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

HCC Clinical Trial

— START-FIT  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03817736
• Other study ID #: UW 18-541
• Status: Completed
• Phase: Phase 2
• Start date: March 1, 2019
• Est. completion date: July 26, 2023

Study information

• Verified date: May 2024
• Source: The University of Hong Kong
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 33
• Est. completion date: July 26, 2023
• Est. primary completion date: June 14, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• HCC

Intervention

Procedure:
• TACE
Procedure of TACE will be standardized.

Radiation:
• SBRT
SBRT screening and planning will be performed by radiation therapists, medical physicists, and oncologists.

Drug:
• Immune Checkpoint Inhibitor
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.

Locations

Country	Name	City	State
Hong Kong	Department of Clinical Oncology	Hong Kong

Sponsors (2)

Lead Sponsor	Collaborator
The University of Hong Kong	Merck KGaA, Darmstadt, Germany

Country where clinical trial is conducted

Hong Kong, 

References & Publications (17)

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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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

Radiation Therapy Oncology Group RTOG 1112 protocol. Available from: https://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1112.

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. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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