Trial Title:
HAIC Combined With Donafenib Tosilate and Toripalimab for Unresectable HCC
NCT ID:
NCT05493332
Condition:
Hepatocellular Carcinoma
Conditions: Official terms:
Carcinoma
Carcinoma, Hepatocellular
Leucovorin
Oxaliplatin
Fluorouracil
Conditions: Keywords:
HCC
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Unknown status
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
HAIC(FOLFOX)
Description:
After successful percutaneous hepatic artery cannulation, superior mesenteric arteriogram
and hepatic arteriogram were performed, and after confirming that the subjects were
eligible for enrollment according to the results, the hepatic artery was cannulated to
the predetermined position. The catheter was connected to a syringe pump in the ward for
continuous pumping of chemotherapy drugs.
Arm group label:
HAIC-Donafenib-Toripalimab Group
Other name:
Hepatic Artery Infusion Chemotherapy
Other name:
FOLFOX
Intervention type:
Drug
Intervention name:
Oxaliplatin
Description:
85mg/m2 IVdrip from hour 0 to 2 on D1,Q3W
Arm group label:
HAIC-Donafenib-Toripalimab Group
Intervention type:
Drug
Intervention name:
Leucovorin
Description:
400mg/m2 IVdrip , from hour 0 to 2 on D1 to D2,Q3W
Arm group label:
HAIC-Donafenib-Toripalimab Group
Intervention type:
Drug
Intervention name:
Fluorouracil
Description:
400mg/m2 , bolus at hour 3 ; and 600mg/m2 IVdrip over 46 hours on D1 to D2,Q3W
Arm group label:
HAIC-Donafenib-Toripalimab Group
Intervention type:
Drug
Intervention name:
Toripalimab
Description:
240mg IVdrip,D3, Q3W
Arm group label:
HAIC-Donafenib-Toripalimab Group
Intervention type:
Drug
Intervention name:
Donafenib
Description:
0.1g. P.O, BID, continuously
Arm group label:
HAIC-Donafenib-Toripalimab Group
Summary:
This is a prospective, single-armed, multicentric, explorative phase II clinical research
of conversional therapy with combination of hepatic arterial infusion chemotherapy(HAIC),
Donafenib Tosilate and Toripalimab for unresectable hepatocellular carcinoma.
Detailed description:
Compared with systemic intravenous chemotherapy, hepatic arterial infusion
chemotherapy(HAIC) has the advantages of increasing local drug concentration and reducing
systemic toxic and side effects. Currently, it is gradually used in the treatment of
hepatocellular carcinoma (HCC) with good safety and high objective response rate.
Immunotherapy combined with targeted and chemotherapy was well tolerated. At present,
anti-programmed cell death protein-1(PD-1) antibody combined with chemotherapy and
targeted therapy for advanced biliary tract tumors has initially shown good safety and
encouraging efficacy, which is worthy of further exploration. Therefore, this study aims
to evaluate the efficacy and safety of HAIC (FOLFOX) combined with Toripalimab and
Donafenib Tosilate in unresectable HCC.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Signed an informed consent form, abled to comply with visits and related procedures
specified in the program;
- Age 18-75 years old (including the boundary value), male or female;
- Zubrod-ECOG-WHO scored 0 to 1;
- Expected survival time ≥ 12 weeks;
- Serum AFP detection and imaging examination meet the clinical diagnostic criteria
for hepatocellular carcinoma in the "National Health Commission of the People's
Republic of China. Guidelines for diagnosis and treatment of primary liver cancer in
China (2019 edition)";
- Liver function grading: Child-Pugh grade A or better B grade (≤7 points);
- According to the modified solid tumor efficacy evaluation criteria (mRECIST), at
least one imaging measurable lesion;
- Newly diagnosed hepatocellular carcinoma patients who have not undergone any local
or systematic treatment for hepatocellular carcinoma in the past;
- Patients with hepatocellular carcinoma who have been evaluated by researchers and do
not have the conditions for radical resection surgery, but are expected to achieve
radical resection through translational therapy, include but are not limited to one
of the following situations:
1. The tumor is massive, close to or involves the main intrahepatic ducts, and the
surgical margin is expected to be 1 cm or closer to the edge of the tumor,
making it difficult to achieve R0 resection;
2. The tumor is large, but limited to the target resection of the liver segment;
3. Tumors with large vascular carcinoma suppositories, such as portal vein primary
branch carcinoma suppositories (not entering the main trunk), hepatic vein
cancer suppositories (not entering the inferior vena cava), but portal vein
cancer embolus can only be limited to one side and cannot affect the
contralateral side;
4. Tumor nodules ≥ 4, and mainly concentrated on the side of the liver;
5. other conditions in which the researcher believes that radical resection may be
achieved through translational therapy;
- Full organ and bone marrow function, and the laboratory test values within 7 days
before enrollment meet the following requirements (no blood components, cell growth
factors, albumin, and other drugs for corrective treatment are allowed within the
first 14 days of obtaining laboratory tests), as follows:
1. Blood count: absolute neutrophil count (ANC) ≥ 1.5×10^9/L; Platelet count (PLT)
≥75×10^9/L; Hemoglobin content (hemoglobin, HGB) ≥80g/L;
2. Liver function: serum total bilirubin (TBIL) ≤ 1.5× upper limit of normal value
(ULN); Alanine aminotransferase (ALT) and aspartate aminotransase (AST) ≤5×ULN;
Serum albumin ≥ 28 g/L; alkaline phosphatase (ALP) ≤5×ULN;
3. Renal function: serum creatinine (creatinine, Cr) ≤ 1.5× ULN or clearance of
creatinine (CCr) ≥ 45mL/min (Cockcroft-Gault formula); Urinalysis results show
urine protein <2+;
4. Coagulation function: the international normalized ratio (INR) is ≤2, and the
activated partial thromboplastin time (APTT) ≤ 1.5 times ULS;
5. Normal thyroid function, defined as thyroid-stimulating hormone (TSH) in the
normal range. If the baseline TSH is outside the normal range, subjects with
total T3 (or FT3) and FT4 within the normal range can also be enrolled;
6. Myocardial enzyme profile is within the normal range (if the researcher
comprehensively judges that it is not clinically significant as a simple
laboratory abnormality, it is also allowed to enroll);
- Female subjects of childbearing age should undergo a negative urine or serum
pregnancy test within 7 days prior to receiving the first study drug administration
(day 1 of the first cycle). If the results of the urine pregnancy test cannot be
confirmed as negative, a blood pregnancy test is required. Women of non-reproductive
age are defined as at least 1 year after menopause, or have undergone surgical
sterilization or hysterectomy;
- If there is a risk of conception, all subjects (whether male or female) should use
contraception with an annual failure rate of less than 1% throughout the treatment
period until 120 days after the last study drug administration of treatment.
Exclusion Criteria:
- Histology contains fibroblast hepatocellular carcinoma, sarcoma-like hepatocellular
carcinoma, cholangiocarcinoma and other components;
- Patients with hepatocellular carcinoma who have previously undergone radical
resection and recurrent hepatic cancer;
- Have received liver transplantation in the past;
- Have previously received systemic therapy for hepatocellular carcinoma, including
targeted drug therapy such as sorafenib, renvatinib, and rigofenib, or
immunomodulatory agent therapy such as anti-PD-1, anti-PD-L1/L2, and anti-CTLA-4,
excluding antiviral therapy; If the patient has previously used Chinese medicine
with anti-tumor indications, he or she must be > 2 weeks or 5 drug half-lives
(whichever is longer) after the completion of treatment and before the use of this
study;
- Before starting treatment, there has not been sufficient recovery from toxicity and
/ or complications caused by any intervention (i.e., ≤ grade 1 or reach baseline,
excluding fatigue or hair loss);
- Patients with any extrahepatic organ or lymph node metastases, including but not
limited to: lung metastases, bone metastases, brain metastases or local lymph node
metastases;
- There are tumors in the left and right liver lobes, such as diffuse multiple tumors
of the whole liver, tumor infiltration of contralateral phylloscopic vein branches,
and concomitant inferior vena cava cancer suppositories, etc. There is no potential
possibility of transformable resection;
- There is difficult to control hepatic encephalopathy, hepatorenal syndrome, ascites,
pleural effusion or pericardial effusion;
- Active bleeding or coagulation abnormalities, bleeding tendencies, or receiving
thrombolytic, anticoagulant, or antiplatelet therapy;
- Major surgical procedures (craniotomy, thoracic or abdominal opening) or unhealed
wounds, ulcers, or fractures that have not healed within 4 weeks prior to the first
dose. Tissue aspiration biopsy or other minor surgical procedures within 7 days
prior to the first administration, with the exception of a venipuncture catheter for
the purpose of intravenous infusion;
- History of gastrointestinal bleeding within the previous 4 weeks or a clear tendency
to bleed from the gastrointestinal tract (e.g., known focal active ulcer lesions,
fecal occult blood++, gastroscopy if persistent fecal occult blood +), or other
conditions determined by the researcher that may cause gastrointestinal bleeding
(e.g., severe floor/esophageal varices);
- History of any arteriovenous thrombosis, embolism or ischemia in the previous 6
months, such as myocardial infarction, unstable angina, deep vein thrombosis,
pulmonary embolism, cerebrovascular accident or transient ischemic attack;
- History of gastrointestinal perforation, abdominal fistula or abdominal abscess
within the previous 6 months;
- Patients with past and current objective evidence of a history of pulmonary
fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis,
drug-related pneumonia, and severe impairment of lung function;
- Previously or currently suffering from congenital or acquired immunodeficiency
diseases;
- Active autoimmune diseases requiring systemic therapy or a history of the disease
within the previous 2 years (vitiligo, psoriasis, alopecia, or Grave's disease that
do not require systemic treatment within the last 2 years, hypothyroidism requiring
thyroid hormone replacement therapy only, and patients with type I diabetes who
require only insulin replacement therapy can be selected). Known history of primary
immunodeficiency. Only patients with positive autoimmune antibodies need to be
confirmed as to whether an autoimmune disease is present according to the
investigator's judgment;
- Immunosuppressive drugs have been used within the previous 4 weeks, excluding nasal
spray, inhalation or other routes of local glucocorticoids or physiological doses of
systemic glucocorticoids (i.e., not more than 10 mg/day prednisone or equivalent
doses of other glucocorticoids), allowing the temporary use of glucocorticoids for
the treatment of symptoms of dyspnea in the treatment of asthma, chronic obstructive
pulmonary disease and other diseases;
- Attenuated live vaccines were received within the previous 4 weeks or planned for
the duration of the study;
- Other malignancies are diagnosed within 5 years prior to the first dose, excluding
radically cured cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma,
and/or radically resected carcinoma in situ. If other malignant tumors are diagnosed
more than 5 years before administration, pathological or cytological diagnosis of
intrahepatic lesions is required to determine whether the original malignancy is a
recurrence of liver metastasis;
- Pregnant or lactating women, as well as women with fertility or male patients who
are unwilling or unable to use effective contraception;
- Untreated active hepatitis B (defined as HBsAg-positive simultaneous detection of
HBV-DNA copies greater than the upper limit of normal in the laboratory at the site)
Note: Hepatitis B subjects who meet the following criteria can also be enrolled: 1)
HBsAg (+) and/or HBcAb (+) before first administration, especially HBV replication
is active (HBV-DNA≥1000copies/ml or 2000IU/ml), subjects should receive anti-HBV
therapy throughout the duration of the study treatment; 2) For subjects with HBcAg
(+) and HBsAg(-), HBsAg(-) and HBV viral load (-), prophylactic anti-HBV therapy is
not required, but close monitoring for viral reactivation is required;
- Active HCV-infected subjects (HCV antibody positive and HCV-RNA levels above the
lower detection limit);
- There are any serious or uncontrollable systemic disorders, such as: 1) Have grade
II myocardial ischemia or myocardial infarction, poorly controlled arrhythmias
(including QTc interval male ≥ 450 ms, female ≥ 470 ms) 2) According to NYHA
standard III. to IV. cardiac insufficiency or cardiac color ultrasound examination:
LVEF (left ventricular ejection fraction) < 50% 3) Unsatisfactory blood pressure
control (systolic blood pressure > 140 mmHg, diastolic blood pressure >90 mmHg); 4)
Poor control of diabetes mellitus (fasting blood glucose (FBG) >10mmol/L); 5) Urine
routine indicates urine protein ≥++, and confirms that the quantitative > of urine
protein in 24 hours is 1.0 g; 6) Patients with mental disorders who cannot cooperate
with treatment;
- Medical history or disease evidence that may interfere with test results, prevent
participants from participating in the study throughout the study, abnormal
treatment or laboratory test values, or other circumstances that the investigator
deems unsuitable for enrolment The investigator considers other potential risks to
participate in this study.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Start date:
September 2022
Completion date:
September 2024
Lead sponsor:
Agency:
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Agency class:
Other
Source:
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05493332