TACE and SBRT Followed by Double Immunotherapy for Downstaging Hepatocellular Carcinoma

NCT04988945 | Recruiting Phase 2

• 1 other identifier: UW 20-046
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 2

Brief Summary

This study is a prospective phase II, single arm mono-institutional 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 immune checkpoint inhibitors in unresectable hepatocellular carcinoma (HCC) patients.

Conditions

HCC

Keywords

HCC; TACE; SBRT; immunotherapy; hepatocellular carcinoma; liver cancer; unresectable; large liver tumour

Outcome Measures

Primary Outcomes (1)

• Downstaging for hepatectomy

  To assess the number of patients amendable to curative surgical interventions (resection or radiofrequency ablation) after successful down-sizing of tumor(s) by intervention in HCC patients treated with combined TACE and SBRT followed by Durvalumab plus Tremelimumab

  From the date of first study treatment to the date of last study treatment, an average of 3 years

Secondary Outcomes (7)

• Response rate measured by mRECIST criteria

  From the date of screening to radiographically documented progression according to mRECIST 1.1, assessed up to 3 years

• Time to progression (TTP)

  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)

  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)

  From the date of first study treatment to the date of death from any cause, assessed up to 5 years

• Toxicity tolerability measurement in treatment related procedure

  From the date of screening to 90 days after last treatment, around 3 years and 90 days

Study Arms (1)

Durvalumab + Tremelimumab

EXPERIMENTAL

1500mg Durvalumab administered IV over 60 minutes on Day 1 of each immunotherapy treatment every 4 weeks until disease progression (PD) and 300mg Tremelimumab administered over 60 minutes on Day 1 of cycle 1.

Procedure: TACE; Radiation: SBRT; Drug: Durvalumab; Drug: Tremelimumab

Interventions

TACE PROCEDURE

Procedure of TACE will be standardized.

Durvalumab + Tremelimumab

SBRT RADIATION

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

Durvalumab + Tremelimumab

Durvalumab DRUG

1500mg Durvalumab administered IV over 60 minutes on Day 1 of each immunotherapy treatment every 4 weeks until disease progression (PD)

Durvalumab + Tremelimumab

Tremelimumab DRUG

300mg Tremelimumab administered over 60 minutes on Day 1 of cycle 1.

Durvalumab + Tremelimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
• Diagnosis of unresectable 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 \[either computed tomography (CT) or magnetic resonance imaging (MRI)\] of intense arterial uptake and "washout" in portal venous and delayed phases.
• Adult male or female aged \>18 years at time of study entry
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
• Body weight \>30kg
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
• Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• Must have a life expectancy of at least 12 weeks
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
• Tumor size 5-25cm and number of lesions ≤3
• Portal vein involvement (Vp1-3) is allowed: Vp1, presence of a tumor thrombus distal to, but not within, the second-order branches of the portal vein; Vp2, presence of a tumor thrombus in the second-order branches of the portal vein; Vp3, presence of a tumor thrombus in the first-order branches of the portal vein.
• Liver volume minus gross tumor volume (GTV) \> 700cc

You may not qualify if:

• Participation in another clinical study with an investigational product within 4 weeks prior to the first dose of study treatment
• Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with Durvalumab or Tremelimumab may be included only after consultation with the Study Physician.
• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
• Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
• Prior radiotherapy to the region of liver or selective internal radiotherapy
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
• History of primary immunodeficiency or allogenic organ transplantation.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• Any chronic skin condition that does not require systemic therapy
• Patients without active disease in the last 5 years may be included but only after consultation with the study physician
• Patients with celiac disease controlled by diet alone

Sponsors & Collaborators

• The University of Hong Kong: lead

Study Sites (2)

Department of Surgery, The University of Hong Kong

Hong Kong, Hong Kong

RECRUITING

The University of Hong Kong

Hong Kong, Hong Kong

RECRUITING

Related Publications (9)

• 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.

  PMID: 16541431 BACKGROUND

• Seong J, Kim SH, Suh CO. Enhancement of tumor radioresponse by combined chemotherapy in murine hepatocarcinoma. J Gastroenterol Hepatol. 2001 Aug;16(8):883-9. doi: 10.1046/j.1440-1746.2001.02533.x.

  PMID: 11555102 BACKGROUND

• 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.

  PMID: 30413833 BACKGROUND

• Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64. doi: 10.1038/nrc3239.

  PMID: 22437870 BACKGROUND

• Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev. 2008 Aug;224:166-82. doi: 10.1111/j.1600-065X.2008.00662.x.

  PMID: 18759926 BACKGROUND

• Stewart R, Morrow M, Hammond SA, Mulgrew K, Marcus D, Poon E, Watkins A, Mullins S, Chodorge M, Andrews J, Bannister D, Dick E, Crawford N, Parmentier J, Alimzhanov M, Babcook JS, Foltz IN, Buchanan A, Bedian V, Wilkinson RW, McCourt M. Identification and Characterization of MEDI4736, an Antagonistic Anti-PD-L1 Monoclonal Antibody. Cancer Immunol Res. 2015 Sep;3(9):1052-62. doi: 10.1158/2326-6066.CIR-14-0191. Epub 2015 May 5.

  PMID: 25943534 BACKGROUND

• Tarhini AA, Kirkwood JM. Tremelimumab (CP-675,206): a fully human anticytotoxic T lymphocyte-associated antigen 4 monoclonal antibody for treatment of patients with advanced cancers. Expert Opin Biol Ther. 2008 Oct;8(10):1583-93. doi: 10.1517/14712598.8.10.1583.

  PMID: 18774925 BACKGROUND

• Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, Patt D, Chen TT, Berman DM, Wolchok JD. Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol. 2015 Jun 10;33(17):1889-94. doi: 10.1200/JCO.2014.56.2736. Epub 2015 Feb 9.

  PMID: 25667295 BACKGROUND

• Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33. doi: 10.1056/NEJMoa1302369. Epub 2013 Jun 2.

  PMID: 23724867 BACKGROUND

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Liver Neoplasms

Interventions

durvalumab; tremelimumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Study Officials

• Albert CHAN

  Department of Surgery, The University of Hong Kong

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Albert CHAN

CONTACT

+85222553025; acchan@hku.hk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 29, 2021
• First Posted: August 4, 2021
• Study Start: December 1, 2020
• Primary Completion: December 1, 2024
• Study Completion (Estimated): December 1, 2026
• Last Updated: September 6, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

HK (2)