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

August 7, 2020 updated by: Shanghai Zhongshan Hospital

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

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).

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

128

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • China
    • Shanghai
      • Shanghai, Shanghai, China, 200032
        • Recruiting
        • Zhongshan hospital
        • Contact:
        • Principal Investigator:
          • Jia Fan, MD&PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 68 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Neoadjuvant treatment

  1. 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.

  2. Lenvatinib (8mg/d) for 9 weeks of continuous use.
  3. 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
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 undergoing resection use capecitabine 2500mg/m2 twice a day, stopping for 1 week as a course of treatment, totaling 8 courses.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Event-free survival
Time Frame: 18 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.
18 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival
Time Frame: 24 months
the time period from the randomization of the patient to the death event due to any reason
24 months
Objective response rate
Time Frame: 6 months
The proportion of patients whose tumor volume has decreased to a predetermined value
6 months
Pathological remission rate
Time Frame: 6 months
the ratio of the estimated active tumor size divided by the tumor bed size
6 months
Adverse events
Time Frame: 12 months
the severity of adverse events will be evaluated according to the NCI CTCAE 5.0 standard
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Shanghai Zhongshan Hospital

Collaborators

Shenzhen University General Hospital
Xuhui Central Hospital, Shanghai
Minhang Hospital, Fudan University
Shanghai Jinshan Hospital

Investigators

  • Study Chair: Jia Fan, MD & PhD, Shanghai Zhongshan Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

August 10, 2020

Primary Completion (Anticipated)

August 1, 2021

Study Completion (Anticipated)

August 1, 2023

Study Registration Dates

First Submitted

August 7, 2020

First Submitted That Met QC Criteria

August 7, 2020

First Posted (Actual)

August 10, 2020

Study Record Updates

Last Update Posted (Actual)

August 10, 2020

Last Update Submitted That Met QC Criteria

August 7, 2020

Last Verified

August 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • zs-ICC-neoadjuvant

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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