Trial Title:
Combined HAIC, Lenvatinib and Pucotenlimab As Conversion Therapy for Unresectable Intrahepatic Cholangiocarcinoma
NCT ID:
NCT06192797
Condition:
Cholangiocarcinoma Non-resectable
Conditions: Official terms:
Cholangiocarcinoma
Lenvatinib
Conditions: Keywords:
Intrahepatic Cholangiocarcinoma
Pucotenlimab
Lenvatinib
HAIC
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 gemcitabine and oxaliplatin via the tumor feeding arteries every 3
weeks.
Arm group label:
HAIC-len-puco
Other name:
hepatic arterial infusion chemotherapy of GEMOX
Intervention type:
Drug
Intervention name:
Lenvatinib plus pucotenlimab
Description:
lenvatinib (8mg, qd) plus pucotenlimab (200mg, q3w)
Arm group label:
HAIC-len-puco
Other name:
levima plus pucotenlimab
Summary:
This is an open-label, single-arm, phase 2 study. The purpose of study is to evaluate the
feasibility and safety of hepatic artery infusion chemotherapy combined with lenvatinib
and pucotenlimab as conversion therapy for unresectable intrahepatic cholangiocarcinoma.
Detailed description:
Pucotenlimab is a new humanized PD-1-specific monoclonal antibody. On September 29, 2022,
the National Medical Products Administration of China approved the marketing application
of Pucotenlimab Injection for the treatment of patients with microsatellite highly
unstable (MSI-H)/mismatch repair function defective (dMMR) solid tumors who have failed
prior first-line and above systemic therapy. There have been studies and reports on
systemic chemotherapy with GEMOX regimen combined with lenvatinib and PD-1 monoclonal
antibody for the treatment of intrahepatic cholangiocarcinoma. Currently, a multicenter,
phase 2 study evaluating the efficacy of pucotenlimab in patients with mismatch
repair-deficient (dMMR) or microsatellite instabilityhigh (MSI-H) tumors is underway. The
objective response rate (ORR) is 49.0% (95% CI 38.86%-59.20%), while the median
progression-free survival and overall survival have not been reached. Grade ≥3
treatment-related adverse events were observed in 18 of 100 patients. The efficacy of
this antibody in patients is promising. Based on the results of these previous studies,
this study intends to evaluate the efficacy and safety of hepatic artery infusion
chemotherapy (GEMOX regimen) combined with lenvatinib and pucotenlimab in the down-stage
conversion treatment of patients with unresectable intrahepatic cholangiocarcinoma.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Histologically confirmed intrahepatic cholangiocarcinoma.
- Age ≥18 years.
- ECOG performance status score of 0 or 1.
- Not suitable for radical surgery (including radical hepatic resection, liver
transplantation or ablation) after evaluation by the MDT expert group of treating
hepatobiliary cancer. 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 patients with cirrhosis, the volume of
normal liver parenchyma is less than 40% of the total volume, or ICG-R15>15%.
3. Number of lesions >1.
- No prior systemic anti-tumor treatment for intrahepatic cholangiocarcinoma 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 sarcomatoid intrahepatic cholangiocarcinoma,
mixed hepatocellular carcinoma, etc.
- History of hepatic encephalopathy or liver transplantation.
- Clinically symptomatic pleural effusion, ascites, or pericardial effusion requiring
drainage. Patients with only radiologically detected minimal pleural effusion,
ascites, or pericardial effusion without symptoms can be included.
- 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. Patients
who meet the above criteria after antiviral treatment with nucleoside analogs can be
included.
- Presence of central nervous system metastases.
- History of esophageal or gastric variceal bleeding due to portal hypertension within
the past 6 months. Patients 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.
- Uncontrolled/uncorrectable metabolic disorders or other non-malignant neoplastic
organ diseases or systemic diseases or secondary reactions to cancer that could
result in higher medical risk and/or uncertainty in survival evaluation, or the
presence of other conditions that, in the judgment of the investigator, make
enrollment inappropriate.
- Diagnosis of other malignancy within 5 years prior to first dose, excluding
radically treated basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, and/or radically resected carcinoma in situ. If other malignancy was diagnosed
more than 5 years prior to dosing, even if the liver lesion meets the EASL-ILCA
clinical diagnostic criteria for intrahepatic cholangiocarcinoma, the liver lesion
must still be diagnosed pathologically or cytologically and those who are
definitively intrahepatic cholangiocarcinoma may be enrolled.
- 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 pucotenlimab; 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, in the investigator's judgment, make
the patient ineligible to participate in the study.
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:
June 11, 2024
Completion date:
June 30, 2028
Lead sponsor:
Agency:
Tongji Hospital
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/NCT06192797
