DEB-TACE, Lenvatinib and Anti-PD(L)1 Antibody as Conversion Therapy for Intrahepatic Cholangiocarcinoma (CCGLC-009)

Combination of Transcatheter Arterial Chemoembolization With Drug-eluting Beads, Lenvatinib and Anti-PD(L)1 Antibody for Downstaging Intrahepatic Cholangiocarcinoma for Radical Surgical Treatment

The aim of this study is to the efficacy, prognosis, adverse effects, and factors for predicting therapeutic effects and clinical prognosis of combined therapy of Drug-eluting Beads-transarterial chemoembolization (DEB-TACE), lenvatinib, and anti-PD-1/ PD-L1 antibody for patients with advanced intrahepatic cholangiocarcinoma who were initially unsuitable for the radical therapy, including resection, transplantation, or ablation.

Study Overview

• Status: Recruiting
• Conditions: Cholangiocarcinoma Non-resectable
• Intervention / Treatment: Procedure: drug eluting beads-transcatheter arterial chemoembolization; Drug: envatinib plus anti-PD(L)1

Detailed Description

The multicenter, non-random, open and prospective real-world cohort study is conducted at 4 research centers, including 3 centers (Hankou, Sino-French New District, and Optical Valley) of Tongji hospital (Wuhan, China) and one in the second affiliated hospital of Fujian Medical University (Quanzhou, China). It is estimated that 100 patients with advanced intrahepatic cholangiocarcinoma will be enrolled in these 4 research centers. And it is planned to complete the enrollment within 2 year and it is expected that all enrolled subjects will reach the observation end point in 3 years. Radiological assessments are performed every two cycles over the course of treatment, then every 3 months within the first two years following the completion of treatment and every 6 months thereafter, until PD were recorded. All subjects are followed until death or lost to follow up.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Ze-yang Ding, M.D.; Phone Number: +8613407156200; Email: zyding@tjh.tjmu.edu.cn
• Study Contact Backup: Name: Han Gao; Phone Number: +8617730117747; Email: gh1023606887@163.com

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430030
      • Recruiting
      • Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
      • Contact: Ze-yang Ding, M.D.; Phone Number: +8613407156200; Email: zyding@tjh.tjmu.edu.cn
      • Contact: Han Gao; Phone Number: +8617730117747; Email: gh1023606887@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

patients with unresectable intrahepatic cholangiocarcinoma.

Description

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.

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.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

DEB-TACE-len-anti-PD(L)1; Patients with advanced intrahepatic cholangiocarcinoma who was initially evaluated unsuitable for the radical therapy and received combined DEB-TACE plus lenvatinib (Len) and anti-PD1 or anti-PD-L1 antibodies as conversion therapy for downstaging.

Procedure: drug eluting beads-transcatheter arterial chemoembolization; transcatheter arterial chemoembolization with doxorubicin embedded eluting beads- was performed every 3 weeks through the tumor feeding arteries.; Other Names: DEB-TACE; Drug: envatinib plus anti-PD(L)1; oral use of lenvatinib plus intravenous injection of anti-PD(L)1 antibodies. Anti-PD-L1 antibodies includes duravalumab, atezolizumab, or envolizumab, and anti-PD1 antibodies include pembrolizumab, nivolumab, camrelizumab, tislelizumab, sintilimab, or toripalimab.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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]
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
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
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
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

Collaborators and Investigators

• Sponsor: Ze-yang Ding, MD
• Collaborators: Geneplus-Beijing Co. Ltd.; Chinese Cooperative Group of Liver Cancer (CCGLC)
• Investigators: Principal Investigator: Ze-yang Ding, M.D., Tongji Hospital

Publications and helpful links

General Publications

• Oh DY, Lee KH, Lee DW, Yoon J, Kim TY, Bang JH, Nam AR, Oh KS, Kim JM, Lee Y, Guthrie V, McCoon P, Li W, Wu S, Zhang Q, Rebelatto MC, Kim JW. Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study. Lancet Gastroenterol Hepatol. 2022 Jun;7(6):522-532. doi: 10.1016/S2468-1253(22)00043-7. Epub 2022 Mar 9. Erratum In: Lancet Gastroenterol Hepatol. 2023 Jun;8(6):e5.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2022
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: December 22, 2023
• First Submitted That Met QC Criteria: December 22, 2023
• First Posted (Actual): January 8, 2024

Study Record Updates

• Last Update Posted (Actual): January 9, 2024
• Last Update Submitted That Met QC Criteria: January 7, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Lenvatinib; Intrahepatic Cholangiocarcinoma; DEB-TACE; anti-PD(L)1 antibodies
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Cholangiocarcinoma
• Other Study ID Numbers: TJ-IRB20221203

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No