Combined HAIC, Lenvatinib and Pucotenlimab as Conversion Therapy for Unresectable Intrahepatic Cholangiocarcinoma

Cholangiocarcinoma Non-resectable Clinical Trial

— CCGLC-013  

Official title:

A Phase 2, Open-label, Single Arm Study of Combined HAIC, Lenvatinib and Pucotenlimab as Conversion Therapy for Unresectable Intrahepatic Cholangiocarcinoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06192797
• Other study ID #: 2023-S080
• Status: Recruiting
• Phase: Phase 2
• Start date: January 31, 2024
• Est. completion date: June 1, 2026

Study information

• Verified date: January 2024
• Source: Tongji Hospital
• Contact: Ze-yang Ding
• Phone: +8613407156200
• Email: zyding[@]tjh.tjmu.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: June 1, 2026
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Cholangiocarcinoma
• Cholangiocarcinoma Non-resectable

Intervention

Procedure:
• HAIC
administration of gemcitabine and oxaliplatin via the tumor feeding arteries every 3 weeks.

Drug:
• Lenvatinib plus pucotenlimab
lenvatinib (8mg, qd) plus pucotenlimab (200mg, q3w)

Locations

Country	Name	City	State
China	Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology	Wuhan	Hubei

Sponsors (3)

Lead Sponsor	Collaborator
Ze-yang Ding, MD	Chinese Cooperative Group of Liver Cancer (CCGLC), Geneplus-Beijing Co. Ltd.

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Patients Amendable to Curative Surgical Interventions	Number of patients amendable to curative surgical interventions defined as number of patients receiving curative surgical resection, transplantation, or ablation after successful down-sizing of tumor(s) by intervention.	from the date of first treatment to the date of last treatment, an average of 3 years
Secondary	overall response rate (ORR) measured by mRECIST criteria	Complete response (CR): Disappearance of any intra-tumoral arterial enhancement in all target lesions; Partial response (PR): At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions; Stable disease (SD): Any cases that do not qualify for either partial response or progressive disease; Progressive disease (PD): An increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started.	from the date of first treatment to radiographically documented progression according to mRECIST, assessed up to 3 years
Secondary	Overall survival (OS)	measured from date of first treatment to the date of death from any cause. Participants alive or lost to follow-up will be censored at the date of their last visit.	from the date of first treatment to the date of death from any cause, assessed up to 5 years
Secondary	Progression-free survival (PFS)	measured from the date of first treatment to radiographically documented progression according to mRECIST 1.1 or death from any cause (whichever occurs first). Participants alive and without disease progression or lost to follow-up will be censored at the date of their last radiographic assessment.	from the date of first treatment to radiographically documented progression according to mRECIST 1.1 or death from any cause, whichever occurs first, assessed up to 3 years
Secondary	Time to progression (TTP)	Time to progression (TTP): measured from the date of first treatment to radiographically documented progression according to mRECIST 1.1. This does not include death from any cause.	from the date of first treatment to radiographically documented progression according to mRECIST, assessed up to 3 years
Secondary	Time to intrahepatic tumor progression (TTITP)	Time to intrahepatic tumor progression (TTITP): measured from the date of first treatment to radiographically documented intrahepatic tumor progression according to mRECIST 1.1. This does not include death from any cause.	from the date of first treatment to radiographically documented intrahepatic tumor progression according to mRECIST, assessed up to 3 years
Secondary	Incidence of Study-Related Adverse Events	Incidence, nature, and severity of adverse events graded according to the United States National Cancer Institute The Common Terminology Criteria for Adverse Events (NCI-CTCAE 5.0)	from the date of first treatment to 90 days after last treatment, around 3 years and 90 days
Secondary	Pathological complete response (pCR)	Pathological response is assessed as the percentage of surface with non-viable cancer cells (represented by necrosis or fibrosis, the ultimate stage of necrosis) in relation to the total tumor area and will be equal to: 100% - viable cancer cells (%). If there are multiple tumors, the mean percentage will be used.	from the date of first study treatment to radiographically documented progression according to mRECIST 1.1 or death from any cause, whichever occurs first, assessed up to 5 years
Secondary	Disease control rate (DCR)	percentage of patients with CR, PR, or stable disease (SD) =6 months based on mRECIST	from the date of first treatment to radiographically documented response according to mRECIST, assessed up to 3 years
Secondary	Duration of response (DoR)	Defined as the time from first documented evidence of CR or PR until the first documented sign of disease progression (PD) or death from any cause	from the date of first documented evidence of CR or PR to first documented sign of PD or death from any cause according to mRECIST 1.1, assessed up to 3 years
Secondary	Quality of Life (QoL) after treatment	The life quality of every subject is assessed every 3 months during follow up according to the 45-item FACT-Hep questionnaire, which assesses generic HRQL concerns and disease-specific issues.	assessed form the date of first followup to radiographically documented progression or or death from any cause, up to 3 years