Hepatocellular Carcinoma Non-Resectable
Conditions
Keywords
radiotherapy, radioembolization, hepatocellular carcinoma, immunotherapy, EBRT, TARE
Brief summary
Each year, approximately 1,000 patients in the Netherlands are diagnosed with liver cancer. When liver cancer can no longer be treated with surgery or thermal ablation, cure is no longer possible. In recent years, immunotherapy has become increasingly important in the treatment of liver cancer. Unfortunately, the combination of immunotherapy (atezolizumab) and an anti-angiogenic agent (bevacizumab) results in a durable response in only 15-20% of patients. The aim of this study is to identify a strategy to enhance the effectiveness of immunotherapy, enabling the patient's immune system to better recognize and attack the cancer. Two recent clinical observations suggested that the immune system may be activated by external radiotherapy or radioembolization. Following these treatments, both patients unexpectedly showed regression of multiple non-irradiated liver metastases. One of these patients had initially experienced disease progression during immunotherapy, but after radiotherapy subsequently demonstrated regression of all metastatic lesions. In this clinical study (16 patients in total), we will investigate whether the immune system can be reactivated after failure of immunotherapy. Patients will be eligible for participation after disease progression during immunotherapy for liver cancer. In Group A, eight patients will receive three fractions of external radiotherapy directed at the most dominant liver lesion or an extrahepatic metastasis. In Group B, eight patients will receive radioembolization of the most dominant liver lesion. There will be no randomization. Group A will be enrolled first, and Group B will open only after completion of enrollment in Group A. The primary outcome measure is the number of patients in each group who achieve disease control at 6 months, defined as stable disease or tumor regression lasting for at least 6 months. During the study, participating patients will undergo extensive blood analyses, tumor biopsies of both treated and untreated lesions, and multiple CT scans. Through these investigations, we aim to characterize the tumor microenvironment in detail, evaluate the role of different immune cell populations, and gain a better understanding of why these treatments administered after immunotherapy failure may still be capable of reactivating the immune system.
Detailed description
This is a prospective, non-randomized proof-of-concept clinical trial in which patients with unresectable multifocal or metastatic HCC will be treated with external beam radiotherapy (EBRT) (cohort A; n=8) or radioactive yttrium-90 based transarterial radioembolization (TARE) (cohort B; n=8) after failure of first-line systemic treatment with atezolizumab and bevacizumab to overcome immunotherapy resistance and consequently improve clinical outcome. Eligible patients will be informed about the study at the outpatient clinic. Regular CT imaging will take place at baseline and three months post-therapy. Directly after TARE (cohort B) SPECT-CT imaging will be performed. These scans are all standard of care. Study related blood withdrawal, and target and non-target lesion ultrasound-guided biopsies (2 biopsies per lesion) will take place: 1. at baseline; 2. 72-120 hours post-therapy (after last radiation fraction in cohort A; after Y-90 treatment in cohort B); 3. blood withdrawal at one month post-therapy (20) 4. three months post-therapy. At the described timepoints, two biopsies will be taken from the irradiated lesion as well as from a non-irradiated lesion. The second biopsy, obtained 72-120 hours after EBRT or TARE, is essential for characterizing the early treatment-induced immune response. This early time point enables the assessment of treatment-related changes in, among others, immune cell infiltration, immune cell activation, and the expression of immune-related markers. The later biopsy, obtained three months after treatment, provides insight into the more sustained and long-term effects of therapy. Comparing these two time points is crucial for understanding the dynamics and evolution of the immune response and constitutes a key research objective of this study. Standard-of-care baseline and 3-monthly regular CT chest and abdomen will be performed until progressive disease to evaluate the primary endpoint according to RECIST v1.1.
Interventions
RADIATIONExternal beam radiotherapy
Treatment will be given according to standard-of-care procedures. Patients receive 24 Gy in 8 Gy fractions (3x 8 Gy), 2-3 times per week, using a VMAT technique and taking into account standard dose constraints for the (healthy) liver and other relevant organs at risk.
RADIATIONtransarterial radioembolization
Treatment will be given according to standard-of-care procedures. The most dominant liver lesion will be treated with Y-90 based transarterial radioembolization (TARE). The initial dose-rate of yttrium-90 is lower to that of EBRT, approximately 0.7 Gy per hour versus 2 Gy per minute, respectively. The expected tumor dose will be ≥100 Gy and an acceptable healthy liver dose of ≤30 Gy will be given.
Sponsors
Radboud University Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants will be assigned sequentially to one of two cohorts. The first cohort will receive external beam radiotherapy. After completion of enrollment in the first cohort, a second cohort will receive transarterial radioembolization. The cohorts are not randomized and are not intended for formal comparison.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult individuals at least 18 years old * Unresectable multifocal or metastatic HCC, as determined by the multidisciplinary tumor board; * Subject has histologically or cytologically confirmed unresectable multifocal or metastatic HCC (all other histological types are excluded); * Child-Pugh (CP) class A (well-compensated disease) or B ≤ 7 (acceptable functional compromise); * Progressive HCC after failure of first-line atezolizumab-based systemic therapy; * Life expectancy ≥12 weeks per investigator assessment; * At least one non-targeted measurable lesion per RECIST version 1.1 (the irradiated/targeted lesion in both cohorts will not be considered as measurable); * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; * Agree to undergo multiple tumor biopsies, CT imaging, and blood withdrawals; * Adequate baseline laboratory results (defined as a hemoglobin ≥5.0 mmol/l, an absolute neutrophil count ≥1.5 x 109/l, platelet count ≥75 x 109/l, creatinine clearance ≥30 ml/min, bil-irubin \<3x ULN and liver transaminases ALT and AST \<5x ULN); * Allowance of temporary cessation of anticoagulants (no bridge therapy); * Subjects must voluntarily sign and date the informed consent forms; * Informed consent must be signed prior to any single study-related activity.
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded from participation in this study: * Subjects who have received palliative radiation therapy after disease progression upon first-line treatment with atezolizumab and bevacizumab (note: prior palliative radiation therapy before or during treatment with atezolizumab and bevacizumab is allowed, provid-ed the final dose was administered ≥6 weeks before enrollment); * Subjects who have received holmium-166 or yttrium-90 TARE after disease progression up-on first-line treatment with atezolizumab and bevacizumab (note: prior TARE before treat-ment with atezolizumab and bevacizumab is allowed); * Large arterio-portal venous shunting per investigator assessment; * Previous surgical hepatico-enterostomy; * Lung shunt fraction \>10%; * The presence of significant ascites * Pregnancy or inadequate anticonception; * History of other malignancies within 3 years prior to screening, except for malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate \> 90%); * Evidence of bleeding diathesis or clinically significant coagulopathy; * Requirement for immunosuppressive doses of systemic corticosteroids (\>10 mg/day prednisone equivalents) or other systemic immunosuppressive medication.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The 6-month disease control rate | The 6-month disease control rate will be calculated from randomization to the date of the CT scan of chest and abdomen planned at 6 months post-randomization (+/- 7 days). | The 6-month disease control rate is defined by stable disease for at least 6 months, partial responses, and complete responses of non-targeted lesions, in both cohort A and B, according to RECIST version 1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate | Complete duration of study up to 24 weeks | The objective response rate is defined as the percentage of patients who experience a partial or complete response of non-targeted lesions, according to RECIST version 1.1. |
| Progression-free survival | From date of randomization until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 60 months | The progression-free survival is defined as the time interval from randomization to the first event of disease progression, according to RECIST version 1.1, or death, whichever comes first. Kaplan-Meier curves will be shown. This study is not designed to show differences between cohort A and B. |
| Overall survival | From the date of randomization to the date of death from any cause assessed up to 60 months | Overall survival is calculated from the date of randomization to the date of death due to any cause. For patients alive at trial closure, date of last follow-up. Kaplan-Meier curves will be shown. This study is not designed to show differences between cohort A and B. |
| Therapy-related toxicity | Up to three months after the last radiotherapy fraction (cohort A) or radio-embolization (cohort B). | This is defined as the number of patients with any grade ≥ 3 therapy-related toxicity according to the CTCAE version 5.0. |
| Feasibility of treatment | Through study completion, an average of 6 months | Study feasibility of post-immunotherapy treatment is defined as: 1) the proportion of patients that complete all radiotherapy fractions (cohort A) and radioembolization (cohort B); 2) the proportion of patients that complete all study-related imaging, blood withdrawal and biopsies (cohort A and B). |
| Health-related Quality of life | At baseline, 72-120h post treatmen, 3 months post treatment and 6 months post treatment (EOT) | Health-Related Quality of Life (HRQoL) will be scored and reported according to the EORTC scoring manual (19). Descriptive statistics will be reported per treatment arm. Quality of Life Symptom Scale: Scores range from 1 to 4, where 1 = not at all bothered by the symptom and 4 = very much bothered by the symptom. Higher scores indicate greater symptom burden and therefore a worse outcome. |
Countries
Netherlands
Contacts
CONTACTHarm Westdorp, MD, PhD
Outcome results
None listed