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.,
Tumor confined to the liver that is beyond the up-to-7 criteria, and/or
Tumor with vascular invasion VP 1-3 and/or Vv 1-2 (at the discretion of site investigator) Both local and central assessments are required at screening, prior to any study treatment. Sites are required to send all CT/MRI images for central imaging review. The central assessment result will be made known to sites and will take precedence in determining a patient's study eligibility in case of a discrepancy between local and central review.
Aged 21 years old and above of either gender.
Patient not eligible for SIRT-Y90 treatment after assessment with macro-aggregated albumin labeled with technetium-99 (MAA) scan on SPECT/CT or planar imaging.
Patients who have SAE > grade 3 within 4 weeks after receiving SIRT-Y90. For patients who experience SAE > grade 3 after receiving SIRT-Y90 (1st or 2nd administration), the duration between the SIRT-Y90 dose and randomization and/or 1st and 2nd SIRT-Y90 dose (for two-staged delivery) may be extended by an additional 4 weeks to re-assess the patient's eligibility.
Patients who have had >2 administrations of hepatic artery directed therapy.
Patients who have had hepatic artery directed therapy done <4 weeks prior to date of ICF signing.
Parallel
SIRT-Y90 with Atezolizumab + Bevacizumab
Combination productSingle or two-staged delivery of SIRT-Y90 (4 to 6 weeks), followed by 1200mg atezolizumab + 15mg/kg bevacizumab administered by IV at every 3 weeks for 18 months.
SIRT-Y90 with Placebo (IV)
Combination productSingle or two-staged delivery of SIRT-Y90 (4 to 6 weeks), followed by placebo at every 3 weeks for 18 months.
Best Overall Response Rate (BORR) at 9 months post-randomization.
The number of patients whose Best Overall Response (BOR) at 9 months post-randomization is a partial response or complete response per RECIST v1.1 and mRECIST, divided by the total number of patients in the analysis population.
Best Overall Response Rate (BORR) at 12-months and 18-months post-randomization.
The number of patients whose Best Overall Response (BOR) at 12 and 18 months post-randomization is a partial response or complete response per RECIST v1.1 and mRECIST, divided by the total number of patients in the analysis population.
Sustained response rates at 9, 12 and 18 months.
The number of patients whose BOR at time t (t = 9, 12 and 18 months) is a partial response or complete response confirmed on a subsequent visit by CT scan, divided by the total number of patients in the analysis population.
Disease control rates at 9, 12 and 18 months.
The number of patients whose BOR at time t (t = 9, 12 and 18 months) is a partial response, complete response, or stable disease per RECIST v1.1 and mRECIST, divided by the total number of patients in the analysis population.
Time to response.
The time between randomization and the date of first partial response or complete response. For those who have no partial response or complete response by the time of analysis will be censored on the date of last evaluable tumor assessment on or before the time of analysis or the end of study treatment, whichever is earlier.
SIRT-Y90 post-treatment dosimetry.
Voxel-level mean tumor absorbed dose (Dmean) and mean biological effective dose (BEDmean) for SIRT-Y90 will be calculated using CT images using local deposition method. In addition, administered activity and mean absorbed dose to treated liver volume (including both tumoral and non-tumoral tissue) will be used as dosimetry parameters. Dose response evaluation will be attempted based on the information obtained and follow-up anatomical evaluation. The impact of tumour absorbed dose on BORR, tumour response as assessed by RECIST v1.1 and mRECIST and outcomes of patients receiving SIRT-Y90 (3, 6, 12 and 18 months) will be assessed.
Hepatic progression-free survival (HPFS).
Hepatic progression-free survival (HPFS) is defined as the time from randomization and the date of tumor progression in liver or death from any cause, whichever is earlier. For those who remain alive and have not progressed in the liver, HPFS will be censored on the date of the last evaluable tumor assessment on or before the time of analysis or end of study treatment, whichever is earlier.
Tumor resectability rates at 12 and 18 months.
Tumor resectability rate at time t (t = 12 and 18 months) is defined as the number of patients undergone surgical resection for the target lesions of HCC by time t, divided by the total number of patients in the analysis population.
Impact of Albumin-Bilirubin (ALBI) grade on the overall survival and progression-free survival outcomes of HCC patients undergoing SIRT-Y90.
The ALBI (Albumin-Bilirubin) score is calculated based on serum albumin and bilirubin levels and values are classified into three ALBI grades: Grade 1, Grade 2 and Grade 3, where Grade 1 indicates a better outcome. In this trial, the ALBI grade at screening will be correlated to information obtained during treatment and follow up visits such as clinical outcomes like mortality, grade 3 or 4 adverse events and/or radiological responses as measured by RECIST v1.1 and mRECIST.
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National Cancer Centre, Singapore
Lead sponsor
Hoffmann-La Roche
Collaborator
Sirtex Medical
Collaborator
Singapore Clinical Research Institute
Collaborator
