<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03817736</url>
  </required_header>
  <id_info>
    <org_study_id>UW 18-541</org_study_id>
    <nct_id>NCT03817736</nct_id>
  </id_info>
  <brief_title>Sequential TACE and SBRT Followed by ImmunoTherapy for Downstaging HCC for Hepatectomy</brief_title>
  <acronym>START-FIT</acronym>
  <official_title>Sequential TransArterial Chemoembolization and Stereotactic RadioTherapy Followed by ImmunoTherapy for Downstaging Hepatocellular Carcinoma for Hepatectomy (START-FIT)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The University of Hong Kong</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck KGaA, Darmstadt, Germany</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>The University of Hong Kong</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is a prospective phase II, single arm clinical study conducted in Queen Mary&#xD;
      Hospital (Hong Kong) assessing the efficacy and safety of the sequential administration of&#xD;
      trans-arterial chemo-embolization (TACE) and stereotactic body radiotherapy (SBRT) with an&#xD;
      immune checkpoint inhibitor in hepatocellular carcinoma (HCC) patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      All the patients must be registered with the Investigator(s) prior to initiation of&#xD;
      treatment. The registration desk will confirm all eligibility criteria and obtain essential&#xD;
      information (including patient number).&#xD;
&#xD;
      TACE should start within 28 days of study registration and its procedure will be&#xD;
      standardised.&#xD;
&#xD;
      SBRT screening and planning will be performed by radiation therapists, medical physicists,&#xD;
      and oncologists.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">March 1, 2019</start_date>
  <completion_date type="Anticipated">January 31, 2023</completion_date>
  <primary_completion_date type="Actual">June 14, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Patients Amendable to Curative Surgical Interventions</measure>
    <time_frame>from the date of first study treatment to the date of last study treatment, an average of 3 years</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Response rate measured by mRECIST criteria</measure>
    <time_frame>from the date of screening to radiographically documented progression according to mRECIST 1.1, assessed up to 3 years</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to progression (TTP)</measure>
    <time_frame>from the date of first study treatment to radiographically documented progression according to mRECIST 1.1, assessed up to 3 years</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>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</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>from the date of first study treatment to the date of death from any cause, assessed up to 5 years</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Score</measure>
    <time_frame>from the date of screening to radiographically documented progression according to mRECIST 1.1, an average of 3 years</time_frame>
    <description>Quality-of-Life (QoL) is assessed by the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) Score</measure>
    <time_frame>from the date of screening to radiographically documented progression according to mRECIST 1.1, an average of 3 years</time_frame>
    <description>Quality-of-Life (QoL) is also assessed by the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaires.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Study-Related Adverse Events [Safety and Tolerability]</measure>
    <time_frame>from the date of screening to 90 days after last treatment, around 3 years and 90 days</time_frame>
    <description>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)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pathological response</measure>
    <time_frame>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</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease control rate</measure>
    <time_frame>from the date of first study treatment to radiographically documented response according to mRECIST 1.1, assessed up to 3 years</time_frame>
    <description>Percentage of patients that had a CR, PR, or SD ≥ 6 months per mRECIST</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Local control</measure>
    <time_frame>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</time_frame>
    <description>Defined as absence of recurrence within the high-dose region (80% isodose volume), demonstrated by new enhancement or mRECIST progressive disease</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response</measure>
    <time_frame>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</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pattern of failure</measure>
    <time_frame>from the date of first study treatment to radiographically documented failure type according to mRECIST 1.1, assessed up to 3 years</time_frame>
    <description>(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</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">33</enrollment>
  <condition>HCC</condition>
  <arm_group>
    <arm_group_label>START-FIT</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single group assignment combining TACE and SBRT with immune checkpoint inhibitor as treatment in HCC patients.&#xD;
Procedure of TACE will be standardized.&#xD;
SBRT screening and planning will be performed by radiation therapists, medical physicists, and oncologists.&#xD;
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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>TACE</intervention_name>
    <description>Procedure of TACE will be standardized.</description>
    <arm_group_label>START-FIT</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>SBRT</intervention_name>
    <description>SBRT screening and planning will be performed by radiation therapists, medical physicists, and oncologists.</description>
    <arm_group_label>START-FIT</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Immune Checkpoint Inhibitor</intervention_name>
    <description>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.</description>
    <arm_group_label>START-FIT</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Diagnosis of HCC confirmed pathologically or made according to American Association&#xD;
             for the Study of Liver Diseases (AASLD) practice guideline 2010: patients with&#xD;
             cirrhosis of any etiology and patients with chronic hepatitis B (HBV) who may not have&#xD;
             fully developed cirrhosis, the presence of liver nodule &gt;1cm and demonstrated in a&#xD;
             single contrast-enhanced dynamic imaging [magnetic resonance imaging (MRI)] of intense&#xD;
             arterial uptake and &quot;washout&quot; in portal venous and delayed phases.&#xD;
&#xD;
          2. Male or female subjects with age: 18-75 years old&#xD;
&#xD;
          3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1&#xD;
&#xD;
          4. Tumor size 5-15cm or number of lesions ≤3 or segmental portal vein involvement&#xD;
&#xD;
          5. Child-Pugh liver function class A-B7&#xD;
&#xD;
          6. Liver volume minus intrahepatic GTV &gt;700 cc.&#xD;
&#xD;
          7. Minimal distance from GTV to stomach, duodenum, small or large bowel &gt;1 cm.&#xD;
&#xD;
          8. No prior systemic therapy nor immunotherapy&#xD;
&#xD;
          9. No prior trans-arterial chemo-embolization (TACE)&#xD;
&#xD;
         10. No prior radiotherapy to the liver or selective internal radiation (SIRT)&#xD;
&#xD;
         11. Written informed consent obtained for clinical trial participation and providing&#xD;
             archival tumor tissue, if available.&#xD;
&#xD;
         12. Subjects with confirmed concomitant HBV infection (defined as HBsAg positive or HBV&#xD;
             DNA detectable) that are eligible for inclusion must be treated with antiviral therapy&#xD;
             (per local institutional practice) prior to enrollment to ensure adequate viral&#xD;
             suppression (HBV DNA &lt;2000 IU/mL), must remain on antiviral therapy for the study&#xD;
             duration, and continue therapy for 6 months after the last dose of investigational&#xD;
             product(s)&#xD;
&#xD;
         13. At least one measurable lesion according to RECIST v1.1.&#xD;
&#xD;
         14. Adequate organ and marrow function, as defined below:&#xD;
&#xD;
               -  Hemoglobin ≥9 g/dL&#xD;
&#xD;
               -  Absolute neutrophil count ≥1,500/μL&#xD;
&#xD;
               -  Platelet count ≥100,000/μL&#xD;
&#xD;
               -  Total bilirubin ≤2.0 × ULN&#xD;
&#xD;
               -  ALT ≤3 × ULN&#xD;
&#xD;
               -  Albumin ≥2.8 g/dL&#xD;
&#xD;
               -  INR ≤1.6&#xD;
&#xD;
               -  Calculated creatinine clearance ≥45 mL/minute as determined by Cockcroft-Gault&#xD;
                  (using actual body weight) or 24-hour urine creatinine clearance&#xD;
&#xD;
         15. Females of childbearing potential or non-sterilized male who are sexually active must&#xD;
             use a highly effective method of contraception&#xD;
&#xD;
         16. Females of childbearing potential must have negative serum or urine pregnancy test&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Prior invasive malignancy within 2 years except for noninvasive malignancies such as&#xD;
             cervical carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma of the&#xD;
             skin, lobular or ductal carcinoma in situ of the breast that has been surgically cured&#xD;
&#xD;
          2. Contraindicated of SBRT: Any one hepatocellular carcinoma &gt;15 cm; Total maximal sum of&#xD;
             hepatocellular carcinoma &gt;20 cm; More than 3 discrete hepatic nodule; Direct tumor&#xD;
             extension into the stomach, duodenum, small bowel, large bowel, common or main branch&#xD;
             of biliary tree&#xD;
&#xD;
          3. Severe, active co-morbidity&#xD;
&#xD;
          4. Presence of extra-hepatic metastases (M1)&#xD;
&#xD;
          5. Left portal vein, right portal vein, main portal vein or inferior vena cava (IVC)&#xD;
             thrombosis or involvement&#xD;
&#xD;
          6. Presence of clinically meaningful ascites as ascites requiring non pharmacologic&#xD;
             intervention (eg, paracentesis) or escalation in pharmacologic intervention to&#xD;
             maintain symptomatic control&#xD;
&#xD;
          7. Hepatic encephalopathy&#xD;
&#xD;
          8. Active or untreated gastrointestinal varices&#xD;
&#xD;
          9. Untreated central nervous system (CNS) metastatic disease, lepto-meningeal disease, or&#xD;
             cord compression&#xD;
&#xD;
         10. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular&#xD;
             accident/stroke ( &lt;6 months prior to enrollment), myocardial infarction ( &lt;6 months&#xD;
             prior to enrollment), unstable angina, congestive heart failure (&gt;= New York Heart&#xD;
             Association Classification Class II), or serious cardiac arrhythmia requiring&#xD;
             medication.&#xD;
&#xD;
         11. Prior treatment with any immune checkpoint inhibitors or an antibody targeting&#xD;
             immuno-regulatory receptors or mechanisms&#xD;
&#xD;
         12. Irritable bowel syndrome or other serious gastrointestinal chronic conditions&#xD;
             associated with diarrhea within the past 3 years prior to the start of treatment&#xD;
&#xD;
         13. Known history of testing positive for HIV or known acquired immunodeficiency syndrome.&#xD;
&#xD;
         14. On chronic systemic steroid or any other forms of immunosuppressive medication within&#xD;
             14 days prior to the treatment. Except:&#xD;
&#xD;
               1. intranasal, inhaled, topical steroids, or local steroid injection (e.g.,&#xD;
                  intra-articular injection);&#xD;
&#xD;
               2. Systemic corticosteroids at physiologic doses &lt;=10 mg/day of prednisone or&#xD;
                  equivalent;&#xD;
&#xD;
               3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan&#xD;
                  premedication).&#xD;
&#xD;
         15. Active or prior documented autoimmune or inflammatory disorders in the past 2 years,&#xD;
             except diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not&#xD;
             requiring immunosuppressive treatment&#xD;
&#xD;
         16. History of primary immunodeficiency or solid organ transplantation&#xD;
&#xD;
         17. Receipt of live, attenuated vaccine within 28 days prior to the study treatment&#xD;
&#xD;
         18. Active infection requiring systemic therapy&#xD;
&#xD;
         19. Severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb)&#xD;
&#xD;
         20. Females who are pregnant, lactating, or intend to become pregnant during their&#xD;
             participation in the study&#xD;
&#xD;
         21. Psychiatric disorders and substance (drug/alcohol) abuse&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Chi Leung Chiang, Chiang</last_name>
    <role>Principal Investigator</role>
    <affiliation>The University of Hong Kong</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Clinical Oncology</name>
      <address>
        <city>Hong Kong</city>
        <country>Hong Kong</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Hong Kong</country>
  </location_countries>
  <reference>
    <citation>Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, Fan ST, Wong J. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002 May;35(5):1164-71. doi: 10.1053/jhep.2002.33156.</citation>
    <PMID>11981766</PMID>
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    <citation>Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Sola R, Rodes J, Bruix J; Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002 May 18;359(9319):1734-9. doi: 10.1016/S0140-6736(02)08649-X.</citation>
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    <citation>Shim SJ, Seong J, Han KH, Chon CY, Suh CO, Lee JT. Local radiotherapy as a complement to incomplete transcatheter arterial chemoembolization in locally advanced hepatocellular carcinoma. Liver Int. 2005 Dec;25(6):1189-96. doi: 10.1111/j.1478-3231.2005.01170.x.</citation>
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    <citation>Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378-90. doi: 10.1056/NEJMoa0708857.</citation>
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    <citation>Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009 Jan;10(1):25-34. doi: 10.1016/S1470-2045(08)70285-7. Epub 2008 Dec 16.</citation>
    <PMID>19095497</PMID>
  </reference>
  <reference>
    <citation>Blomgren H, Lax I, Naslund I, Svanstrom R. Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Clinical experience of the first thirty-one patients. Acta Oncol. 1995;34(6):861-70. doi: 10.3109/02841869509127197.</citation>
    <PMID>7576756</PMID>
  </reference>
  <reference>
    <citation>Cardenes HR, Price TR, Perkins SM, Maluccio M, Kwo P, Breen TE, Henderson MA, Schefter TE, Tudor K, Deluca J, Johnstone PA. Phase I feasibility trial of stereotactic body radiation therapy for primary hepatocellular carcinoma. Clin Transl Oncol. 2010 Mar;12(3):218-25. doi: 10.1007/s12094-010-0492-x.</citation>
    <PMID>20231127</PMID>
  </reference>
  <reference>
    <citation>Andolino DL, Johnson CS, Maluccio M, Kwo P, Tector AJ, Zook J, Johnstone PA, Cardenes HR. Stereotactic body radiotherapy for primary hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2011 Nov 15;81(4):e447-53. doi: 10.1016/j.ijrobp.2011.04.011. Epub 2011 Jun 7.</citation>
    <PMID>21645977</PMID>
  </reference>
  <reference>
    <citation>Kang JK, Kim MS, Cho CK, Yang KM, Yoo HJ, Kim JH, Bae SH, Jung DH, Kim KB, Lee DH, Han CJ, Kim J, Park SC, Kim YH. Stereotactic body radiation therapy for inoperable hepatocellular carcinoma as a local salvage treatment after incomplete transarterial chemoembolization. Cancer. 2012 Nov 1;118(21):5424-31. doi: 10.1002/cncr.27533. Epub 2012 May 8.</citation>
    <PMID>22570179</PMID>
  </reference>
  <reference>
    <citation>Bujold A, Massey CA, Kim JJ, Brierley J, Cho C, Wong RK, Dinniwell RE, Kassam Z, Ringash J, Cummings B, Sykes J, Sherman M, Knox JJ, Dawson LA. Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol. 2013 May 1;31(13):1631-9. doi: 10.1200/JCO.2012.44.1659. Epub 2013 Apr 1.</citation>
    <PMID>23547075</PMID>
  </reference>
  <reference>
    <citation>Radiation Therapy Oncology Group RTOG 1112 protocol. Available from: https://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1112.</citation>
  </reference>
  <reference>
    <citation>Huo YR, Eslick GD. Transcatheter Arterial Chemoembolization Plus Radiotherapy Compared With Chemoembolization Alone for Hepatocellular Carcinoma: A Systematic Review and Meta-analysis. JAMA Oncol. 2015 Sep;1(6):756-65. doi: 10.1001/jamaoncol.2015.2189.</citation>
    <PMID>26182200</PMID>
  </reference>
  <reference>
    <citation>Hawkins MA, Dawson LA. Radiation therapy for hepatocellular carcinoma: from palliation to cure. Cancer. 2006 Apr 15;106(8):1653-63. doi: 10.1002/cncr.21811.</citation>
    <PMID>16541431</PMID>
  </reference>
  <reference>
    <citation>Chiang CL, Chan MKH, Yeung CSY, Ho CHM, Lee FAS, Lee VWY, Wong FCS, Blanck O. Combined stereotactic body radiotherapy and trans-arterial chemoembolization as initial treatment in BCLC stage B-C hepatocellular carcinoma. Strahlenther Onkol. 2019 Mar;195(3):254-264. doi: 10.1007/s00066-018-1391-2. Epub 2018 Nov 9.</citation>
    <PMID>30413833</PMID>
  </reference>
  <reference>
    <citation>Gehring AJ, Ho ZZ, Tan AT, Aung MO, Lee KH, Tan KC, Lim SG, Bertoletti A. Profile of tumor antigen-specific CD8 T cells in patients with hepatitis B virus-related hepatocellular carcinoma. Gastroenterology. 2009 Aug;137(2):682-90. doi: 10.1053/j.gastro.2009.04.045. Epub 2009 Apr 23.</citation>
    <PMID>19394336</PMID>
  </reference>
  <reference>
    <citation>Bernstein MB, Krishnan S, Hodge JW, Chang JY. Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach? Nat Rev Clin Oncol. 2016 Aug;13(8):516-24. doi: 10.1038/nrclinonc.2016.30. Epub 2016 Mar 8.</citation>
    <PMID>26951040</PMID>
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  <reference>
    <citation>Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, Mu Z, Rasalan T, Adamow M, Ritter E, Sedrak C, Jungbluth AA, Chua R, Yang AS, Roman RA, Rosner S, Benson B, Allison JP, Lesokhin AM, Gnjatic S, Wolchok JD. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012 Mar 8;366(10):925-31. doi: 10.1056/NEJMoa1112824.</citation>
    <PMID>22397654</PMID>
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  <verification_date>October 2022</verification_date>
  <study_first_submitted>December 6, 2018</study_first_submitted>
  <study_first_submitted_qc>January 23, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 25, 2019</study_first_posted>
  <last_update_submitted>October 24, 2022</last_update_submitted>
  <last_update_submitted_qc>October 24, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 25, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The University of Hong Kong</investigator_affiliation>
    <investigator_full_name>Dr. Chi-Leung Chiang</investigator_full_name>
    <investigator_title>Clinical Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>HCC</keyword>
  <keyword>START-FIT</keyword>
  <keyword>TACE</keyword>
  <keyword>SBRT</keyword>
  <keyword>immunotherapy</keyword>
  <keyword>hepatectomy</keyword>
  <keyword>hepatocellular carcinoma</keyword>
  <keyword>liver cancer</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Immune Checkpoint Inhibitors</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 27, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/36/NCT03817736/Prot_002.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03817736
org study id: UW 18-541
nct id: NCT03817736
lead sponsor: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Patients Amendable to Curative Surgical Interventions
time frame: from the date of first study treatment to the date of last study treatment, an average of 3 years
description: 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.
measure: Response rate measured by mRECIST criteria
time frame: from the date of screening to radiographically documented progression according to mRECIST 1.1, assessed up to 3 years
description: 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
measure: Time to progression (TTP)
time frame: from the date of first study treatment to radiographically documented progression according to mRECIST 1.1, assessed up to 3 years
description: 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.
measure: Progression-free survival (PFS)
time frame: 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
description: 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.
measure: Overall survival (OS)
time frame: from the date of first study treatment to the date of death from any cause, assessed up to 5 years
description: 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.
measure: European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Score
time frame: from the date of screening to radiographically documented progression according to mRECIST 1.1, an average of 3 years
description: Quality-of-Life (QoL) is assessed by the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30).
measure: Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) Score
time frame: from the date of screening to radiographically documented progression according to mRECIST 1.1, an average of 3 years
description: Quality-of-Life (QoL) is also assessed by the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaires.
measure: Incidence of Study-Related Adverse Events [Safety and Tolerability]
time frame: from the date of screening to 90 days after last treatment, around 3 years and 90 days
description: 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)
measure: Pathological response
time frame: 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
description: 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.
measure: Disease control rate
time frame: from the date of first study treatment to radiographically documented response according to mRECIST 1.1, assessed up to 3 years
description: Percentage of patients that had a CR, PR, or SD ≥ 6 months per mRECIST
measure: Local control
time frame: 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
description: Defined as absence of recurrence within the high-dose region (80% isodose volume), demonstrated by new enhancement or mRECIST progressive disease
measure: Duration of response
time frame: 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
description: 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
measure: Pattern of failure
time frame: from the date of first study treatment to radiographically documented failure type according to mRECIST 1.1, assessed up to 3 years
description: (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
arm group label: START-FIT
arm group type: Experimental
description: 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.
intervention type: Procedure
intervention name: TACE
description: Procedure of TACE will be standardized.
arm group label: START-FIT
intervention type: Radiation
intervention name: SBRT
description: SBRT screening and planning will be performed by radiation therapists, medical physicists, and oncologists.
arm group label: START-FIT
intervention type: Drug
intervention name: Immune Checkpoint Inhibitor
description: 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.
arm group label: START-FIT
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Chi Leung Chiang, Chiang
role: Principal Investigator
affiliation: The University of Hong Kong
facility: 
country: Hong Kong
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responsible party type: Principal Investigator
investigator affiliation: The University of Hong Kong
investigator full name: Dr. Chi-Leung Chiang
investigator title: Clinical Assistant Professor
mesh term: Immune Checkpoint Inhibitors
provided document: 