Multinational Phase II Trial to Compare Safety and Efficacy of SIRT (Y-90 Resin Microspheres) Followed by Atezolizumab Plus Bevacizumab, vs SIRT (SIRT-Y90) Followed by Placebo in Locally Advanced HCC Patients

Trial number:
NCT05377034
Trial phase:
2
Study type:
Local/Regional therapies, Immunotherapy, Targeted therapy
Overall status:
Not yet recruiting

Study start date

August, 2022

Scientific title

A Multinational, Double-blind, Placebo-Controlled, Parallel Randomized Arms, Phase II Trial to Compare Safety and Efficacy of Selective Internal Radiation Therapy (Y-90 Resin Microspheres) Followed by Atezolizumab Plus Bevacizumab) Versus Selective Internal Radiation Therapy (SIRT-Y90) Followed by Placebo in Patients With Locally Advanced Hepatocellular Carcinoma (HCC)

Summary

This is a multi-national, phase II, parallel-arm, double-blind, placebo-controlled, two-arm study designed to assess the efficacy and safety of SIRT-Y90 followed by atezolizumab plus bevacizumab [study arm], versus SIRT-Y90 followed by placebo [control arm] in patients with locally advanced Hepatocellular Carcinoma (HCC).

Unequivocal diagnosis of HCC (AASLD 2010 diagnostic criteria or histology) that is locally advanced without extra-hepatic metastases but with significant tumor burden, i.e., Barcelona Clinic for Liver Cancer (BCLC) Bolondi sub-stage B2 or BCLC C with PVT(Vp1 - 3) but with no distant metastases.Aged 21 - 80 years of either gender. Patient eligible for SIRT-Y90 treatment after assessment with macro-aggregated albumin labeled with technetium-99 (MAA) scan on SPECT/CT.

No prior radiation to the liver.

Eligible for receiving Y90 radioembolization therapy as determined by Tc-99m MAA assessment with the following criteria:

• Lung shunting <20% on SPECT/CT

No prior systemic adjuvant or neoadjuvant therapy for HCC.HCC in Bolondi sub-stage B2, or BCLC C with PVT but with no distant metastases, which cannot be optimally treated with local ablative techniques such as radio-frequency ablation, consistent with the practice of the clinical trial center. Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥10 mm with spiral CT scan or MRI. Negative HIV test at screening. Documented virology status of hepatitis, as confirmed by screening hepatitis B virus (HBV) and hepatitis C virus (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 randomization, and willingness to continue anti-HBV treatment during the study (per local standard of care; e.g., entecavir). ECOG performance status 0 - 1. Child-Pugh A (up to 6 points).

Adequate hematological, renal, and hepatic function as follows:

Leukocytes ≥2,500/μLPlatelets ≥75,000/μL without transfusion Hemoglobin >9.5 g/dL (Patients may be transfused to meet this criterion.) Total bilirubin <2.0 mg/dL INR ≤2.0 ALP ≤5×institutional upper limit of normal AST and ALT ≤5×institutional upper limit of normal Albumin ≥2.8 g/dL Creatinine ≤2.0 mg/dL For patients not receiving therapeutic anticoagulation: INR or aPTT ≤2×ULN Absolute Neutrophil Count ≥1.5×10**9/L Life expectancy of at least 3 months without any active treatment. Suitable for protocol treatment as determined by clinical assessment undertaken by the site investigator Performance of an esophagogastroduodenoscopy before receiving Y90 radioembolization as part of pre-procedure work-up or during screening, and assessment and complete treatment of varices of all sizes per local standard of care within 6 months prior to randomization. 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. Female patients must be either postmenopausal or, if premenopausal, must have a negative pregnancy test and agree to use two forms of contraception if sexually active during the treatment period, for at least 5 months after the last dose of atezolizumab and 6 months after the last dose of bevacizumab. Male patients must be surgically sterile, or if sexually active and having a pre-menopausal female partner, they must be using an acceptable form of contraception during the treatment period and for 6 months after the last dose of bevacizumab.

The following criteria should be checked at the time of randomization. If ANY apply, the patient must not be included in the study:

Patient not eligible for SIRT-Y90 treatment after assessment with macro-aggregated albumin labeled with technetium-99 (MAA) scan on SPECT/CT.Patients who have SAE >3 in the 4 weeks after receiving SIRT-Y90. Patients who have had >2 administrations of hepatic artery directed therapy. Patients who have had hepatic artery directed therapy done <4 weeks prior to study entry. Patients who have had systemic adjuvant or neoadjuvant therapy for HCC. Prior hepatic radiation therapy for HCC or other malignancy. Patient who has received any immunotherapy (including interferon-alfa, peginterferon alfa-2a, peginterferon alfa-2b, thymosin-α1, etc.) within 30 days prior to randomization, is currently receiving immunotherapy or is planned to start immunotherapy during the study (e.g., for the management of active CHB or CHC according to local guidelines). Has evidence that <30% of the total liver volume is disease-free. Currently receiving any other investigational agents for the treatment of their cancer. Has intractable clinical ascites (in spite of optimal diuretic treatment) or any other clinical signs of liver failure, on physical examination. Prior bleeding event due to untreated or incompletely treated esophageal and/or gastric varices within 6 months prior to randomization Presence of tumor thrombus in the main trunk of the portal vein or a portal vein branch contralateral to the primarily involved lobe (or both) (Vp4). Any metastatic disease. In this context, local-regional lymph nodes measuring <2 cm in greatest diameter or lung nodules measuring <1 cm are not contraindications at the discretion of site investigator. Any other concurrent malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for at least five years. Presence of clinical signs of CNS metastases due to their poor prognosis and because progressive neurologic dysfunction would confound the evaluation of neurologic and other adverse events. Uncontrolled inter-current illness including, but not limited to, ongoing or active infection (except viral hepatitis), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Inadequately controlled arterial hypertension (defined as systolic blood pressure [BP]>150 mmHg and/or diastolic BP >100 mmHg), based on an average of at least three BP readings at two or more sessions.

• Anti-hypertensive therapy to achieve these parameters is allowed.

Any of the following contraindications to angiography and selective visceral catheterization:

Bleeding diathesis, not correctable by the standard forms of therapy.Severe peripheral vascular disease that would preclude arterial catheterization. Portal hypertension with hepato-fugal flow as documented on baseline spiral CT scan. Current or recent (within 10 days of Day 1 of Cycle 1) use of aspirin (>325 mg/day) or current or recent treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol.

Current or recent (within 10 days prior to Day 1 of Cycle 1) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose.

Prophylactic anticoagulation for the patency of venous access devices is allowed provided the activity of the agent results in an INR <1.5×ULN and aPTT is within normal limits (according to institutional standards) within 14 days prior to Day 1 of Cycle 1.Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day) is allowed. However, the use of direct oral anticoagulant therapies such as dabigatran (Pradaxa®) and rivaroxaban (Xarelto®) is not recommended due to bleeding risk. History of allergic reactions attributed to compounds of similar chemical or biologic composition to SIRT-Y90 or atezolizumab or bevacizumab. The patient has a history of an autoimmune disease or immune deficiency such as, but not limited to, multiple sclerosis, lupus, and inflammatory bowel disease. Patients with vitiligo are not excluded. The patient requires concomitant treatment with any immunosuppressive or immunostimulant agent, or with systemic corticosteroids prescribed for chronic treatment (more than 7 consecutive days). Inability or unwillingness to understand or sign a written informed consent document. Female patients who are pregnant or currently breastfeeding. Current enrolment in any other investigational therapeutic drug or device study.

Study design

Primary purpose: Treatment, Allocation: Randomized, Intervention model: Parallel Assignment, Masking: Quadruple, Masking description: This study will be performed in a double-blind manner. The investigators, monitoring team, site staff, and all patients will be blinded to the study treatments from the time of randomization until database lock. Biostatisticians involved in preparing the randomization and safety data analysis for Data and Safety Monitoring Board (independent to study statistician) will be unblinded., Subject masked: Yes, Caregiver masked: Yes, Investigator masked: Yes, Outcomes assessor masked: Yes,

Conditions

Locally Advanced Hepatocellular Carcinoma

Other study ID numbers

AHCC09 STRATUM

Choose trial site (2)

National Cancer Centre Singapore
National Cancer Centre Singapore Recruiting
11 Hospital Cres, Singapore 169610