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Bile Duct Cancer

Intrahepatic Cholangiocarcinoma

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Gemcitabine

Oxaliplatin

Antibodies

Lenvatinib

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1. Gemox chemotherapy Day1 oxaliplatin 85mg/m2+ gemcitabine 1g/m2, Day8 gemcitabine 1g/m2 Three weeks is a course of treatment with a total of 6 courses.
2. Lenvatinib (8mg/d), continuous use for 1 year.
3. PD-1 antibody (JS001) (240mg every 3 weeks), continuous use for 1 year.

combined therapy using oxaliplatin and gemcitabine chemotherapy, Lenvatinib and PD1 antibody (JS001)

Jian Zhou, MD&PhD

In this phase 2 study, the investigators aim to evaluate the effects and safety of combined therapy using oxaliplatin and gemcitabine chemotherapy, Lenvatinib and immune checkpoint inhibitor PD-1 antibody (JS001) for patients with advanced and unresectable intrahepatic cholangiocarcinoma

Most intrahepatic cholangiocarcinoma (ICC) patients are often accompanied by local or distant metastases and lose the opportunity for surgical resection. For patients with unresectable ICC who have been in stages IIIb and IV (AJCC/UICC, V2, 2018), the survival time is less than 4 months, and there is currently no standard treatment. The Gemox chemotherapy (oxaliplatin + gemcitabine) has been used in the treatment of advanced intrahepatic cholangiocarcinoma, but the efficacy is still unsatisfactory. Lenvatinib is a small molecule multi-kinase inhibitor, the main targets including VEGFR1-3, fibroblast growth factor receptor 1-4, PDGFRα, RET(ret proto-oncogene ), KIT(KIT proto-oncogene, receptor tyrosine kinase), have anti-angiogenic effects, have been proven effective in hepatocellular carcinoma. In recent years, monoclonal antibodies against programmed cell death protein 1 (PD1) have shown remarkable therapeutic effects in the treatment of various solid tumors. Combined with other means such as chemotherapy and targeted drugs is an important direction to improve the therapeutic effect of immunological checkpoint inhibitors. In this study, the investigators aim to evaluate the effects and safety of Gemox chemotherapy combined with Lenvatinib and immune checkpoint inhibitor PD-1 antibody (JS001) for patients with advanced and unresectable intrahepatic cholangiocarcinoma.

Combined Therapy Using Oxaliplatin and Gemcitabine Chemotherapy, Lenvatinib and PD1 Antibody (JS001) for Patients With Advanced and Unresectable Intrahepatic Cholangiocarcinoma

a Single-arm Study of Combined Therapy Using Oxaliplatin and Gemcitabine Chemotherapy, Lenvatinib and Programmed Cell Death Protein 1 Antibody (JS001) for Patients With Advanced and Unresectable Intrahepatic Cholangiocarcinoma

Objective response rate of advanced and unresectable intrahepatic cholangiocarcinoma in combination therapy

From the beginning date of combined therapy to the date of death

From the beginning date of combined therapy to the date of disease progression

Shanghai Zhongshan Hospital

Recurrence

Disease Attributes

Capecitabine

Tin Fluorides

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

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.

PD1 antibody (Toripalimab) combined with GEMOX chemotherapy and Lenvatinib neoadjuvant treatment

neoadjuvant treatment

xiao-yong Huang, MD

Guo-ming Shi, MD

Xiao-yong Huang, MD

Guo-Ming Shi

Jia Fan, MD&PhD

Jia Fan, MD & PhD

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).

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.

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

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

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.

the time period from the randomization of the patient to the death event due to any reason

The proportion of patients whose tumor volume has decreased to a predetermined value

the ratio of the estimated active tumor size divided by the tumor bed size

the severity of adverse events will be evaluated according to the NCI CTCAE 5.0 standard

Xuhui Central Hospital, Shanghai

Minhang Hospital, Fudan University

Shanghai Jinshan Hospital

Shenzhen University General Hospital

1. Toripalimab: 240 mg, intravenous infusion, Q3W;
2. Lenvatinib: 8mg (body weight \<60kg) or 12mg (body weight ≥60kg), qd;

1. Lenvatinib: 8mg (body weight \<60kg) or 12mg (body weight ≥60kg), qd
2. Gemox chemotherapy D1: Oxaliplatin 85mg / m2, Gemcitabine 1g / m2 D8: Gemcitabine 1g / m2 Three weeks are a course, a total of 6-8 courses

Lenvatinib combined with gemox

Toripalimab combined with lenvatinib

Jian Zhou, MD & PhD

We aim to explore the effects and safety of the two cohorts of toripalimab combined with lenvatinib or gemox combined with lenvatinib as first-line therapy in advanced or unresectable intrahepatic cholangiocarcinoma

For advanced intrahepatic cholangiocarcinoma (ICC) that cannot be surgically removed or accompanied by metastasis, the NCCN guidelines (NCCN guidelines hepatobiliary cancer, 2019) recommend that the current treatment options are limited, mainly recommending gemcitabine combined with platinum-based antitumor drugs (cisplatin, oxaliplatin, etc.) chemotherapy as first-line treatment. Adding targeted drugs can enhance the anti-tumor effect. For those with microsatellite instability, it is recommended to add anti-PD1(programmed cell death protein 1) antibody. Gemox chemotherapy (oxaliplatin + gemcitabine) has been used in the treatment of advanced intrahepatic cholangiocarcinoma, but the efficacy is still not satisfactory. Lenvatinib is a small-molecule multi-kinase inhibitor that is currently approved for first-line treatment of advanced hepatocellular carcinoma. In recent years, the anti-PD1 antibody has shown efficacy in the treatment of primary liver cancer. Lenvatinib combined with anti-PD1 antibody or chemotherapy may have a better effect than single use for advanced ICC. At present, lenvatinib combined with anti-PD1 antibody or lenvatinib combined with Gemox in the first-line treatment of advanced ICC has not been reported.

Arm1: toripalimab combined with lenvatinib， Arm 2: lenvatinib combined with Gemox

Two-cohort Study of Toripalimab(PD1)+Lenvatnib, or Gemox+Lenvatinib in Advanced Intrahepatic Cholangiocarcinoma

A Randomized, Open, Two-cohort Phase 2 Study of Toripalimab(PD1) Combined With Lenvatnib, or Gemox Chemotherapy Combined With Lenvatinib as First-line Therapy in Patients With Advanced or Unresectable Intrahepatic Cholangiocarcinoma

Objective response rate of advanced and unresectable intrahepatic cholangiocarcinoma

From the beginning date of combined therapy to disease progression or death, whichever occurs first.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Combined Therapy Using Oxaliplatin and Gemcitabine Chemotherapy, Lenvatinib and PD1 Antibody (JS001) for Patients With Advanced and Unresectable Intrahepatic Cholangiocarcinoma	NCT03951597	Cholangiocarcin...	combined therap...	18 Years - 75 Years	Shanghai Zhongshan Hospital
PD1 Antibody (Toripalimab), GEMOX and Lenvatinib Neoadjuvant Treatment for Resectable Intrahepatic Cholangiocarcinoma With High-risk Recurrence Factors	NCT04506281	Cholangiocarcin...	neoadjuvant tre...	18 Years - 70 Years	Shanghai Zhongshan Hospital
PD1 Antibody (Toripalimab), GEMOX and Lenvatinib Neoadjuvant Treatment for Resectable Intrahepatic Cholangiocarcinoma With High-risk Recurrence Factors	NCT04506281	Cholangiocarcin...	neoadjuvant tre...	18 Years - 70 Years	Shanghai Zhongshan Hospital
PD1 Antibody (Toripalimab), GEMOX and Lenvatinib Neoadjuvant Treatment for Resectable Intrahepatic Cholangiocarcinoma With High-risk Recurrence Factors	NCT04506281	Cholangiocarcin...	neoadjuvant tre...	18 Years - 70 Years	Shanghai Zhongshan Hospital
Two-cohort Study of Toripalimab(PD1)+Lenvatnib, or Gemox+Lenvatinib in Advanced Intrahepatic Cholangiocarcinoma	NCT04361331	Cholangiocarcin...	Lenvatinib comb... Toripalimab com...	18 Years - 75 Years	Shanghai Zhongshan Hospital
Combined Therapy Using Oxaliplatin and Gemcitabine Chemotherapy, Lenvatinib and PD1 Antibody (JS001) for Patients With Advanced and Unresectable Intrahepatic Cholangiocarcinoma	NCT03951597	Cholangiocarcin...	combined therap...	18 Years - 75 Years	Shanghai Zhongshan Hospital
PD1 Antibody (Toripalimab), GEMOX and Lenvatinib Neoadjuvant Treatment for Resectable Intrahepatic Cholangiocarcinoma With High-risk Recurrence Factors	NCT04506281	Cholangiocarcin...	neoadjuvant tre...	18 Years - 70 Years	Shanghai Zhongshan Hospital

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