Deep, Multi-omics Phenotyping to Predict Response, Resistance and Recurrence to Adjuvant Atezolizumab Plus Bevacizumab in Resected Hepatocellular Carcinoma

Recruiting now · Phase 2

Conditions studied: Hepatocellular Carcinoma

In brief

Hepatocellular carcinoma (HCC) is the 7th most common cancer worldwide but is the 4th 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 2016-22. 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 defence. These investigations will be continued in PLANet 2.0 and in this new phase, the research team 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 the research team to collect longitudinal, before and after treatment biosamples and clinical data. These clinical studies will serve as proof-of-concept to the study team's translational findings and allow it to uncover predictive biomarkers which will help clinicians to institute more efficacious and personalized treatment in the future. The 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 the team 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).

Key facts

Study ID

NCT05516628

Run by

National Cancer Centre, Singapore

People needed

30

Starts

2023-02-28

Expected to finish

2027-03-01

Last updated by the study team

2026-06-29

Who can join

Age: 21 and older, up to 90. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• Patient is willing, able and mentally competent to provide written informed consent prior to any testing undertaken for this study protocol, including screening tests and evaluations that are not considered to be part of the patient's routine care.
• Male and female patients, age 21 to 90 at the time of signature of the informed consent form.
• Patient is able to comply with scheduled visits, assessments and other study procedures.
• Patient diagnosed with HCC or its histological variants who has undergone a resection within 4-12 weeks prior to Day 1 of Cycle 1.
• Multimodality treatment is not permitted, for example resection and ablation
• Combination treatment is not permitted.
• Patient has clinically AND histologically proven HCC after liver resection as described below:
• Patients must have documented histological HCC confirmation of negative surgical margins (R0) which is documented in a pathology report (patients with microscopically positive [R1] or grossly positive [R2] resection margins or unknown margins will be excluded from the study).
• Patients must have disease-free status documented within 4 weeks prior to Day 1 of Cycle 1 by a complete physical examination and radiographic images, with no subsequent evidence of residual or recurrent disease prior to Day 1 of Cycle 1. A complete set of baseline (post-resection) radiographic images and accompanying report must be available prior to Day 1 of Cycle 1.
• Patient has an absence of major macrovascular (gross vascular) invasion of the portal vein (Vp3 or Vp4) or major macrovascular invasion in the inferior vena cava (Vv3).
• Patient has an absence of extrahepatic spread as confirmed by CT or MRI scan of the chest, abdomen, pelvis, and head prior to and following resection . If head scan was not performed prior to resection, this must be performed after resection.
• Patient has a full recovery from surgical resection within 4 weeks prior to Day 1 of Cycle 1.
• Patient is at high risk for HCC recurrence after resection as defined below:
• Tumour confined to the liver that is (i) beyond the 'up-to-7' criteria, as defined as the sum of the diameter of the largest tumour (in cm) and the number of tumours, or (ii) with macrovascualr invasion (Vp1 or Vp2).
• In the event that the pathology and the pre- resection radiology report are discordant with regards to tumour size and number, the modality demonstrating the largest tumour size and number should be used to determine high risk features. If macrovascular invasion of Vp1 or Vp2 is detected on either the pre-operative CT/MRI scan or the pathology report, this should be a high-risk feature
• Patient is known to be negative for the Human Immunodeficiency Virus (HIV).
• Patient with documented virology status of hepatitis, as confirmed by screening HBV and HCV tests
• For patients with active HBV: HBV DNA < 500 IU/mL during screening, initiation of anti-HBV treatment at least 14 days prior to Day 1 of Cycle 1 and willingness to continue anti-HBV treatment during the study (per local standard of care; e.g., entecavir). Patients with HBV DNA > 500 IU/mL should be continued on antiviral treatment to obtain HBV DNA < 500 IU/mL before Day 1 of Cycle 1. Antiviral treatment shall continue throughout the entire Atezo+Bev treatment phase.
• Patients with HCV, either with resolved infection (as evidenced by detectable antibody) or chronic infection (as evidenced by detectable HCV RNA), are eligible
• For patients with detectable HCV RNA and for whom HCV treatment is deemed appropriate by the investigator, treatment should begin no sooner than 6 months following resection consistent with AASLD guidelines
• Patient is willing to receive an esophagogastroduodenoscopy, either before resection as part of pre-procedure work-up or following resection, and assessment and treatment of varices of all sizes per local standard of care prior to Day 1 of Cycle 1.
• Patient is willing to receive an electrocardiogram, either before resection as part of pre-procedure work-up or following resection, prior to Day 1 of Cycle 1.
• Patient with Child-Pugh A (up to 6 points) without clinical ascites before surgery
• Patient with ECOG performance status 0-1.
• Patient has adequate hematological, renal and hepatic function, defined by the following laboratory test results, obtained within 7 days prior to Day 1 of Cycle 1 unless otherwise specified:

You may not qualify if…

• Patient is unable to provide informed consent or refuse blood taking.
• Patient has evidence of residual, recurrent, or metastatic disease prior to initiation of treatment.
• Patient has clinically significant ascites or any other clinical signs of liver failure on physical examination at time of enrolment.
• Patient has a history of hepatic encephalopathy.
• Patient has a bleeding event due to untreated or incompletely treated esophageal and/or gastric varices prior to Day 1 of Cycle 1.
• Patient has active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:
• Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.
• Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
• Rash must cover < 10% of body surface area.
• Disease is well controlled at baseline and requires only low-potency topical corticosteroids.
• There is no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the 12 months prior to Day 1 of Cycle 1.
• Patient has a history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on chest CT scan at screening.
• Patient has significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to Day 1 of Cycle 1, unstable arrhythmia, or unstable angina
• Patient has a history of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival [OS] rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer. Effectively treated malignancies,including HCC that have been in remission for over 5 years can be allowed as they are highly likely to have been cured.
• Patient has active tuberculosis at screening
• Patient has a severe infection within 4 weeks prior to Day 1 of Cycle 1, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that in the opinion of the investigator, could impact patient safety
• Patient has received treatment with therapeutic oral or IV antibiotics within 2 weeks prior to Day 1 of Cycle 1
• Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
• Patient has prior allogeneic stem cell or solid organ transplantation
• Patient is on the waiting list for liver transplantation
• Patient has any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
• Patient has a co-infection with HBV and HCV or Hepatitis D viral infection
• Patients with a history of HCV infection but who are negative for HCV RNA by polymerase chain reaction will be considered to be negative for HCV infection.
• Patient has clinically significant uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12mg/dL, or corrected serum calcium > ULN)

Where it is running

• National University Hospital Singapore — Singapore, Singapore (enrolling)
• National Cancer Centre Singapore — Singapore, Singapore (enrolling)
• Singapore General Hospital — Singapore, Singapore (enrolling)
• Changi General Hospital — Singapore, Singapore (enrolling)
• Sengkang General Hospital — Singapore, Singapore (enrolling)
• Tan Tock Seng Hospital — Singapore, Singapore

Full record on ClinicalTrials.gov

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