Sintilimab Combined With Bevacizumab Biosimilar as Adjuvant Treatment After Resection of Ruptured Hepatocellular Carcinoma: A Prospective, Exploratory, Single-Arm Study (CLEAR-2)
Overview
- Phase
- Phase 2
- Status
- Recruiting
- Sponsor
- Ruijin Hospital
- Enrollment
- 35
- Locations
- 1
- Primary Endpoint
- DIsease-free Survival (DFS)
Overview
Brief Summary
Primary liver cancer-particularly hepatocellular carcinoma (HCC)-remains a major health burden in China, characterized by high incidence and mortality rates and poor 5-year survival. Spontaneous rupture of HCC (SRHCC), although a relatively uncommon complication, is associated with extremely high mortality and marked geographic variation, with disproportionately higher incidence and rupture-related deaths reported in Asian populations. For patients with preserved liver function and resectable tumors, hepatic resection can offer favorable long-term survival and even a potential cure. However, despite surgical removal, the risk of postoperative recurrence is substantially increased, and long-term outcomes remain unsatisfactory. Currently, there is no validated adjuvant therapy to reduce recurrence or improve survival after resection.
In recent years, immune checkpoint inhibitors (ICIs) in combination with anti-angiogenic agents have demonstrated synergistic antitumor activity and manageable safety in advanced HCC. Notably, studies of sintilimab plus a bevacizumab biosimilar have shown significant improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Moreover, emerging evidence in the adjuvant and perioperative settings suggests that PD-1 blockade may delay recurrence in high-risk patients, such as those with microvascular invasion.
Based on the high postoperative recurrence rate in SRHCC patients and the existing therapeutic gap, along with established evidence of the efficacy of immune checkpoint inhibitors combined with antiangiogenic therapy in advanced HCC, conducting a prospective Phase II single-arm study of adjuvant therapy with sintilimab plus the bevacizumab biosimilar holds significant clinical and scientific value. This study aims to evaluate the tolerability of this combination regimen in postoperative SRHCC patients at high risk of recurrence. It is expected to provide a more effective treatment option for patients diagnosed with spontaneously ruptured hepatocellular carcinoma, improve their prognosis, and offer scientific evidence for future treatment strategies.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patients voluntarily provide written informed consent, with authorization obtained from the patient or legal representative prior to any protocol-related procedures.
- •Age ≥ 18 years and ≤ 75 years; both female and male
- •Spontaneous tumor rupture with hemorrhage confirmed by imaging prior to or during surgery, with a postoperative pathological diagnosis of hepatocellular carcinoma (HCC).
- •a) For cases where tumor rupture is an incidental finding during surgery, a clinical history of abdominal pain within the two weeks preceding surgery is required.
- •CNLC Stage I-II.
- •Having undergone curative surgical resection, with intraoperative irrigation using ≥5000 mL of distilled water or normal saline, confirmed negative surgical margins on postoperative pathology, and achieving a complete response (CR) confirmed by imaging within 4-8 weeks after surgery.
- •ECOG PS 0-1
- •Child-Pugh A (score ≤6).
- •Life expectancy ≥12 months
- •Laboratory test results obtained within 3 days prior to the first dose must meet the following criteria:
Exclusion Criteria
- •Pathological diagnosis other than hepatocellular carcinoma, including cholangiocarcinoma or combined hepatocellular-cholangiocarcinoma.
- •Intraoperative intraperitoneal lavage with chemotherapeutic agents
- •Child-Pugh class B or C
- •ECOG PS \> 1
- •Postoperative imaging confirming the presence of extrahepatic metastasis, residual disease, or recurrence.
- •Prior systemic antitumor therapy, including targeted therapy, immunotherapy, investigational drugs, or local therapies such as TACE (preoperative TAE for hemostasis is allowed). Patients who received adjuvant TACE after resection are also excluded.
- •Clinically symptomatic moderate or severe ascites requiring therapeutic paracentesis or drainage, or a Child-Pugh ascites score \>2 (the presence of minimal ascites on imaging only, without associated symptoms, is excluded). Uncontrolled or moderate-to-large pleural effusion or pericardial effusion.
- •Current interstitial lung disease (ILD), or a history of ILD requiring glucocorticoid treatment, or other conditions that might interfere with the diagnosis or management of immune-related pulmonary toxicity, including pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), pneumoconiosis, drug-induced pneumonia, or idiopathic pneumonia. Patients with evidence of active pneumonia on screening chest computed tomography (CT) scans or severely impaired pulmonary function are excluded. History of radiation pneumonitis within the radiation field is permitted. Active tuberculosis.
- •Presence of an active autoimmune disease, or a history of autoimmune disease with potential for recurrence \[including, but not limited to, autoimmune hepatitis, pneumonitis, uveitis, colitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism (patients with hypothyroidism controlled only with hormone replacement therapy are eligible)\]. Patients with vitiligo, psoriasis, or alopecia not requiring systemic treatment, or well-controlled type I diabetes on insulin, or childhood asthma that has completely resolved in adulthood without any intervention are eligible. Asthmatic patients requiring bronchodilators for medical intervention are excluded.
- •Use of immunosuppressive agents or systemic corticosteroids for immunosuppressive purposes (at doses \>10 mg/day prednisone or equivalent) within 2 weeks prior to initiation of study treatment. Inhaled or topical corticosteroids, and adrenal replacement steroid doses ≤10 mg/day prednisone equivalent, are permitted in the absence of active autoimmune disease.
Arms & Interventions
Experimental Arm
Sintilimab (200 mg, iv, d1, q3w) in combination with bevacizumab biosimilar (15mg/kg, iv, d1, q3w)
Intervention: Sintilimab plus bevacizumab biosimilar (Drug)
Outcomes
Primary Outcomes
DIsease-free Survival (DFS)
Time Frame: Through out the study (up to 3 years)
The time from initial curative-intent treatment to the date of the first documented tumor progression as determined by the investigator (per RECIST 1.1), or death due to any cause.
Secondary Outcomes
- Overall Survival (OS)(Through out the study (up to 3 years))
- Adverse Event description as assessed by CTCAE V5.0(Through out the study (up to 3 years))
- the proportion and timing of intrahepatic recurrence(Through out the study (up to 3 years))
- the proportion and timing of extrahepatic metastasis(Through out the study (up to 3 years))
- the proportion and timing of peritoneal metastasis(Through out the study (up to 3 years))