Downstaging Protocol Containing Immunotherapy for HCC Beyond the Milan Criteria Before Liver Transplantation

Hepatocellular Carcinoma Clinical Trial

Official title:

A Prospective, Single-arm Study of Downstaging Protocol Containing Immunotherapy for HCC Beyond the Milan Criteria Before Liver Transplantation

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05475613
• Other study ID #: SYSKY-2022-145-01
• Status: Recruiting
• Phase: Phase 2
• Start date: August 1, 2023
• Est. completion date: August 1, 2028

Study information

• Verified date: May 2023
• Source: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
• Contact: Li PANG, PhD
• Phone: +86 13622860325
• Email: pangli5[@]mail.sysu.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Hepatocellular Carcinoma (HCC) is the most common liver malignancy and the third leading cause of cancer death worldwide. Due to the shortage of donor organs and the risk of tumor recurrence after transplantation, the restrictive Milan criteria is the standard guideline for liver transplantation (LT) in patients with HCC and liver cirrhosis. The XXL study (Mazzaferro et al, 2020) is the first prospective trial validating that effective and sustained downstage therapy could expand the selection criteria and improve the prognosis of recipients with HCC beyond Milan criteria. However, the optimal DT protocol is poorly defined, especially in the Asian population. Recently, immunotherapies such as immune-checkpoint inhibitors (ICIs) are revolutionizing the management of advanced HCC, the combination of the ICI and other treatment regimens (Anti-VEGF, locoregional therapies et al) produced superior results in patients with advanced-stage HCC compared to those with traditional therapeutic regimens. Therefore, we hypothesize an intensive downstage regimen containing immunotherapy could expand the selection criteria for HCC LT

Description:

This will be a single-arm, open-label, non-randomized phase II study aiming to access the efficacy and safety of the downstage protocol containing immunotherapy for HCC beyond Milan Criteria. This study contains 4 phases:

1. Screening and Downstaging phase Eligible patients (See inclusion and exclusion criteria) will undergo downstaging treatment containing Anti-PD-1 inhibitor (tislelizumab, pembrolizumab, nivolumab et al). Anti-PD-1 inhibitor will be given every 3-4 weeks intravenously. Other combination regimens, such as locoregional therapies and targeted therapies will be given to patients according to the protocol decided by the multidisciplinary team of Centers. Patients that have reached the Criteria for Successful Downstage within 12 cycles of downstaging treatment will proceed to the observation phase, while those who fail to meet the Criteria for Successful Downstage after the maximum length of downstaging procedures will drop out from the study.

Criteria for Successful Downstage

Patients that meet 1-4 criteria are considered to have achieved the downstaging goal, otherwise, the downstaging treatment is considered to have failed within 12 cycles of downstaging treatment:

• CR or PR evaluated by iRECIST/mRECIST after at least 2 cycles of downstaging treatment.

• Patients with onset AFP<400ng/ml: AFP <400ng/ml at the end of downstaging therapy; Patients with onset AFP>400ng/ml: AFP levels decrease more than 30%, and must be less than 1000ng/ml at the end of downstage therapy.

• Estimated 5-year overall survival ≥60% at the end of downstaging therapy according to the Metroticket model (http://www.hcc-olt-metroticket.org/calculator).

• For patients with portal vein tumor thrombus (PVTT1-3), tumor thrombus needs to retract above the bifurcation of the main portal vein, and portal vein anastomosis is feasible during liver transplantation according to the surgeons' judgment.

2. Observation phase Patients that have reached the Criteria for Successful Downstage within 12 cycles of downstaging treatment will proceed to the observation phase ≥ 3 months. Patients at this phase can optionally receive TKIs (sorafenib, lenvatinib et al), and other anti-tumor treatments (such as locoregional therapies, surgery, and immunotherapies et al) are not allowed at this phase. Patients with a sustained response and whose tumors still meet the Criteria for Successful Downstage at the end of the observation phase will be enrolled in the waiting list for liver transplantation, while patients with tumor progression (PD) and their tumors fail to meet the Criteria for Successful Downstage at the end of observation phase will drop out from the study.

3. Waiting and Bridging phase During the waiting period before liver transplantation, patients can optionally receive a non-immunotherapy protocol as bridging treatment determined by the multidisciplinary team (MDT). Surgery is not allowed at this phase.

4. Liver transplantation and post-transplantation phase Patients will undergo liver transplantation unless major medical or oncological contraindications should occur during the waiting phase.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 59
• Est. completion date: August 1, 2028
• Est. primary completion date: August 1, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Written informed consent must be obtained prior to any screening procedures. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.

2. Patients must have pathologically or cytologically or by radiological criteria proven hepatocellular carcinoma based on the AASLD practice guidelines

3. Patients with HCC must be beyond Milan criteria without extrahepatic metastases or lymph node metastases:

3.1 Patients without previous treatment: Barcelona clinic liver cancer B-C (China liver cancer stage IIb-IIIa) HCC with or without portal vein tumor thrombus (PVTT 1-3 according to Japanese Vp classification).

3.2 Patients with late recurrent HCC: The recurrent HCC must be identified no less than 2 years after primary curative treatment (Resection or Radiofrequency, et al), and the recurrent lesions must be localized in the liver and beyond Milan criteria.

3.3 Patients with early recurrent HCC: The recurrent HCC must be identified within 2 years after primary curative treatment (R0 resection or radiofrequency, et al), and the primary tumor must be within Milan criteria, and the accumulating tumor burden(Primary tumor plus recurrent tumor) must be beyond Milan criteria.

4. Child-Pugh score=7, with no encephalopathy. Ascites that can be controlled by diuretics are permitted in this study.

5. Eastern Cooperative Oncology Group (ECOG) Scale for Assessment of Patient Performance Status (PS score) = 2; KPS score =60.

6. Have not received any immunotherapies 6 months before enrollment.

7. Adequate bone marrow, liver, and renal function.

8. The estimated survival before liver transplantation must be more than 12 weeks (Based on the Model for end-stage liver disease, MELD).

9. No other lethal malignancy outside the liver in recent 5 years, such as leukemia, lung cancer, melanoma, et al.

10. Patients with a history of hypertension should be well-controlled (< 140/90 mmHg) on a regimen of anti-hypertensive therapy.

11. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and 6 months after the completion of the trial.

12. Patients voluntarily joined the study and signed informed consent with good compliance and follow-up.

Related Conditions & MeSH terms

• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma
• Liver Transplantation

Intervention

Procedure:
• Downstaging procedures containing immunotherapy
Anti-PD-1 inhibitor will be given every 3-4 weeks intravenously according to the manufacturer's instruction. Other combination regimens, such as locoregional therapies or targeted therapies will be given to patients according to the protocol decided by the multidisciplinary team of Centers.
• Liver transplantation
Patients with successful downstaging therapy at the end of the observation phase will enroll and undergo liver transplantation unless major medical or oncological contraindications should occur during the waiting phase.

Locations

Country	Name	City	State
China	Sun Yat-sen Memorial Hospital, Sun Yat-sen University	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Country where clinical trial is conducted

China, 

References & Publications (6)

Mazzaferro V, Citterio D, Bhoori S, Bongini M, Miceli R, De Carlis L, Colledan M, Salizzoni M, Romagnoli R, Antonelli B, Vivarelli M, Tisone G, Rossi M, Gruttadauria S, Di Sandro S, De Carlis R, Luca MG, De Giorgio M, Mirabella S, Belli L, Fagiuoli S, Martini S, Iavarone M, Svegliati Baroni G, Angelico M, Ginanni Corradini S, Volpes R, Mariani L, Regalia E, Flores M, Droz Dit Busset M, Sposito C. Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial. Lancet Oncol. 2020 Jul;21(7):947-956. doi: 10.1016/S1470-2045(20)30224-2. Erratum In: Lancet Oncol. 2020 Aug;21(8):e373. — View Citation

Sangro B, Sarobe P, Hervas-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021 Aug;18(8):525-543. doi: 10.1038/s41575-021-00438-0. Epub 2021 Apr 13. — View Citation

Schwacha-Eipper B, Minciuna I, Banz V, Dufour JF. Immunotherapy as a Downstaging Therapy for Liver Transplantation. Hepatology. 2020 Oct;72(4):1488-1490. doi: 10.1002/hep.31234. No abstract available. — View Citation

Tabrizian P, Holzner ML, Mehta N, Halazun K, Agopian VG, Yao F, Busuttil RW, Roberts J, Emond JC, Samstein B, Brown RS Jr, Najjar M, Chapman WC, Doyle MM, Florman SS, Schwartz ME, Llovet JM. Ten-Year Outcomes of Liver Transplant and Downstaging for Hepatocellular Carcinoma. JAMA Surg. 2022 Sep 1;157(9):779-788. doi: 10.1001/jamasurg.2022.2800. — View Citation

Tan DJH, Lim WH, Yong JN, Ng CH, Muthiah MD, Tan EX, Xiao J, Lim SY, Pin Tang AS, Pan XH, Kabir T, Bonney GK, Sundar R, Syn N, Kim BK, Dan YY, Noureddin M, Loomba R, Huang DQ. UNOS Down-Staging Criteria for Liver Transplantation of Hepatocellular Carcinoma: Systematic Review and Meta-Analysis of 25 Studies. Clin Gastroenterol Hepatol. 2022 Feb 16:S1542-3565(22)00144-6. doi: 10.1016/j.cgh.2022.02.018. Online ahead of print. — View Citation

Tran NH, Munoz S, Thompson S, Hallemeier CL, Bruix J. Hepatocellular carcinoma downstaging for liver transplantation in the era of systemic combined therapy with anti-VEGF/TKI and immunotherapy. Hepatology. 2022 Oct;76(4):1203-1218. doi: 10.1002/hep.32613. Epub 2022 Jul 30. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	For patients with liver transplantation: The 2-year event-free survival rate	From the date of transplantation to the date of tumor recurrence or the date of tumor progression otherwise, with censoring at the date of death or last contact for event-free patients.	2 years
Secondary	For patients with liver transplantation: The 2-year overall survival	The time elapsed from the liver transplantation to death during the 2-year follow-up period.	2 years
Secondary	For all patients with HCC downstaging: 1, 2 year overall survival rate	The probability of survival from the beginning of treatment to the end of 1-year and 2-year follow-up.	1, 2 years
Secondary	For patients with liver transplantation: Rate of early allograft dysfunction (EAD)	Number of recipients developing EAD after liver transplantation	1 week posttransplantation
Secondary	For patients with liver transplantation: Rate of allograft rejection	Number of recipients developing allograft rejection after liver transplantation	1 year
Secondary	For all patients with HCC downstaging: Rate of successful tumor downstaging	Number of patients reaching the successful downstaging criteria for liver transplantation	1 year