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Phase II-III Clinical Trial of PD1 Antibody (Toripalimab), Lenvatinib and GEMOX Neoadjuvant Treatment for Resectable Intrahepatic Cholangiocarcinoma With High-risk Recurrence Factors

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ClinicalTrials.gov Identifier: NCT04669496
Recruitment Status : Recruiting
First Posted : December 16, 2020
Last Update Posted : July 7, 2021
Sponsor:
Collaborators:
Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
Shanghai 6th People's Hospital
Shanghai Public Health Clinical Center
RenJi Hospital
Shenzhen University General Hospital
Information provided by (Responsible Party):
Shanghai Zhongshan Hospital

Brief Summary:
A randomized controlled, multicenter, open, seamless phase II-III clinical trial is designed to target patients with resectable intrahepatic cholangiocarcinoma with high-risk recurrence factors which has extremely low postoperative recurrence-free survival. In this study, we aim to compare the prognosis in intrahepatic cholangiocarcinoma between Toripalimab combined with leventinib and GEMOX neoadjuvant treatment and the current clinical surgical treatment (traditional group).

Condition or disease Intervention/treatment Phase
Intrahepatic Cholangiocarcinoma PD1 Antibody Lenvatinib Gemox Chemotherapy Drug: Neoadjuvant treatment Phase 2 Phase 3

Detailed Description:
Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor of biliary epithelial cells that originates from the branches of the intrahepatic bile duct at the second level and above. Its incidence accounts for about 15%-20% of primary liver malignancies, showing a gradual increase trend. Surgical resection is currently the main method for the treatment of ICC. The data of a large number of ICC cases shows that even radical resection (R0) patients have an average survival of only 18.3 months, while for palliative resection patients, the average survival is only 6.6 months, and laparotomy patients only 5.6 months. Retrospective studies reported that positive resection margins, lymph node metastasis, lymphatic vessel invasion, nerve bundle invasion, preoperative CA199>200U/ml, multiple tumor nodules and differentiation are the main factors affecting the survival of ICC patients after surgery. How to improve the surgical results of ICC patients, especially those with high risk factors for postoperative recurrence, is an important way to improve the overall survival of ICC. Neoadjuvant therapy refers to some treatments taken before surgery for newly treated tumor patients who have not found distant metastasis, including chemotherapy, radiotherapy, targeted therapy, etc., to reduce tumors, reduce tumor stages, and reduce postoperative recurrence rate, prolonging survival time. Our previous study using Toripalimab combined with lenvatinib and Gemox chemotherapy in the first-line treatment of unresectable advanced cholangiocarcinoma (NCT03951597,2020ESMO) showed that the ORR was 80% and the DCR reached 93.3%, of which 1 case was CR, 23 cases were PR, and 2 cases were successfully treated with radical resection after downstage. And the adverse reactions are controllable. These data suggest that Toripalimab combined with lenvatinib and Gemox chemotherapy may be an ideal neoadjuvant treatment for patients with resectable intrahepatic cholangiocarcinoma with high-risk recurrence factors, needing more investigation.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 178 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Controlled, Multicenter, Open, Seamless Phase II-III Clinical Trial of PD1 Antibody (Toripalimab), Lenvatinib and GEMOX Neoadjuvant Treatment for Resectable Intrahepatic Cholangiocarcinoma With High-risk Recurrence Factors
Actual Study Start Date : January 20, 2021
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2024


Arm Intervention/treatment
Experimental: Neoadjuvant treatment
  1. Gemox chemotherapy D1 Oxaliplatin 85mg/m2+ gemcitabine 1g/m2, D8 gemcitabine 1g/m2 Three weeks is a course of treatment, a total of 3 courses.
  2. Lenvatinib (8mg/d) for 9 weeks of continuous use.
  3. Toripalimab (240 mg, once every 3 weeks), used 3 times in a row. All patients undergoing resection use capecitabine 2500mg/m2 twice a day for 2 weeks, stopping for 1 week as a course of treatment, totaling 8 courses.
Drug: Neoadjuvant treatment
PD1 antibody (Toripalimab) combined with GEMOX chemotherapy and Lenvatinib neoadjuvant treatment

No Intervention: Traditional group
No anti-tumor drug treatment before surgery. All patients after resection use capecitabine 2500mg/m2 twice a day for 2 weeks, stopping for 1 week as a course of treatment, a total of 8 courses.



Primary Outcome Measures :
  1. Event-free survival [ Time Frame: 24 months ]
    From randomization to the occurrence of the following events: disease progression prevents radical surgery; local or distant recurrence; second primary tumor; death due to various causes.


Secondary Outcome Measures :
  1. Overall survival [ Time Frame: 24 months ]
    the time period from the randomization of the patient to the death event due to any reason

  2. Objective response rate [ Time Frame: 6 months ]
    The proportion of patients whose tumor volume has decreased to a predetermined value

  3. Pathological remission rate [ Time Frame: 6 months ]
    the ratio of the estimated active tumor size divided by the tumor bed size

  4. Adverse events [ Time Frame: 12 months ]
    the severity of adverse events will be evaluated according to the NCI CTCAE 5.0 standard


Other Outcome Measures:
  1. Exploratory markers [ Time Frame: 24 months ]
    the relationship between treatment response and clinical factors: carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), carbohydrate antigen 125 (CA125), tumor mutation burden (TMB), PD-L1 expression, microsatellite instability (MSI), dynamic changes of PET-CT Standard uptake value, dynamic changes of contrast Ultrasound and MRI



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 1) Sign written informed consent 2) Male or female patients aged 18-70; 3) ECOG score 0 points, Child-Pugh rating A; 4) Clinically diagnosed as ICC as a potential entry, the neoadjuvant group must be histopathologically diagnosed as intrahepatic cholangiocarcinoma before neoadjuvant, and the traditional group must be pathologically confirmed as intrahepatic cholangiocarcinoma after surgery; 5) Resectable ICC patients with high risk factors for recurrence (tumor diameter>5cm or imaging vascular invasion, multiple tumor nodules or hilar lymph node metastasis or preoperative CA199>37U/ml); 6) The functional indicators of important organs meet the following requirements

    1. Neutrophils≥1.5*109/L; platelets≥90*109/L; hemoglobin≥9g/dl; serum albumin≥3.5g/dl;
    2. Coagulation function: International standardization (prothrombin time) ratio (INR) <1.2;
    3. T3 and T4 do not exceed the normal upper and lower limits by 2 times;
    4. Bilirubin ≤ 1.5 times the upper limit of normal; ALT and AST ≤ 3 times the upper limit of normal;
    5. Serum creatinine ≤ 1.5 times the upper limit of normal, creatinine clearance ≥ 60ml/min; 7) The subject has at least 1 measurable liver disease (according to RECIST1.1); 8) For women who are not breastfeeding or pregnant, use contraception during treatment or 3 months after the end of treatment.

Exclusion Criteria:

  • 1) Pathological diagnosis of hepatocellular carcinoma, mixed hepatocellular carcinoma and other non-biliary cell carcinoma malignant tumor components; 2) Patients who relapse after surgery, have received PD1 antibody, PDL1 antibody or CTLA4 antibody, lenvatinib, chemotherapy in the past; participated in other clinical trials 30 days before screening; 3) Past or simultaneous suffering from other malignant tumors, except for fully treated non-melanoma skin cancer, cervical carcinoma in situ and thyroid papillary carcinoma; 4) Active tuberculosis infection. Patients with active tuberculosis infection within 1 year before enrollment; a history of active tuberculosis infection more than 1 year before enrollment, no formal anti-tuberculosis treatment or tuberculosis is still active; 5) Suffer from active, known or suspected autoimmune diseases. Subjects with hypothyroidism who only need hormone replacement therapy and skin diseases without systemic therapy can be selected; 6) Past interstitial lung disease, or (non-infectious) pneumonia and need oral or intravenous steroid therapy; 7) Long-term use of systemic hormones (dose equivalent to >10mg prednisone/day) or any other form of immunosuppressive therapy is required. Subjects using inhaled or topical corticosteroids can be selected; 8) Active infections that require systemic treatment; 9) Human immunodeficiency virus (HIV, HIV1/2 antibody) positive; 10) A history of psychotropic drug abuse, alcohol or drug abuse; 11) Significant clinically significant bleeding symptoms or a clear tendency to appear within 3 months before enrollment; 12) Suspected of being allergic to study drugs; 13) Suffer from hypertension, and cannot be well controlled by antihypertensive medication (systolic blood pressure ≥140mmHg or diastolic blood pressure ≥90mmHg); 14) After antiviral therapy, HBvDNA>104 copies/ml, HCV RNA>1000; 15) Accompanied by ascites, hepatic encephalopathy, Gilbert syndrome, sclerosing cholangitis, etc. Combined with insufficiency of other organs, it is expected that they cannot accept general anesthesia or hepatectomy; 16) Other factors judged by the investigator that may affect the safety of the subject or the compliance of the trial. Such as serious illnesses (including mental illness) that require combined treatment, serious laboratory abnormalities, or other family or social factors.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04669496


Contacts
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Contact: Xiao-yong Huang, MD +8615021519215 huang.xiaoyong@zs-hospital.sh.cn
Contact: Guo-ming Shi, MD +8613916969578 shi.guoming@zs-hospital.sh.cn

Locations
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China, Shanghai
Zhongshan hospital Recruiting
Shanghai, Shanghai, China, 200032
Contact: xiao-yong Huang, MD    +8615021519215    huang.xiaoyong@zs-hospital.sh.cn   
Contact: Guo-Ming Shi, MD    +8613916969578    shi.guoming@zs-hospital.sh.cn   
Principal Investigator: Jia Fan, MD&PhD         
Sponsors and Collaborators
Shanghai Zhongshan Hospital
Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
Shanghai 6th People's Hospital
Shanghai Public Health Clinical Center
RenJi Hospital
Shenzhen University General Hospital
Investigators
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Study Chair: Jia Fan, MD & PhD Shanghai Zhongshan Hospital
Publications:
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Responsible Party: Shanghai Zhongshan Hospital
ClinicalTrials.gov Identifier: NCT04669496    
Other Study ID Numbers: ZS--ICC-NA
First Posted: December 16, 2020    Key Record Dates
Last Update Posted: July 7, 2021
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Cholangiocarcinoma
Recurrence
Disease Attributes
Pathologic Processes
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms