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PD1 Antibody (Toripalimab), GEMOX and Lenvatinib Neoadjuvant Treatment for Resectable Intrahepatic Cholangiocarcinoma With High-risk Recurrence Factors

Primary Purpose

Cholangiocarcinoma, Intrahepatic

Status
Unknown status
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
neoadjuvant treatment
Sponsored by
Shanghai Zhongshan Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cholangiocarcinoma, Intrahepatic focused on measuring intrahepatic Cholangiocarcinoma, Lenvatinib, Gemox chemotherapy, Programmed cell death protein 1 antibody

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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>200U/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.

Sites / Locations

  • Zhongshan hospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Neoadjuvant treatment

Traditional group

Arm Description

Gemox chemotherapy: Day1 Oxaliplatin 85mg/m2+ gemcitabine 1g/m2, Day 8 gemcitabine 1g/m2 Three weeks is a course of treatment, a total of 3 courses. Lenvatinib (8mg/d) for 9 weeks of continuous use. Toripalimab (240mg, once every 3 weeks), used 3 times. Evaluate the resectability of the operation within 2-4 weeks after the end of the neoadjuvant treatment course, and implement radical resection. All patients after resection use capecitabine 2500mg/m2 twice a day for 2 weeks, stopping for 1 week as a course of treatment, totaling 8 courses

No anti-tumor drug treatment before surgery. All patients undergoing resection use capecitabine 2500mg/m2 twice a day, stopping for 1 week as a course of treatment, totaling 8 courses.

Outcomes

Primary Outcome Measures

Event-free survival
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

Overall survival
the time period from the randomization of the patient to the death event due to any reason
Objective response rate
The proportion of patients whose tumor volume has decreased to a predetermined value
Pathological remission rate
the ratio of the estimated active tumor size divided by the tumor bed size
Adverse events
the severity of adverse events will be evaluated according to the NCI CTCAE 5.0 standard

Full Information

First Posted
August 7, 2020
Last Updated
August 7, 2020
Sponsor
Shanghai Zhongshan Hospital
Collaborators
Xuhui Central Hospital, Shanghai, Minhang Hospital, Fudan University, Shanghai Jinshan Hospital, Shenzhen University General Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04506281
Brief Title
PD1 Antibody (Toripalimab), GEMOX and Lenvatinib Neoadjuvant Treatment for Resectable Intrahepatic Cholangiocarcinoma With High-risk Recurrence Factors
Official Title
A Randomized Controlled, Multicenter, Open-label, Phase II Clinical Study of PD1 Antibody (Toripalimab) Combined With GEMOX Chemotherapy and Lenvatinib Neoadjuvant Treatment for Resectable Intrahepatic Cholangiocarcinoma With High-risk Recurrence Factors
Study Type
Interventional

2. Study Status

Record Verification Date
August 2020
Overall Recruitment Status
Unknown status
Study Start Date
August 10, 2020 (Anticipated)
Primary Completion Date
August 2021 (Anticipated)
Study Completion Date
August 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Shanghai Zhongshan Hospital
Collaborators
Xuhui Central Hospital, Shanghai, Minhang Hospital, Fudan University, Shanghai Jinshan Hospital, Shenzhen University General Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
A randomized controlled, multi-center, open, phase II clinical study 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 Lenvatinib and GEMOX neoadjuvant treatment and the current clinical surgical treatment (traditional group).
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 gradually increasing trend. Surgical resection is currently the main method for the treatment of ICC. The data of a large number of ICC cases show 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cholangiocarcinoma, Intrahepatic
Keywords
intrahepatic Cholangiocarcinoma, Lenvatinib, Gemox chemotherapy, Programmed cell death protein 1 antibody

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
128 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Neoadjuvant treatment
Arm Type
Experimental
Arm Description
Gemox chemotherapy: Day1 Oxaliplatin 85mg/m2+ gemcitabine 1g/m2, Day 8 gemcitabine 1g/m2 Three weeks is a course of treatment, a total of 3 courses. Lenvatinib (8mg/d) for 9 weeks of continuous use. Toripalimab (240mg, once every 3 weeks), used 3 times. Evaluate the resectability of the operation within 2-4 weeks after the end of the neoadjuvant treatment course, and implement radical resection. All patients after resection use capecitabine 2500mg/m2 twice a day for 2 weeks, stopping for 1 week as a course of treatment, totaling 8 courses
Arm Title
Traditional group
Arm Type
No Intervention
Arm Description
No anti-tumor drug treatment before surgery. All patients undergoing resection use capecitabine 2500mg/m2 twice a day, stopping for 1 week as a course of treatment, totaling 8 courses.
Intervention Type
Drug
Intervention Name(s)
neoadjuvant treatment
Intervention Description
PD1 antibody (Toripalimab) combined with GEMOX chemotherapy and Lenvatinib neoadjuvant treatment
Primary Outcome Measure Information:
Title
Event-free survival
Description
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.
Time Frame
18 months
Secondary Outcome Measure Information:
Title
Overall survival
Description
the time period from the randomization of the patient to the death event due to any reason
Time Frame
24 months
Title
Objective response rate
Description
The proportion of patients whose tumor volume has decreased to a predetermined value
Time Frame
6 months
Title
Pathological remission rate
Description
the ratio of the estimated active tumor size divided by the tumor bed size
Time Frame
6 months
Title
Adverse events
Description
the severity of adverse events will be evaluated according to the NCI CTCAE 5.0 standard
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility 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>200U/ml); 6) The functional indicators of important organs meet the following requirements Neutrophils≥1.5*109/L; platelets≥90*109/L; hemoglobin≥9g/dl; serum albumin≥3.5g/dl; Coagulation function: International standardization (prothrombin time) ratio (INR) <1.2; T3 and T4 do not exceed the normal upper and lower limits by 2 times; Bilirubin ≤ 1.5 times the upper limit of normal; ALT and AST ≤ 3 times the upper limit of normal; 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
xiao-yong Huang, MD
Phone
+8615021519215
Email
huang.xiaoyong@zs-hospital.sh.cn
First Name & Middle Initial & Last Name or Official Title & Degree
Guo-ming Shi, MD
Phone
+8613916969578
Email
shi.guoming@zs-hospital.sh.cn
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jia Fan, MD & PhD
Organizational Affiliation
Shanghai Zhongshan Hospital
Official's Role
Study Chair
Facility Information:
Facility Name
Zhongshan hospital
City
Shanghai
State/Province
Shanghai
ZIP/Postal Code
200032
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Xiao-yong Huang, MD
Phone
+8615021519215
Email
huang.xiaoyong@zs-hospital.sh.cn
First Name & Middle Initial & Last Name & Degree
Guo-Ming Shi
Phone
+8613916969578
Email
shi.guoming@zs-hospital.sh.cn
First Name & Middle Initial & Last Name & Degree
Jia Fan, MD&PhD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
15192785
Citation
Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis. 2004 May;24(2):115-25. doi: 10.1055/s-2004-828889.
Results Reference
result
PubMed Identifier
20014463
Citation
Shen WF, Zhong W, Xu F, Kan T, Geng L, Xie F, Sui CJ, Yang JM. Clinicopathological and prognostic analysis of 429 patients with intrahepatic cholangiocarcinoma. World J Gastroenterol. 2009 Dec 21;15(47):5976-82. doi: 10.3748/wjg.15.5976.
Results Reference
result
PubMed Identifier
20165987
Citation
Cho SY, Park SJ, Kim SH, Han SS, Kim YK, Lee KW, Lee SA, Hong EK, Lee WJ, Woo SM. Survival analysis of intrahepatic cholangiocarcinoma after resection. Ann Surg Oncol. 2010 Jul;17(7):1823-30. doi: 10.1245/s10434-010-0938-y. Epub 2010 Feb 18.
Results Reference
result
PubMed Identifier
22762399
Citation
Fisher SB, Patel SH, Kooby DA, Weber S, Bloomston M, Cho C, Hatzaras I, Schmidt C, Winslow E, Staley CA 3rd, Maithel SK. Lymphovascular and perineural invasion as selection criteria for adjuvant therapy in intrahepatic cholangiocarcinoma: a multi-institution analysis. HPB (Oxford). 2012 Aug;14(8):514-22. doi: 10.1111/j.1477-2574.2012.00489.x. Epub 2012 May 22.
Results Reference
result
PubMed Identifier
18751418
Citation
Yamashita Y, Taketomi A, Morita K, Fukuhara T, Ueda S, Sanefuji K, Iguchi T, Kayashima H, Sugimachi K, Maehara Y. The impact of surgical treatment and poor prognostic factors for patients with intrahepatic cholangiocarcinoma: retrospective analysis of 60 patients. Anticancer Res. 2008 Jul-Aug;28(4C):2353-9.
Results Reference
result

Learn more about this trial

PD1 Antibody (Toripalimab), GEMOX and Lenvatinib Neoadjuvant Treatment for Resectable Intrahepatic Cholangiocarcinoma With High-risk Recurrence Factors

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