Trial Title:
Combined HAIC, Lenvatinib and Cadonilimab As Conversion Therapy for Unresectable Hepatocellular Carcinoma
NCT ID:
NCT06187961
Condition:
Hepatocellular Carcinoma Non-resectable
Conditions: Official terms:
Carcinoma
Carcinoma, Hepatocellular
Lenvatinib
Conditions: Keywords:
Cadonilimab
Lenvatinib
Downstaging conversion therapy
Hepatocellular Carcinoma
Hepatic Arterial Infusion Chemotherapy
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
HAIC
Description:
administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding
arteries every 3 weeks.
Arm group label:
HAIC-len-cado
Other name:
hepatic arterial infusion chemotherapy of FOLFOX
Intervention type:
Drug
Intervention name:
Lenvatinib plus cadonilimab
Description:
lenvatinib (8mg, qd) plus cadonilimab (10mg/kg, q3w)
Arm group label:
HAIC-len-cado
Other name:
levima plus cadonilimab
Summary:
This is an open-label, single-arm, phase 2 study. The purpose of study is to evaluate the
feasibility and safety of hepatic arterial infusion chemotherapy combined with lenvatinib
and cadonilimab as conversion therapy for unresectable hepatocellular carcinoma.
Detailed description:
Cadonilimab is the world's first PD-1/CTLA-4 bispecific antibody tumor immunotherapy new
drug, a tetrameric PD-1/CTLA-4 bispecific antibody, which can only bind to TIL
tetravalent co-expressing PD-1 and CTLA-4. This design not only retains the efficacy
observed in the combination therapy of PD-1 plus CTLA-4 inhibitors, but also reduces the
risk of activated T cells attacking healthy tissues, thereby alleviating the toxicity
problem outside the tumor. On June 29, 2022, the National Medical Products Administration
of China approved the new drug Cadonilimab for the treatment of recurrent or metastatic
cervical cancer patients who have failed platinum-based chemotherapy. Currently, a phase
II clinical study of lenvatinib combined with Cadonilimab systemic treatment for advanced
hepatocellular carcinoma is underway, and preliminary results reveal that in 30 enrolled
patients, the ORR was 44.4%, the DCR was 77.8%, the treatment-related adverse reaction
rate was 83.3%, but the incidence of grade 3 or above adverse reactions was only 26.7%.
The safety of this antibody in patients is generally good. This study intends to evaluate
the safety and efficacy of HAIC combined with lenvatinib and cadonilimab as a conversion
regimen in unresectable hepatocellular carcinoma.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- hepatocellular carcinoma is proven on biopsy or confirmed by the presence of
radiological hallmarks, according to the American Association for the Study of Liver
Diseases or European Association for the Study of the Liver guidelines.
- Age ≥18 years.
- Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
- Not suitable for radical surgery (including radical hepatic resection, liver
transplantation or liver cancer ablation) after evaluation by the hepatobiliary
tumor MDT expert group. Specifically, any of the following conditions are met:
1. R0 resection is not feasible.
2. In subjects without cirrhosis, the volume of normal liver parenchyma is less
than 30% of the total volume, or in subjects with cirrhosis, the volume of
normal liver parenchyma is less than 40% of the total volume, or ICG-R15>15%.
3. BCLC stage B or C.
- No prior systemic anti-tumor treatment for hepatocellular carcinoma before the first
dose.
- According to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST
V1.1), at least 1 measurable lesion, or a measurable lesion that has clearly
progressed (based on RECIST V1.1 criteria) after local treatment.
- Subjects with portal vein tumor thrombus (PVTT):
1. Chen's group A and B, or Cheng's type I-III can be enrolled.
2. Chen's group C, or Cheng's type IV (superior vena cava tumor thrombus) cannot
be enrolled.
- Subjects with hepatic vein tumor thrombus:
1. VV1 and VV2 types can be enrolled.
2. VV3 type, or Sakamoto type I (inferior vena cava tumor thrombus) can also be
enrolled.
3. Sakamoto type II (inferior vena cava tumor thrombus extending above the
diaphragm), or Sakamoto type III (inferior vena cava tumor thrombus reaching
the right atrium) cannot be enrolled.
- Subjects with oligometastases outside the liver can be enrolled: Oligometastases
outside the liver are defined as up to three metastatic lesions in a maximum of two
organs, with the largest diameter being 3cm.
- Child-Pugh score less than or equal to 7.
- Adequate organ and bone marrow function, with laboratory test values meeting the
following requirements within 7 days prior to inclusion (no blood components, cell
growth factors, albumin, or other intravenous or subcutaneous corrective treatment
drugs are allowed within 14 days prior to obtaining laboratory tests):
1. Complete blood count: Absolute Neutrophil Count (ANC) ≥1.5×10^9/L; Platelet
count (PLT) ≥75×10^9/L; Hemoglobin (HGB) ≥9.0 g/dL.
2. Liver function: Total Bilirubin (TBIL) ≤2×Upper Limit of Normal Value (ULN);
Alanine Aminotransferase (ALT) and Aspartate Transferase (AST) ≤5×ULN; Serum
albumin ≥28 g/L; Alkaline Phosphatase (ALP) ≤5×ULN.
3. Kidney function: Serum Creatinine (Cr) ≤ 1.5×ULN or Clearance of Creatinine
(CCr) ≥50mL/min (Cockcroft-Gault formula); Urinalysis shows proteinuria <2+;
For subjects with baseline urinalysis showing proteinuria ≥2+, a 24-hour urine
collection should be performed and 24-hour urinary protein quantification <1g.
4. Coagulation function: International Normalized Ratio (INR) ≤2.3 or Prothrombin
Time (PT) extension ≤6 seconds.
- Estimated life expectancy of ≥12 weeks.
- Female subjects of childbearing age or male subjects whose sexual partners are of
childbearing age need to take effective contraceptive measures during the entire
treatment period and for 6 months after the last medication.
- Signed written informed consent, and able to comply with the visit and related
procedures stipulated in the protocol.
Exclusion Criteria:
- Histologically/cytologically confirmed fibrolamellar hepatocellular carcinoma,
sarcomatoid hepatocellular carcinoma, cholangiocarcinoma, etc.
- History of hepatic encephalopathy or liver transplantation.
- Clinically symptomatic pleural effusion, ascites, or pericardial effusion requiring
drainage. Subjects with only radiologically detected minimal pleural effusion,
ascites, or pericardial effusion without symptoms can be enrolled.
- Acute or chronic active hepatitis B or C infection, with hepatitis B virus (HBV) DNA
>2000IU/ml or 10^4 copies/ml; hepatitis C virus (HCV) RNA >10^3 copies/ml;
co-positive for hepatitis B surface antigen (HbsAg) and anti-HCV antibody. Subjects
who meet the above criteria after antiviral treatment with nucleoside analogs can be
enrolled.
- Presence of central nervous system metastases.
- History of esophageal or gastric variceal bleeding due to portal hypertension within
the past 6 months. Subjects assessed by the investigator to be at high risk of
bleeding.
- Any life-threatening bleeding event within the past 3 months, including those
requiring blood transfusion, surgery or local treatment, or continuous drug
treatment.
- History of arterial or venous thromboembolic events within the past 6 months,
including myocardial infarction, unstable angina, cerebrovascular accident or
transient ischemic attack, pulmonary embolism, deep vein thrombosis, or any other
serious thromboembolic events. Exceptions are made for thrombosis formation related
to implanted venous infusion ports or catheters, or superficial vein thrombosis that
has stabilized after routine anticoagulation treatment. Preventive use of low-dose
low molecular weight heparin (such as enoxaparin 40 mg/day) is allowed.
- Continuous use of aspirin (>325 mg/day) or other known platelet function inhibitors
such as clopidogrel or ticlopidine for 10 days within 2 weeks prior to the first
dose.
- Uncontrolled hypertension, with systolic blood pressure ≥150mmHg or diastolic blood
pressure ≥100mmHg after optimal medical treatment, history of hypertensive crisis or
hypertensive encephalopathy.
- Presence of any toxicity caused by previous treatment that has not recovered to
grade 0 or 1 according to the National Cancer Institute Common Terminology Criteria
for Adverse Events version 5.0 (NCI CTCAE 5.0) before the first dose of study
treatment (excluding alopecia, non-clinically significant and asymptomatic
laboratory abnormalities).
- Symptomatic congestive heart failure (New York Heart Association class II-IV), left
ventricular ejection fraction (LVEF) <50% as indicated by echocardiography.
- Symptomatic or poorly controlled arrhythmia. History of congenital long QT syndrome
or corrected QTc >500 ms (calculated using the Fridericia formula) at screening.
- Severe bleeding tendency or coagulation disorder, or currently receiving
thrombolytic therapy.
- History of gastrointestinal perforation and/or fistula, intestinal obstruction
(including incomplete intestinal obstruction requiring parenteral nutrition),
extensive intestinal resection (partial colectomy or extensive small bowel resection
with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea
within the past 6 months.
- Received radiotherapy within 3 weeks prior to the first dose of study treatment. For
patients who received radiotherapy more than 3 weeks prior to the first dose of
study treatment, all of the following conditions must be met for inclusion: no
current radiation-related toxicities, no need for corticosteroids, and exclusion of
radiation pneumonitis, radiation hepatitis, radiation enteritis, etc.
- History or current diagnosis of pulmonary fibrosis, interstitial pneumonia,
pneumoconiosis, drug-related pneumonia, severe impairment of lung function, and
other lung diseases.
- Active pulmonary tuberculosis, currently receiving anti-tuberculosis treatment, or
received anti-tuberculosis treatment within 1 year prior to the first dose.
- Infection with human immunodeficiency virus (HIV) (HIV 1/2 antibody positive), known
syphilis infection requiring treatment.
- Active or clinically uncontrolled severe infection. Severe infection within 4 weeks
prior to the first dose, including but not limited to hospitalization for
complications of infection, sepsis, or severe pneumonia.
- Active autoimmune disease requiring systemic treatment (such as disease-modifying
drugs, corticosteroids, or immunosuppressants) within 2 years prior to the first
dose. Replacement therapy (such as thyroxine, insulin, or physiological
corticosteroids for adrenal or pituitary insufficiency, etc.) is allowed. History of
primary immunodeficiency. Patients with only autoantibody positivity need to be
confirmed by the investigator whether there is an autoimmune disease.
- Use of immunosuppressive drugs within 4 weeks prior to the first dose, excluding
intranasal, inhaled, or other local corticosteroids or physiological doses of
systemic corticosteroids (i.e., no more than 10mg/day prednisone or equivalent doses
of other corticosteroids). Temporary use of corticosteroids for the treatment of
dyspnea symptoms due to allergies or diseases such as asthma, chronic obstructive
pulmonary disease, etc., is allowed.
- Received a live attenuated vaccine within 4 weeks prior to the first dose or planned
to receive one during the study period.
- Major surgery (craniotomy, thoracotomy, or laparotomy) or unhealed wound, ulcer, or
fracture within 4 weeks prior to the first dose. Minor surgical procedures or tissue
biopsy within 7 days prior to the first dose, excluding venous puncture for the
purpose of intravenous infusion, are excluded.
- Local treatment for hepatocellular carcinoma within 4 weeks prior to the first dose.
- Use of traditional Chinese medicine with anti-tumor indications or drugs with
immunomodulatory effects (including thymosin, interferon, interleukin, etc., except
for local use to control pleural effusion or ascites, etc.) within 2 weeks prior to
the first dose.
- Other acute or chronic diseases, mental illnesses, or laboratory test abnormalities
that may result in increased medical risk and/or uncertainty in survival assessment,
or other conditions deemed by the investigator to be unsuitable for inclusion in the
study.
- Diagnosis of other malignant tumors within 5 years prior to the first dose,
excluding basal cell carcinoma of the skin, squamous cell carcinoma of the skin,
and/or in situ carcinoma that has been radically resected. If other malignant tumors
were diagnosed more than 5 years prior to the first dose, even if the liver lesions
meet the clinical diagnostic criteria for hepatocellular carcinoma of the American
Association for the Study of Liver Diseases (AASLD), pathological or cytological
diagnosis of the liver lesions must be confirmed to be hepatocellular carcinoma for
inclusion.
- Previous treatment with any anti-PD-1 antibody, anti-PD-L1/L2 antibody, anti-CTLA-4
antibody, or other immunotherapy. Previous treatment with targeted therapy against
VEGF and/or VEGFR, RAF, MEK, PDGFR, FGFR, etc.
- Known allergy to any component of oxaliplatin, 5-fluorouracil, calcium folinate,
lenvatinib, or cadonilimab; or severe allergic reaction to other monoclonal
antibodies in the past.
- Patients diagnosed with aortic dissection aneurysm, celiac trunk and superior
mesenteric artery dissection aneurysm.
- Received treatment in other clinical trials within 4 weeks prior to the first dose.
- Pregnant or breastfeeding women.
- Patients with systemic multiple metastases, portal vein tumor thrombus involving the
superior mesenteric vein, inferior vena cava tumor thrombus extending above the
diaphragm or reaching the right atrium.
- Other acute or chronic diseases, mental illnesses, or laboratory test abnormalities
that may result in the following outcomes: increased risk associated with study
participation or study drug administration, or interference with the interpretation
of study results, and other conditions that make the patient ineligible to
participate in the study based on the judgement of the investigators.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Address:
City:
Wuhan
Zip:
430030
Country:
China
Status:
Recruiting
Contact:
Last name:
Ze-yang Ding, M.D.
Phone:
+8613407156200
Email:
zyding@tjh.tjmu.edu.cn
Contact backup:
Last name:
Han Gao
Phone:
+8617730117747
Email:
gh1023606887@163.com
Start date:
December 7, 2023
Completion date:
June 30, 2027
Lead sponsor:
Agency:
Tongji Hospital
Agency class:
Other
Collaborator:
Agency:
Akesobio
Agency class:
Other
Source:
Tongji Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06187961
