Immunotherapy and Radioembolisation for Metastatic Hepatocellular Carcinoma

Hepatocellular Carcinoma Clinical Trial

Official title:

A Phase 2 Study on Immune Checkpoint Inhibitors and Radioembolisation for Previously Untreated Metastatic Hepatocellular Carcinoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05809869
• Other study ID #: UW 22-729
• Status: Recruiting
• Phase: Phase 2
• Start date: February 15, 2023
• Est. completion date: June 30, 2026

Study information

• Verified date: February 2023
• Source: The University of Hong Kong
• Contact: Victor Ho-Fun Lee, MD
• Phone: 852-2255-4352
• Email: vhflee[@]hku.hk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Hepatocellular carcinoma is one of the most intractable primary malignancies in the hepatobiliary and pancreatic tract with a poor overall survival worldwide. Unfortunately, the vast majority of hepatocellular carcinoma patients suffer from advanced unresectable or metastatic disease at diagnosis. Currently targeted therapy alone, or in combination with anti-vascular endothelial growth factor antagonist, is the standard first-line treatment for metastatic hepatocellular carcinoma.

On the other hand, there is growing evidence suggesting that radiation therapy (external or internal) with or without immune checkpoint inhibitors can produce or even augment abscopal effect in which the tumours away from the radiation field also show significant tumour shrinkage. The underlying mechanism of eliciting abscopal effect includes the increased antigen presentation by the myeloid cells within the tumour stroma leading to enhanced tumour cell killing. Previous case reports showed that radiation therapy alone can induce abscopal effect in mice and human models. However, a robust and concrete evidence of abscopal effect with combinational immune checkpoint inhibitors and radioembolisation or external radiation therapy in hepatocellular carcinoma is still lacking.

This study investigates the efficacy and safety of immune checkpoint inhibitors and radioembolisation as first-line treatment for previously untreated metastatic hepatocellular carcinoma.

Description:

Hepatocellular carcinoma is one of the most intractable primary malignancies in the hepatobiliary and pancreatic tract with a poor overall survival worldwide. Surgery in the form of hepatectomy or liver transplantation provides the best chance of cure for early-stage disease. Unfortunately, the vast majority of hepatocellular carcinoma patients suffer from advanced unresectable or metastatic disease at diagnosis. Currently targeted therapy alone, or in combination with anti-vascular endothelial growth factor antagonist, is the standard first-line treatment for metastatic hepatocellular carcinoma.

On the other hand, there is growing evidence suggesting that radiation therapy (external or internal) with or without immune checkpoint inhibitors can produce or even augment abscopal effect in which the tumours away from the radiation field also show significant tumour shrinkage. The underlying mechanism of eliciting abscopal effect includes the increased antigen presentation by the myeloid cells within the tumour stroma leading to enhanced tumour cell killing. Previous case reports showed that radiation therapy alone can induce abscopal effect in mice and human models. However, a robust and concrete evidence of abscopal effect with combinational immune checkpoint inhibitors and radioembolisation or external radiation therapy in hepatocellular carcinoma is still lacking.

This phase 2 single-arm study will investigate the efficacy and safety of combination of immune checkpoint inhibitors and radioembolisation for previously untreated metastatic hepatocellular carcinoma.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 25
• Est. completion date: June 30, 2026
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Metastatic hepatocellular carcinoma (HCC) confirmed by radiological findings with contrast-enhanced triphasic CT scan of the liver and/or MRI scan of the abdomen, without or without histological/cytological confirmation or elevation of serum alpha-feto protein.

• Must be of age 18 years or above.

• Must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at study entry.

• Must be eligible to receive immune checkpoint inhibitor and yttrium-90 microsphere injection.

• Must have baseline efficacy images with CT or MRI and measurable target lesions in the liver according to RECIST 1.1 and mRECIST, taken within 28 days prior to the start of immune checkpoint inhibitor.

• Must be able to provide written informed consent.

• Adequate serum hematological functions defined as:

Absolute neutrophil count (ANC) =1.0 x 10^9/l Platelet =75 x 10^9/l Haemoglobin =9 g/dL

• Adequate serum biochemistry functions defined as:

Serum bilirubin =1.5 x institutional upper limit of normal (ULN). <<This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.>> Serum aspartate aminotransferase (AST) / alanine aminotransferase (ALT) =2.5 times of institutional upper limit of normal unless liver metastases are present, in which case it must be =5 times of ULN

Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:

Males:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)

Females:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)

Exclusion Criteria:

• Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment or 5 half-lives, whichever is shorter.

• Has a diagnosis of severe active scleroderma, lupus, other rheumatologic or autoimmune disease within the past 3 months before study recruitment. Patients with a documented history of clinically severe autoimmune disease or a syndrome requiring systemic steroids or immunosuppressive agents will not be allowed on this study. Subjects with vitiligo or resolved childhood asthma/atopy are an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections are not excluded from the study. Subjects with hypothyroidism stable on hormone replacement are not excluded from this study.

• Has had a prior monoclonal antibody, immunotherapy or immune checkpoint inhibitors before recruitment into this study.

• Has had prior chemotherapy or targeted small molecule therapy (including sorafenib or other anti-vascular endothelial growth factor inhibitor) within 3 weeks prior to administration of the study drug or who has not recovered (i.e., grade =1 or at baseline) from adverse events due to a previously administered agent.

• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, indolent lymphomas, or in situ cervical cancer that has undergone potentially curative therapy.

• Has known carcinomatous meningitis (also known as leptomeningeal carcinomatosis).

• Has an active infection requiring intravenous systemic therapy or hospital admission.

• Has a history or current evidence of any condition, therapy, or laboratory abnormality, including psychiatric or substance abuse disorder, that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 31 weeks after the last dose of trial treatment.

• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). Routine checking for Anti-HIV1 or Anti-HIV2 is not mandatory.

• Untreated hepatitis B infection. Patients with chronic hepatitis B infection (defined as HBsAg positive) are eligible if they have started anti-viral therapy for at least 1 month and is continuing anti-viral treatment throughout the whole duration of this study.

• Has experienced Grade 4 toxicity on treatment with prior radiation.

• Has experienced grade 3-4 intracranial toxicity (hypophysitis or central nervous system toxicity) with either prior intracranial radiation, anti-programmed cell death-1 (PD-1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor therapy.

• Is taking >4mg/day of dexamethasone or its equivalent at the start of immunotherapy or has required >4mg/day of dexamethasone or its equivalent for 3 consecutive days within 1 week of starting treatment.

• Allergies and adverse drug reaction to the following: History of allergy to study drug components; History of severe hypersensitivity reaction to any monoclonal antibody.

• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of study medication. Note: Local surgery of isolated lesions for palliative intent is acceptable.

• Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) =470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart).

• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:

(A) Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) (B) Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent (C) Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma

Intervention

Drug:
• Durvalumab
Durvalumab 1500mg intravenous infusion on week 1, 5, 9, 13, 17, 21 and 25 for a total of 7 cycles
• Tremelimumab
Tremelimumab 300mg intravenous infusion on week 1 only.

Radiation:
• Yttrium-90 radioembolisation
Yttrium-90 radioembolisation on week 2 only.

Locations

Country	Name	City	State
Hong Kong	Department of Clinical Oncology, Queen Mary Hospital	Hong Kong

Sponsors (2)

Lead Sponsor	Collaborator
The University of Hong Kong	Queen Mary Hospital, Hong Kong

Country where clinical trial is conducted

Hong Kong, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Best objective response	Best objective response	3 years
Primary	Rate of abscopal effect	Rate of abscopal effect, which is defined as the rate of objective response of tumour sites outside the liver after radioembolisation and immune checkpoint inhibitor therapy	3 years
Secondary	Progression-free survival	Progression-free survival	3 years
Secondary	Overall survival	Overall survival	3 years
Secondary	Incidence of treatment-related side effects	Incidence of treatment-related side effects as determined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0	3 years
Secondary	Local control rate	Local control rate, which is defined as the percentage of tumour sites in the liver without evidence of progressive disease after radioembolisation and immune checkpoint inhibitor therapy	3 years
Secondary	Distant control rate	Distant control rate, which is defined as the percentage of tumour sites outside the liver without evidence of progressive disease after radioembolisation and immune checkpoint inhibitor therapy	3 years