Efficacy and safety of SBRT combined with sintilimab and IBI305 in patients with advanced HCC and previously failed immunotherapy: study protocol of a phase 2 clinical trial

Inclusion criteria

• Male or female ≥18 years old;

• Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score from 0 to 1;

• According to the Chinese Code of Diagnosis and Treatment for Primary Liver Cancer (2019 version), it is defined as inoperable advanced HCC;

• Have received at least first-line systemic antitumour therapy, including PD-1 inhibitor monotherapy or a combination regimen for HCC;

• Eligible to receive radiation therapy;

• To have at least one measurable lesion according to RECIST1.1 and at least one measurable lesion without RT;

• Child-Pugh grade A;

• Expected survival time >3 months;

• Have full organ and bone marrow function, as follows:

  • Adequate blood function: absolute neutrophil count ≥1.5×10⁹ /L; platelet count ≥60×10⁹ /L; haemoglobin content ≥90 g/L.

  • Adequate liver function: serum total bilirubin ≤3× ULN (upper limit of normal); alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate transferase and ALP ≤5× ULN; serum albumin ≥30 g/L.

  • Adequate renal function: serum creatinine ≤1.5× ULN or clearance of creatinine ≥50 mL/min (Cockcroft-Gault formula); routine urine results show urine protein <2+; for patients with urine protein ≥2+ in routine urine tests at baseline, 24-hour urine collection and 24-hour protein quantity <1 g should be performed.

  • Adequate coagulation function: international normalised ratio and activated partial thromboplastin time ≤1.5 times ULN.

  • Normal thyroid function, with total triiodothyronine (T3), free T3 and free thyroxine levels within the normal range (this can be controlled with thyroid replacement therapy).

• Male and premenopausal women: consent to use a medically approved contraceptive during the study treatment period and for 6 months after the end of the study treatment period. The female patient was not lactating and had a negative blood or urine pregnancy test within 7 days prior to enrolment.

Exclusion criteria

• History of hepatic encephalopathy or liver transplantation;

• History of autoimmune diseases and autoimmune defects;

• Presence of clinical symptoms requiring drainage of pleural fluid, ascites and pericardial effusion;

• Infection of acute or chronic active hepatitis B or C; hepatitis B virus DNA >2000 IU/mL or 10⁴ copies/mL, hepatitis C virus (HCV) RNA>10³ copies/mL, hepatitis B surface antigen and anti-HCV antibodies both positive;

• Central nervous system metastasis;

• Prior RT for liver disease;

• Poor blood pressure control despite medication: systolic >140 mm Hg or diastolic >90 mm Hg;

• Bleeding events of oesophageal or fundus varices caused by portal hypertension that occurred within the past 6 months. Severe (G3) varicose veins observed on endoscopy within 3 months of the initial dosing; Patients with evidence of portal hypertension (including splenomegaly on imaging) and at high risk of bleeding as assessed by the investigator;

• Any life-threatening bleeding event requiring transfusion therapy, surgery or local therapy, or ongoing medication occurred in the 3 months prior to recruitment;

• Arterial or venous thromboembolism events in the 6 months prior to recruitment, including myocardial infarction, unstable angina pectoris, cerebrovascular accident or transient ischaemic attack, pulmonary embolism, deep vein thrombosis or any other serious thromboembolism; Implantable intravenous infusion port or catheter-derived thrombosis, or superficial venous thrombosis, except in cases where the thrombus has stabilised after conventional anticoagulant therapy; Prophylactic use of low dose low molecular weight heparin (eg, enoxaparin 40 mg/day) is permitted;

• Severe bleeding tendency or clotting dysfunction, or being treated with thrombolysis;

• Previous or current pulmonary diseases such as pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, drug-related pneumonia and severe impairment of lung function;

• Patients who have active tuberculosis (TB) are receiving anti-TB therapy or have received anti-TB therapy within 1 year prior to first dosing;

• Patients with HIV infection (HIV 1/2 antibody positive) or known syphilis infection;

• Patients with severe infection who are active or poorly controlled. Severe infection within 4 weeks prior to initial dosing, including but not limited to hospitalisation due to complications of infection, bacteremia or severe pneumonia;

• Immunosuppressive drugs have been used within 4 weeks prior to initial dosing, excluding nasal, inhaled or other routes of topical corticosteroids and physiological doses of systemic corticosteroids (not exceeding 10 mg/day of prednisone or equivalent doses of other corticosteroids), allowing temporary use of corticosteroids to treat symptoms of breathing difficulties in asthma, chronic obstructive pulmonary disease, etc;

• Received Chinese medicines with antitumour indications or immunomodulatory effects (including thymosin, interferon, interleukin, except for topical use to control pleural fluid or ascites) within 2 weeks prior to initial dosing;

• Other malignancies were diagnosed within 5 years prior to initial dosing, excluding basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or carcinoma in situ that had been radically resected;

• Patients who are known to be allergic to any of the components of sintilimab, bevacizumab biosimilar (IBI305) formulations or have had prior severe allergic reactions to other monoclonal antibodies or vascular endothelial growth factor A (VEGFA) inhibitors;

• Received treatment in other clinical trials within 4 weeks prior to initial dosing;

• Pregnant or nursing female patients;

• Other acute or chronic medical conditions, psychiatric disorders or abnormalities in laboratory test values that may increase the risk associated with study participation or study drug administration, or interfere with the interpretation of study results, and the investigator determines that the patient is ineligible to participate in the study.

Immunotherapy

Sintilimab will be administered intravenously at a dose of 200 mg every 21 days. The maximum duration of treatment is 24 months. The first dose of sintilimab will be administered within 3 days of treatment initiation and continue until progressive disease (PD) or intolerable toxicity is observed. If AEs, abnormalities in laboratory tests or other comorbidities occur during treatment, sintilimab will be delayed or suspended; however, dose reduction is not permitted. Patients will be withdrawn from the study if treatment is interrupted for more than 12 weeks (continuous or intermittent). If treatment-related adverse reactions do not return to grades 0–1 or to baseline within 6 weeks of the last dose of sintilimab, it should be permanently discontinued.

Targeted therapy

IBI305 will be administered intravenously at a dose of 15 mg/kg every 21 days, each time after sintilimab administration at least 5 min apart, and continued until the patient develops PD or intolerable toxicity. Dosing adjustments for IBI305 are not allowed during treatment. The dose of IBI305 will be converted from the subject’s weight at baseline (prior to day 1 administration) and remain constant throughout the study unless the patient’s weight changes by more than 10% from baseline.

Radiotherapy

SBRT will start within 7 days of participation in the trial. The RT programme was completed with 4D CT to evaluate tumour movement. General tumour volume (GTV) (including primary and metastatic tumours) will be defined by contrast-enhanced CT or MRI if dose–volume limits for organs at risk can be met.34 And increasing GTV by 5–10 mm produces clinical tumour volume (CTV). The planning target volume will be constructed by adding 5–10 mm of the CTV in all directions. Suitable lesions were selected and short-range RT was performed with 6 MV X-ray linear accelerator at a dose of 30–40 Gy/5–8 times, 5 times a week until the end of RT. The specific RT regimen will be determined by the investigator.

Tumour response assessment

Baseline tumour imaging scans must be performed within 28 days prior to initial dosing. Tumour radiological evaluations will be performed at 6-week intervals (±7 days), beginning with the initial administration. After 48 weeks of treatment, radiological tumour assessments will be performed at 12-week intervals (±7 days). The radiological methods used to evaluate the tumour at baseline must be consistent with those used for each subsequent follow-up evaluation, including but not limited to chest CT and abdominal MRI. Examination of other affected sites is permitted as indicated by the signs and symptoms of each patient.

Based on RECIST version 1.1,35 patients in the trial group who showed evidence of radiological PD at the initial efficacy evaluation will be allowed to continue treatment if the investigator considers that the patients would continue to gain clinical benefit from the study protocol and are re-evaluated for radiological confirmation every 4 weeks (±7 days). If PD is confirmed, the patients should discontinue the study protocol; if no progress is confirmed, the protocol therapy should continue to be studied and evaluated according to the scheduled time point of imaging examination specified in the protocol until PD is confirmed on imaging. For patients first assessed by the investigator as having stable disease (SD), partial response (PR) or complete response (CR), treatment and tumour evaluation will continue until treatment is discontinued.

If the patient becomes clinically unstable during the study, unscheduled radiological evaluation may be performed at any time. Clinical disease instability is defined as follows: (1) presence of clinically significant signs and symptoms suggestive of disease progression (including deterioration of laboratory test values); (2) decreased ECOG PS Score; (3) rapid disease progression and (4) tumour progression at important anatomical sites requiring other urgent medical intervention (eg, spinal cord compression).

For patients who discontinue treatment for reasons other than radiological disease progression, radiological evaluation should be performed at the end of treatment and subsequently continued at planned time points specified in the protocol until any of the following events occur: initiation of new antitumour therapy, objective disease progression, withdrawal of informed consent, loss to follow-up or death.

Safety assessment

All AEs will be evaluated according to the National Cancer Institute (NCI) General Terminology for Adverse Events (CTCAE) version 5.0.36 AEs are defined as any adverse or undesired medical events occurring after the subjects of the clinical study signed the informed consent form, regardless of whether there was a causal relationship with the study drug. AEs include but are not limited to the following:

• An increase in pre-existing (pretrial) medical conditions/diseases (including an increase in symptoms, signs and abnormalities in laboratory tests);

• Any newly occurring adverse medical conditions (including symptoms, signs and newly diagnosed diseases);

• Abnormal laboratory results of clinical significance.

Serious AEs (SAEs) are those that meet at least one of the following criteria:

• Cause death, other than death caused by progression of disease for study indications;

• Life-threatening (‘life threatening’ in the definition means that the subject is at risk of death when this AE occurs and does not include AE that would have caused death if the event had been aggravated);

• Hospitalisation or prolonged hospitalisation is required;

• Permanent or serious disability/disability;

• Congenital abnormalities/birth defects;

• Other medically significant events are defined as events that endanger the patients or require medical intervention to prevent any of the above events.

Any AEs will be fully documented, including the diagnosis (if there is no diagnosis, the symptoms and signs, including abnormal lab tests), start and end dates and times (if applicable), CTCAE severity rating and change (grade 3 or above events), whether there were SAEs, measures taken with study drugs, outcomes of treatments and events given for AE and the relationship between AEs and study drugs.

AEs should be followed-up until recovery to baseline, grade 0 to 1 or if the investigator believes for reasonable reasons (such as no recovery or improvement), further follow-up is not necessary.

Sample size

The sample size was calculated using Simon’s two-stage design. Previous studies have shown that the ORR of second-line TKI or immunotherapy for liver cancer is between 10.6% and 24.1%,37 and it is estimated that the ORR in this study can reach 25%. We plan to enrol 21 subjects, and the 95% CI can be maintained within the range of 8.7%–49.1% (figure 1).

Figure 1

Flow chart. AE, adverse event; DCR, disease control rate; HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RT, radiotherapy; SBRT, stereotactic body RT.

Statistical analysis methods

All statistical analyses will be performed using SAS V.9.2 (later version) statistical analysis software. All statistical tests will be performed using a one-sided validity hypothesis test with p<0.05. The 95% CIs and p values will be provided for comparison between groups. Unless otherwise stated, measurement data will be statistically described as mean±SD or median (minimum, maximum). The frequency (percentage) is used for the statistical description of the counting data. Kaplan-Meier curves will be plotted to compare OS and PFS between the two groups using the log-rank test. The duration of the overall response (DOR) and ORR will be calculated based on binomial distributions using the two-sample Cochran-Mantel-Haenszel method.

Efficacy analysis

• The ORR is defined as the proportion of subjects with CR and PR to the total number of participants;

• The DCR is defined as the proportion of subjects with CR, PR and SD;

• PFS, defined as the time from enrolment to the first progression of a radiological disease or death, whichever occurs first;

• OS, defined as the time from enrolment to death due to any cause;

• The DOR is the time between the first evaluation of a tumour as CR or PR and the first evaluation as PD or death from any cause.

ORR, PFS, DCR and DOR will be evaluated by the investigator according to RECIST v1.1 criteria.

Safety analysis

In this study and during follow-up, the severity of AEs will be graded according to NCI CTCAE (version 5.0). The safety evaluation indicators include the following:

• Incidence and severity of all AEs; treatment-phase AEs, SAEs, immune-related AEs and their associations with study drugs;

• Number and proportion of subjects who discontinue treatment owing to the above AEs;

• Changes in vital signs, physical examination and laboratory results before, during and after treatment.