Clinical trial NCT03817736: Sequential TACE and SBRT Followed by ImmunoTherapy for Downstaging HCC for Hepatectomy
Official title: Sequential TransArterial Chemoembolization and Stereotactic RadioTherapy Followed by ImmunoTherapy for Downstaging Hepatocellular Carcinoma for Hepatectomy (START-FIT)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HCC
Keywords: HCC
START-FIT
TACE
SBRT
immunotherapy
hepatectomy
hepatocellular carcinoma
liver cancer
Lead sponsor: The University of Hong Kong
Sponsor class: OTHER
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2019-01-25
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. 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.
2. Male or female subjects with age: 18-75 years old
3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
4. Tumor size 5-15cm or number of lesions ≤3 or segmental portal vein involvement
5. Child-Pugh liver function class A-B7
6. Liver volume minus intrahepatic GTV \>700 cc.
7. Minimal distance from GTV to stomach, duodenum, small or large bowel \>1 cm.
8. No prior systemic therapy nor immunotherapy
9. No prior trans-arterial chemo-embolization (TACE)
10. No prior radiotherapy to the liver or selective internal radiation (SIRT)
11. Written informed consent obtained for clinical trial participation and providing archival tumor tissue, if available.
12. 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)
13. At least one measurable lesion according to RECIST v1.1.
14. 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
15. Females of childbearing potential or non-sterilized male who are sexually active must use a highly effective method of contraception
16. Females of childbearing potential must have negative serum or urine pregnancy test

Exclusion Criteria:

1. 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
2. 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
3. Severe, active co-morbidity
4. Presence of extra-hepatic metastases (M1)
5. Left portal vein, right portal vein, main portal vein or inferior vena cava (IVC) thrombosis or involvement
6. Presence of clinically meaningful ascites as ascites requiring non pharmacologic intervention (eg, paracentesis) or escalation in pharmacologic intervention to maintain symptomatic control
7. Hepatic encephalopathy
8. Active or untreated gastrointestinal varices
9. Untreated central nervous system (CNS) metastatic disease, lepto-meningeal disease, or cord compression
10. 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.
11. Prior treatment with any immune checkpoint inhibitors or an antibody targeting immuno-regulatory receptors or mechanisms
12. Irritable bowel syndrome or other serious gastrointestinal chronic conditions associated with diarrhea within the past 3 years prior to the start of treatment
13. Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
14. On chronic systemic steroid or any other forms of immunosuppressive medication within 14 days prior to the treatment. Except:

    1. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection);
    2. Systemic corticosteroids at physiologic doses \<=10 mg/day of prednisone or equivalent;
    3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
15. 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
16. History of primary immunodeficiency or solid organ transplantation
17. Receipt of live, attenuated vaccine within 28 days prior to the study treatment
18. Active infection requiring systemic therapy
19. Severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb)
20. Females who are pregnant, lactating, or intend to become pregnant during their participation in the study
21. Psychiatric disorders and substance (drug/alcohol) abuse

Primary outcomes:
measure: Number of Patients Amendable to Curative Surgical Interventions
timeFrame: from the date of first study treatment to the date of last study treatment, an average of 3 years
Secondary outcomes:
measure: Response rate measured by mRECIST criteria
timeFrame: from the date of screening to radiographically documented progression according to mRECIST 1.1, assessed up to 3 years
measure: Time to progression (TTP)
timeFrame: from the date of first study treatment to radiographically documented progression according to mRECIST 1.1, assessed up to 3 years
measure: Progression-free survival (PFS)
timeFrame: 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
measure: Overall survival (OS)
timeFrame: from the date of first study treatment to the date of death from any cause, assessed up to 5 years
measure: European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Score
timeFrame: from the date of screening to radiographically documented progression according to mRECIST 1.1, an average of 3 years
measure: Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) Score
timeFrame: from the date of screening to radiographically documented progression according to mRECIST 1.1, an average of 3 years
measure: Incidence of Study-Related Adverse Events [Safety and Tolerability]
timeFrame: from the date of screening to 90 days after last treatment, around 3 years and 90 days
measure: Pathological response
timeFrame: 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
measure: Disease control rate
timeFrame: from the date of first study treatment to radiographically documented response according to mRECIST 1.1, assessed up to 3 years
measure: Local control
timeFrame: 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
measure: Duration of response
timeFrame: 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
measure: Pattern of failure
timeFrame: from the date of first study treatment to radiographically documented failure type according to mRECIST 1.1, assessed up to 3 years
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Department of Clinical Oncology
Study officials:
affiliation: The University of Hong Kong
name: Chi Leung Chiang, Chiang
role: PRINCIPAL_INVESTIGATOR
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