* An immune checkpoint inhibitor may be administered up to 3 days before or after the scheduled day of administration of each cycle due to administrative reasons.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Amendable to Curative Surgical Interventions | Number of patients amendable to curative surgical interventions defined as number of patients receiving curative surgical resection or transplantation after successful down-sizing of tumor(s) by intervention. | from the date of first study treatment to the date of last study treatment, an average of 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate measured by mRECIST criteria | Complete response (CR): Disappearance of any intra-tumoral arterial enhancement in all target lesions Partial response (PR): At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions Stable disease (SD): Any cases that do not qualify for either partial response or progressive disease Progressive disease (PD): An increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started | from the date of screening to radiographically documented progression according to mRECIST 1.1, assessed up to 3 years | 
| Time to progression (TTP) | Time to progression (TTP): measured from the date of first study treatment to radiographically documented progression according to mRECIST 1.1. This does not include death from any cause. | from the date of first study treatment to radiographically documented progression according to mRECIST 1.1, assessed up to 3 years | 
| Progression-free survival (PFS) | Progression-free survival (PFS): measured from the date of first study treatment to radiographically documented progression according to mRECIST 1.1 or death from any cause (whichever occurs first). Participants alive and without disease progression or lost to follow-up will be censored at the date of their last radiographic assessment. | from the date of first study treatment to radiographically documented progression according to mRECIST 1.1 or death from any cause, whichever occurs first, assessed up to 3 years | 
| Overall survival (OS) | Overall survival (OS): measured from date of first study treatment to the date of death from any cause. Participants alive or lost to follow-up will be censored at the date of their last visit. | from the date of first study treatment to the date of death from any cause, assessed up to 5 years | 
| European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Score | Quality-of-Life (QoL) is assessed by the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30). | from the date of screening to radiographically documented progression according to mRECIST 1.1, an average of 3 years | 
| Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) Score | Quality-of-Life (QoL) is also assessed by the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaires. | from the date of screening to radiographically documented progression according to mRECIST 1.1, an average of 3 years | 
| Incidence of Study-Related Adverse Events [Safety and Tolerability] | Incidence, nature, and severity of adverse events graded according to the United States National Cancer Institute The Common Terminology Criteria for Adverse Events (NCI CTCAE 4.0) | from the date of screening to 90 days after last treatment, around 3 years and 90 days | 
| Pathological response | Pathological response is assessed as the percentage of surface with non-viable cancer cells (represented by necrosis or fibrosis, the ultimate stage of necrosis) in relation to the total tumor area and will be equal to: 100% - viable cancer cells (%). If there are multiple tumors, the mean percentage will be used. Pathological complete response (pCR) is defined by the absence of viable tumor cells in any nodule. | from the date of first study treatment to radiographically documented progression according to mRECIST 1.1 or death from any cause, whichever occurs first, assessed up to 5 years | 
| Disease control rate | Percentage of patients that had a CR, PR, or SD ≥ 6 months per mRECIST | from the date of first study treatment to radiographically documented response according to mRECIST 1.1, assessed up to 3 years | 
| Local control | Defined as absence of recurrence within the high-dose region (80% isodose volume), demonstrated by new enhancement or mRECIST progressive disease | from the date of first study treatment to radiographically documented in-field progression according to mRECIST 1.1, censored at the time of intervention to target lesion, assessed up to 3 years | 
| Duration of response | Defined as the time from first documented evidence of CR or PR until the first documented sign of disease progression (PD) or death from any cause | from the date of first documented evidence of CR or PR to first documented sign of PD or death from any cause according to mRECIST 1.1, assessed up to 3 years | 
| Pattern of failure | (1) In-field failure: defined as recurrence within the high-dose region (80% iso-dose volume), demonstrated by new enhancement or mRECIST progressive disease; (2) Out-field (intra-hepatic): defined as new or mRECIST progressive disease within liver parenchyma, but outside the SBRT treated volume; (3) New vascular invasion: defined as new portal or hepatic vein invasion; (4) Distant failure: defined as new disease outside liver parenchyma | from the date of first study treatment to radiographically documented failure type according to mRECIST 1.1, assessed up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HCC, START-FIT, TACE, SBRT, immunotherapy, hepatectomy, hepatocellular carcinoma, liver cancer