Clinical trial NCT06349317: Neoadjuvant IMRT Combined With Camrelizumab and Apatinib for Resectable HCC With PVTT
Official title: Neoadjuvant Intensity-modulated Radiotherapy Combined With Perioperative Camrelizumab and Apatinib in the Treatment of Resectable Hepatocellular Carcinoma Associated With Portal Vein Tumor Thrombus: a Single-arm Prospective Clinical Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Lead sponsor: Meng Chao Hepatobiliary Hospital of Fujian Medical University
Sponsor class: OTHER
First posted: 2024-04-05
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is an open-label, single-arm prospective clinical trial that evaluates the efficacy and safety of neoadjuvant intensity-modulated radiotherapy combined with perioperative camrelizumab and apatinib in the treatment of resectable hepatocellular carcinoma with portal vein tumor thrombus.


Eligibility criteria: Inclusion Criteria:

1. Signed written informed consent and able to comply with scheduled visits and related procedures;
2. Age ≥18 and ≤75 years, regardless of gender;
3. Patients with HCC who meet the clinical diagnostic criteria of China's "Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma" (2022 Edition) or are diagnosed by biopsy, and have at least one measurable lesion according to the mRECIST criteria;
4. Presence of portal vein tumor thrombus (PVTT) of Cheng's type I/II/III, with the primary tumor being resectable;
5. Child-Pugh score of Class A;
6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1;
7. No prior antitumor treatment (such as surgery, radiotherapy, TACE, ablation, chemotherapy, targeted therapy, immunotherapy, or systemic therapy).
8. For patients with hepatitis B virus (HBV) infection, testing for HBV-DNA is required; direct treatment initiation is allowed if HBV-DNA ≤2000 IU/mL; if HBV-DNA \>2000 IU/mL, antiviral therapy should be administered for one week before starting the treatment; all HBV positive patients will receive continuous antiviral treatment throughout the study; patients with hepatitis C virus (HCV) RNA positive must undergo antiviral treatment as per the guidelines;
9. Participants must provide a fresh tumor biopsy sample during the screening period (can be waived after discussion with the medical monitor) and blood samples for monitoring immune cells, cytokine levels, and other relevant immune status in the tumor microenvironment;
10. Expected survival of ≥12 weeks;
11. Adequate organ and marrow function, as defined by the following laboratory values:

    1. Hematology: Absolute Neutrophil Count ≥1.5×109/L; Platelets ≥80×109/L; Hemoglobin ≥90g/L;
    2. Liver function: Total bilirubin ≤3× upper limit of normal (ULN); Alanine Aminotransferase and Aspartate Aminotransferase ≤5×ULN; Serum albumin ≥30g/L;
    3. Renal function: Serum creatinine (Cr) ≤1.5×ULN, or for patients with Cr \>1.5×ULN, creatinine clearance (CCr) ≥45 mL/min (Cockcroft-Gault formula); Urinalysis showing proteinuria \<2+; For participants with baseline proteinuria ≥2+, a 24-hour urine collection and quantitative protein \<1g is required;
    4. Coagulation: International Normalized Ratio or APTT ≤1.5×ULN;
12. Females of childbearing potential must agree to abstain from heterosexual intercourse or use effective contraception from signing the informed consent until at least 120 days after the last dose of study medication. They must have a negative serum HCG test within 1 week before treatment and must not be breastfeeding. Females who have not reached menopause (≥12 months of amenorrhea without an alternative medical cause) and have not undergone sterilization (e.g., hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) are considered to be of childbearing potential;
13. Male participants with partners of childbearing potential must agree to abstain from heterosexual intercourse or use reliable and effective contraceptive methods from the time of signing the informed consent until at least 120 days after the last dose of study medication. During the same period, male participants must also agree not to donate sperm. Male subjects whose partners are pregnant must use condoms and do not need to use other contraceptive methods.

Exclusion Criteria:

1. PVTT located in the portal vein branch opposite the tumor, or with inferior vena cava tumor thrombus, extrahepatic metastasis, or tumor invasion of adjacent organs;
2. Known intrahepatic cholangiocarcinoma, sarcomatoid HCC, mixed-cell carcinoma, and fibrolamellar carcinoma; active malignant tumors other than HCC within the past 5 years or concurrently, except for cured localized tumors such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, prostate carcinoma in situ, cervical carcinoma in situ, and breast carcinoma in situ, which are allowed;
3. Currently with interstitial pneumonia or interstitial lung disease, or history of interstitial lung disease requiring hormone treatment, or other conditions that may interfere with the judgement and management of immunotherapy-related pulmonary toxicity, such as pulmonary fibrosis, organizing pneumonia (e.g., obliterative bronchiolitis), pneumoconiosis, drug-related pneumonia, idiopathic pneumonia, or participants with active pneumonia or severe impairment of lung function shown on a chest CT during screening; active tuberculosis;
4. Active autoimmune disease or history of autoimmune disease that may recur, including but not limited to autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism (patients controllable with hormone replacement therapy are allowed); Patients with skin conditions that do not require systemic treatment, such as vitiligo, psoriasis, and alopecia, those with controlled Type I diabetes mellitus undergoing insulin therapy, or individuals whose childhood asthma has fully resolved with no need for intervention in adulthood, are allowed; patients requiring bronchodilators for medical intervention of asthma are not allowed;
5. Use of immunosuppressive drugs or systemic corticosteroids for the purpose of immunosuppression (dose \>10mg/day of prednisone or equivalent) within 2 weeks before the start of the study;
6. Active infection, fever of unknown origin ≥38.5°C within 1 week before the study start, or baseline white blood cell count \>15×10\^9/L; therapeutic antibiotics orally or intravenously within 2 weeks before the study start (excluding prophylactic antibiotics given IV for no more than 48 hours);
7. Congenital or acquired immunodeficiency (e.g., HIV infection);
8. Receipt of live attenuated vaccines within 4 weeks before the study start or expectation of needing such vaccines during the camrelizumab treatment period or within 60 days after the last dose of camrelizuma;
9. Significant bleeding symptoms of clinical significance or a clear bleeding tendency within 6 months before the study start, such as gastrointestinal bleeding, hemorrhagic gastric ulcers, or vasculitis; if baseline fecal occult blood is positive, retesting is allowed, and if still positive, gastroduodenoscopy is required;
10. Known genetic or acquired bleeding (e.g., coagulopathy) and thrombotic tendencies, such as hemophilia, coagulation mechanism disorders, thrombocytopenia, etc.; currently receiving full-dose oral or injectable anticoagulants or thrombolytic agents for therapeutic purposes (prophylactic use of low-dose aspirin, etc., is allowed);
11. Arterial thromboembolic events within 6 months before the study start, such as cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, cerebral infarction), CTCAE grade 3 or above deep vein thrombosis, pulmonary embolism, etc;
12. Uncontrolled clinical symptoms or diseases of the heart, such as: (1) heart failure of NYHA class II or above or echocardiography showing LVEF \<50%; (2) unstable angina; (3) myocardial infarction within 1 year before treatment; (4) clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention; (5) QTc \> 450ms for males and \>470ms for females (QTc interval calculated using the Fridericia formula; if QTc is abnormal, continuous testing three times at 2-minute intervals is allowed, taking the average value);
13. Hypertension not well controlled with antihypertensive medication (systolic blood pressure ≥140mmHg or diastolic blood pressure ≥90mmHg based on the average of ≥2 blood pressure readings), allowing achievement of the above parameters through antihypertensive treatment; history of hypertensive crisis or hypertensive encephalopathy;
14. Major vascular diseases within 6 months before the study start (e.g., requiring surgical repair or recent peripheral arterial thrombosis of an aneurysm);
15. Severe, unhealed, or open wounds and active ulcers or untreated fractures;
16. Major surgery (excluding diagnostic) within 4 weeks before the study start;
17. Inability to swallow pills, malabsorption syndrome, or any condition affecting gastrointestinal absorption;
18. Intestinal obstruction and/or clinical signs or symptoms of gastrointestinal obstruction, including partial obstructions requiring parenteral hydration, parenteral nutrition, or tube feeding related to the underlying disease, within 6 months before the study start. Patients with incomplete obstruction/obstruction syndrome/intestinal obstruction signs/symptoms at initial diagnosis who have undergone definitive (surgical) treatment to alleviate symptoms may be eligible for the study;
19. Use of strong CYP3A4/CYP2C19 inducers, including rifampin (and its analogs) and Hypericum perforatum, or strong CYP3A4/CYP2C19 inhibitors within 2 weeks before the study start;
20. Known allergy to any monoclonal antibody, antiangiogenic targeted drugs, or excipients;
21. Participation in other drug clinical studies within 12 weeks before the study start.

Primary outcomes:
measure: 1-year Event-Free Survival (EFS) rate
timeFrame: 1 year
Secondary outcomes:
measure: Event-Free Survival (EFS)
timeFrame: up to 2 years
measure: Overall Survival (OS)
timeFrame: up to 2 years
measure: Disease-Free Survival (DFS)
timeFrame: up to 2 years
measure: R0 resection rate
timeFrame: up to 3 months
measure: Overall Objective Response of primary liver tumor and PVTT
timeFrame: up to 3 months
Other outcomes:
measure: Surgical safety
timeFrame: up to 3 months
measure: Safety of radiotherapy, camrelizumab and apatinib treatment
timeFrame: up to 2 years
measure: Exploratory Endpoints
timeFrame: up to 2 years
Locations:
city: Fuzhou
country: China
facility: Mengchao Hepatobiliary Hospital, Fujian Medical University
state: Fujian
Study officials:
affiliation: Meng Chao Hepatobiliary Hospital of Fujian Medical University
name: Yongyi Zeng, Professor
role: PRINCIPAL_INVESTIGATOR
References: