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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Brief Title

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

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

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).
    

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.
    

Study Phase

Phase 2/Phase 3

Study Type

Interventional


Primary Outcome

Event-free survival

Secondary Outcome

 Overall survival

Condition

Intrahepatic Cholangiocarcinoma

Intervention

Neoadjuvant treatment

Study Arms / Comparison Groups

 Neoadjuvant treatment
Description:  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.
Lenvatinib (8mg/d) for 9 weeks of continuous use.
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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

178

Start Date

December 15, 2020

Completion Date

December 2024

Primary Completion Date

December 2022

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>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.
      

Gender

All

Ages

18 Years - 70 Years

Accepts Healthy Volunteers

No

Contacts

Jia Fan, MD & PhD, +8615021519215, [email protected]

Location Countries

China

Location Countries

China

Administrative Informations


NCT ID

NCT04669496

Organization ID

ZS--ICC-NA


Responsible Party

Sponsor

Study Sponsor

Shanghai Zhongshan Hospital

Collaborators

 Xinhua Hospital, Shanghai Jiao Tong University School of Medicine

Study Sponsor

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


Verification Date

December 2020