AHCC Current Studies

​Multi-national, double-blind, randomized phase II trial to compare the safety and efficacy of SIRT-Y90 followed by atezolizumab plus bevacizumab versus SIRT-Y90 followed by placebo in patients with locally advanced hepatocellular carcinoma (STRATUM)

(Clinicaltrials.gov identifier: NCT05377034)

​Up to a third of patients in the Asia-Pacific and globally presents with Barcelona Clinic for Liver Cancer (BCLC) intermediate-stage hepatocellular carcinoma (HCC) at diagnosis. One of the standard-of-care in intermediate HCC is loco-regional therapy, or also known as radioembolization, delivered through trans-arterial chemoembolization (TACE) or Selective Internal Radiation Therapy (SIRT).

Such localized radiotherapy has been shown to induce a phenomenon known as the abscopal effect, where there is a regression of metastatic cancer a distance away from the irradiated site. It is later found that immunologic mechanisms underpin such abscopal effects. Our own data monitoring the immune landscapes of peripheral blood and tumor microenvironment from HCC patients treated with Y90 radioembolization (Y90-RE) had demonstrated a clear immune activation and subsequent exhaustion post-Y90 therapy. This data is further supported by a recently published study that the timely delivery of immune checkpoint inhibitors (ICIs) may enhance the immunological anti-tumor response in Y90-RE treated patients.

A previous study combining Y90 radioembolization with nivolumab (anti-PD1) for the treatment of angioinvasive HCC provided supportive evidence for combining anti-PD-1/anti-PD-L1 antibodies with radiotherapy in cancer treatment. Promising data from the phase I, II, and III studies suggest that atezolizumab, an anti-PD-L1 antibody, also has the potential to be used in combination with cancer immunotherapies, targeted medicines, and various chemotherapies across a broad range of cancers. In addition, data from several studies of atezolizumab plus bevacizumab (anti-VEGF) in various cancer types such as metastatic Renal Cell Carcinoma (mRCC) and advanced non-squamous non-small cell lung cancer (NSCLC) support a scientific rationale for combining both immunotherapy drugs, including its potential to increase infiltration (trafficking) of T-cells into tumors and other immune-modulatory properties.

In this proposed study, we hypothesize that the creation of a pro-inflammatory environment by SIRT-Y90 radiotherapy, in combination with the administration of immunotherapy drugs atezolizumab and bevacizumab will create a synergistic effect that is superior to monotherapy of either treatment modality in overcoming immune evasion and thus improve abscopal responses.

This study aims to compare the safety and efficacy of SIRT-Y90 followed by atezolizumab plus bevacizumab versus SIRT-Y90 followed by placebo in patients with locally advanced HCC. Outcomes from this study can contribute to the knowledge of using radioembolization and combination immunotherapy in the treatment of locally advanced HCC.

Up to 15 overseas sites in Asia-Pacific 

Singapore

Pierce Chow (National Cancer Centre Singapore), Toh Han Chong (National Cancer Centre Singapore), Chee Cheng Ean (National University Hospital)

South Korea

Kim Yoon Jun (Seoul National University Hospital), Kim Seung Up (Severance Hospital, Yonsei University Health System), Lee Joon Hyeok (Samsung Medical Centre)

Taiwan

Hsu Chiun (National Taiwan University Cancer Center), Liang Po-Chin (National Taiwan University Hospital), Lee Teng-Yu (Taichung Veterans General Hospital), Huang Yi-Hsiang (Taipei Veterans General Hospital), Chen Chao-Long (Kaohsiung Chang Gung Memorial Hospital)

China

Feng Xiaobin (Beijing Tsinghua Changgung Hospital), Zeng Yong (West China Hospital, Sichuan University), Liu Rong (People’s Liberation Army General Hospital), Sun Xiaorong (Shandong Cancer Hospital), Liu Jibing (Shandong Cancer Hospital)

​Pierce Chow

pierce.chow@duke-nus.edu.sg  

​Vennese Low / Rachel Teo

+65 6306 5456 / +65 6306 5455

ahcc09@nccs.com.sg  

​Early Detection of Hepatocellular Carcinoma: miRNA, microbiome and imaging biomarkers in the evolution of chronic liver disease in a high-risk prospective cohort (ELEGANCE)
(Clinicaltrials.gov identifier: NCT04965259)

In Singapore, hepatocellular carcinoma (HCC) is the 3rd leading cause of cancer death in males and 4th in females. A major reason for its lethality is the absence of diagnostic modalities with high accuracy for the detection of early stage HCC. Currently, only 20% of HCC are diagnosed in the early stage when curative treatment can be performed. The inability to diagnose HCC at an early stage for the majority of patients is thus an urgent unmet public health need.

Current guidelines for the surveillance of patients at risk of developing HCC involves a combination of serum alpha-fetoprotein (AFP) and abdominal ultrasound (US) every 6 months. AFP and US have accuracies of 76.6% and 84% respectively for the detection of HCC but for early HCC, sensitivity with US drops to only 47% and adding AFP to US increases sensitivity in this group to only 63%. There is thus an imperative to develop novel diagnostic modalities that can more accurately detect early HCC. Plasma microRNAs (miRNAs) have shown promise in preliminary studies and in this collaboration with MIRXES, we aim to develop the 1st miRNA in-vitro diagnostic (IVD) kit for HCC that has higher accuracy and better ease of use compared with the extant combination of AFP and US.

Patients with chronic liver diseases have increased risk of developing HCC. There is currently no accurate method to identify individuals at higher risk of developing HCC in a sufficiently granular manner such that we can devote more resources for targeted surveillance. We continue our earlier collaboration with Perspectum to develop the 1st AI algorithm with MRI to predict individual risks of developing HCC within a specific timeline.

There is a worldwide increase in the prevalence of metabolic liver disease. The biology and clinical trajectories of metabolic liver diseases and cancer remain unclear but emerging data have shown association with changes in the microbiome and metabolome. There is therefore urgency to study the association between gut microbiome, metabolome and the liver in order to stratify individual patient risks and prevent disease progression and the development of HCC. We collaborate with AMILI to build on their existing microbiome library from healthy donors and to expand our collaboration with the Singapore Phenome Centre (SPC) to examine changes in the microbiome and metabolome in the build-up to the development of HCC. The aim is to identify potential therapeutic targets in the microbiome and metabolome where intervention can prevent the development of HCC and slow the progression of chronic liver diseases.

In this study, we collaborate with MIRXES, Perspectum and AMILI on research that will be carried out on a prospective cohort study of 2,000 patients at risk of developing HCC (AHCC10, main study) and a parallel cohort of 100 patients already diagnosed with HCC (AHCC11, parallel study).

Singapore

Eugene Wong (Changi General Hospital), Toh Han Chong (National Cancer Centre), Lee Guan Huei (National University Hospital), Jason Chang (Singapore General Hospital), Chong Oi Fong (SingHealth Polyclinics – Bedok), Sabrina Wee (SingHealth Polyclinics – Bukit Merah), Tan Kee Tung (SingHealth Polyclinics – Marine Parade), Ong Kok Kiong (SingHealth Polyclinics – Outram), Tan Ngiap Chuan (SingHealth Polyclinics – Pasir Ris), Yeap Xin Yi (SingHealth Polyclinics – Punggol), Choo Wei Song Jeremy (SingHealth Polyclinics – Sengkang), Sulaiha Binte Ithnin (SingHealth Polyclinics – Tampines), Marianne De Roza and Kalki Rajamanickam (Sengkang General Hospital), Yang Wei Lyn (Tan Tock Seng Hospital), Dr Clarice Chen (EnterpriseSG)

​Pierce Chow

pierce.chow@duke-nus.edu.sg  

​Sim Yu Ki / Rachel Teo

+65 6306 5452 / +65 6306 5455

ahcc10@nccs.com.sg  

Prospective Cohort Study of Changes in Circulatory micro-RNA after Surgical Resection of Hepatocellular Carcinoma (PROSECT)
(Clinicaltrials.gov identifier: NCT05148572)

In this proposed study, we continue our collaboration with MIRXES and AMILI on a cohort of 100 patients already diagnosed with HCC. This study will also act as a positive control to the AHCC10 ELEGANCE Study.

We will use the miRNA profiles of 100 patients with diagnosis of HCC confirmed by histology at surgical resection to confirm the hypothesis that the miRNA biomarkers that are predictive of occurrence in HCC will revert back to profiles similar to non-HCC cohort. In addition, we aim to determine if progressive changes in miRNA signatures are predictive of recurrence and to discover new signatures for recurrence prediction.

Singapore

Adrian Chiow (Changi General Hospital), Pierce Chow (National Cancer Centre), Glenn Bonney (National University Hospital), Brian Goh (Singapore General Hospital), Kam Juinn Huar (Sengkang General Hospital), Vishalkumar G. Shelat (Tan Tock Seng Hospital)

​Pierce Chow

pierce.chow@duke-nus.edu.sg  

​Sim Yu Ki / Rachel Teo

+65 6306 5452 / +65 6306 5455

ahcc10@nccs.com.sg

​Precision Medicine in Liver Cancer across an Asia-Pacific Network 2.0
(Clinicaltrials.gov identifier: NCT05516628)

Hepatocellular carcinoma (HCC) is the 6th most common cancer worldwide but is the 3rd deadliest, because diagnosis tend to be late and current systemic therapies are poorly efficacious. Within the same tumour, different parts of the HCC can belong to separate molecular sub-groups. In addition, there is currently no validated predictive biomarkers to help clinicians select the best therapy for an individual patient. This challenge poses an urgent, unmet clinical need.

To address this, the multi-disciplinary research program Precision Medicine in Liver Cancer across an Asia-Pacific Network (PLANet 1.0) was conceptualized and successfully conducted from 2016 to 2022. The program uncovered novel insights into the highly heterogeneous molecular landscape of HCC and novel mechanisms, including how HCC reverts to fetal forms to escape the body’s immunological defence1.

We will continue these investigations in PLANet 2.0 and in this new phase, we will investigate patients receiving best-in-class therapeutics in 2 investigator-initiated clinical studies (AHCC12 and AHCC13), including Atezolizumab plus Bevacizumab (Atezo+Bev) and Yttrium-90, which allows us to collect longitudinal, pre- and post- treatment biosamples and clinical data. These clinical studies will serve as proof-of-concept to our translational findings and allow us to uncover predictive biomarkers which will help clinicians to institute more efficacious and personalized treatment in the future. Our research team comprises of experts in different complementary fields (epigenomics, genomics, immunomics, metabolomics, proteomics, clinical science and data science) and across different institutions. This allows us to adopt an integrative approach in understanding the landscape of the HCC tumour micro-environment and biomarkers co-localisation, and their role in tumour evolution and therapeutic response. By adopting a wide spectrum of converging investigations, PLANet 2.0 will identify and validate biomarkers that correlate with clinical outcomes (response, resistance and recurrence).

Singapore

Adrian Chiow (Changi General Hospital), Pierce Chow (National Cancer Centre), Glenn Bonney (National University Hospital), Brian Goh (Singapore General Hospital), Kam Juinn Huar (Sengkang General Hospital), Vishalkumar G. Shelat (Tan Tock Seng Hospital)

​Theme 1: Deep Phenotyping and Correlation with Clinical Responses to Therapy

Pierce Chow and Patrick Tan (Executive Director, A*STAR Genome Institute of Singapore)

Theme 2: Elucidating Spatial Distribution of Biomarkers at single-cell resolution

Vinay Tergaonkar (Research Director, A*STAR Institute for Molecular and Cell Biology)

Theme 3: Translational and Functional Immunomics

Toh Han Chong (Senior Consultant, Division of Medical Oncology, National Cancer Centre Singapore)

Theme 4: Pre-Clinical Disease Modelling and Target Discovery

Tam Wai Leong (Senior Research Scientist, A*STAR Genome Institute of Singapore) and Polly Chen (Principal Investigator, Cancer Science Institute of Singapore)

Theme 5: Data Architecture, Data Security and Data Science Applications

A/Prof Liu Nan (Centre for Quantitative Medicine, Duke-NUS Medical School)

​Pierce Chow

pierce.chow@duke-nus.edu.sg  

​Chew Sin Chi / Weng Yuqi

+65 6306 5450 / +65 6306 5453

ahcc12@nccs.com.sg  

​RE-BALANCE
(Clinicaltrials.gov identifier: NCT07111130)

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, with incidence continuing to rise, particularly among patients with metabolic liver diseases. In Singapore, HCC is the third leading cause of cancer death among males and fourth among females. Despite surveillance programs, only approximately 20% of HCC cases are diagnosed at an early stage where curative therapies are possible. The current surveillance modalities — serum alpha-fetoprotein (AFP) and abdominal ultrasound (US) — have limited sensitivity for early-stage HCC detection, creating an urgent unmet need for more effective preventive strategies.

Emerging evidence from the Precision Medicine in Liver Cancer across an Asia-Pacific Network (PLANet) and Early detection of hepatocellular carcinoma: miRNA, microbiome and imaging biomarkers in the evolution of chronic liver disease in a high-risk prospective cohort (ELEGANCE) studies has identified dysregulation of bile acid metabolism, mediated through the gut-liver axis, as a significant risk factor for HCC. A shift towards a predominance of classical pathway bile acids (12-hydroxy derivatives) has been observed in patients progressing to HCC, closely associated with gut microbiome alterations and early liver injury.

Despite these discoveries, no proven interventions currently exist to reverse bile acid dysregulation or restore gut-liver homeostasis in high-risk individuals. Given the growing burden of non-viral (non-hepatitis B, non-hepatitis C; NBNC) HCC globally and locally, early targeted interventions to restore metabolic represent a promising new strategy for cancer prevention.

The Restoring Bile Acid Homeostasis via Lifestyle Adjustments to prevent the Development of Liver Cancer (RE-BALANCE) study directly addresses this gap. RE-BALANCE is a prospective, single-arm, non-randomized interventional study designed to modulate bile acid profiles, improve gut microbiome composition, and enhance liver health through structured dietary and lifestyle changes in high-risk NBNC individuals identified from the ELEGANCE cohort.

Participants will undergo a 12-week intervention comprising a low-carbohydrate, high-fibre diet and a structured physical activity program targeting 150 minutes of moderate-intensity exercise per week. Biological endpoints — including plasma bile acid profiling, gut microbiome diversity analysis, and liver fat and fibro-inflammation assessment via Perspectum’s quantitative multiparametric MRI — will be measured at baseline, after intervention (approximately 3 months), and during extended follow-up at 6 and 12 months.

RE-BALANCE symbolizes restoring homeostasis: rebalancing the gut-liver axis, bile acid metabolism, and lifestyle behaviours to prevent hepatocarcinogenesis. The study reflects a philosophy of early, precise, and proactive intervention — aiming to prevent cancer development rather than treat established disease.

This protocol leverages key findings from the NMRC Translational and Clinical Research (TCR) Flagship PLANet program and the A*STAR Industry Alignment Fund - Industry Collaboration Project (IAF-ICP) funded ELEGANCE cohort, forming a comprehensive approach toward advancing precision preventive strategies in liver cancer.

Prof Chow Kah Hoe Pierce (NCCS), Dr Guo Yuxin (SGH), A/ Prof Cindy Ng (SGH), Tan Ai Shan (SGH)

​Pierce Chow

pierce.chow@duke-nus.edu.sg  

​Chew Suet Li / Weng Yuqi

+65 6306 5451 / +65 6306 5453

ahcc14@nccs.com.sg