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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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

Conditions
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Cholangiocarcinoma, Intrahepatic

Intervention / Treatment
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* Drug: Lenvatinib combined with gemox
* Drug: Toripalimab combined with lenvatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. The patient must be required to sign an informed consent; 2. Age 18-75 years old, male or female; 3. ECOG performance status score (PS score) 0 or 1 point; 4. Child-Pugh score A; 5. Intrahepatic cholangiocarcinoma confirmed by histopathology; agree to provide previously stored tumor tissue samples or fresh biopsy tumor lesions; 6. Unresectable ICC patients or postoperative ICC recurrence and metastasis, without systematic treatment within 6 months; 7. The functional indicators of vital organs meet the following requirements Neutrophils ≥1.5 * 109 / L; platelets ≥100 * 109 / L; hemoglobin ≥9g / dl; serum albumin ≥3g/dl; Thyroid stimulating hormone (TSH) ≤ 1 times the upper limit of normal value(ULN), T3 and T4 are in the normal range; Bilirubin ≤ 1.5 times ULN; ALT and AST ≤ 3 times ULN; Serum creatinine ≤ 1.5 times ULN, creatinine clearance rate ≥ 60ml/min (calculated using Cockcroft-Gault formula); 8. Subject has at least 1 measurable lesion (according to RECIST1.1); 9. Non-lactating or pregnant women, contraception during or 3 months after treatment. Exclusion Criteria: 1. Pathological diagnosis of hepatocellular carcinoma, mixed hepatocellular carcinoma and other non-cholangiocarcinoma malignancies; 2. Existing or concurrently suffering from other malignant tumors, except for fully treated non-melanoma skin cancer, cervical carcinoma in situ, and papillary thyroid cancer; 3. Have used lenvatinib or gemcitabine-based chemotherapy within 6 months or have used PD1 monoclonal antibody and PD-L1 monoclonal antibody treatment; 4. Severe cardiopulmonary and renal dysfunction; 5. Hypertension that is difficult to control by the drug (systolic blood pressure (BP) ≥140 mmHg and / or diastolic blood pressure ≥90 mmHg) (based on the average of ≥3 BP readings obtained from ≥2 measurements); 6. Abnormal blood coagulation function (PT> 14s), have bleeding tendency or are receiving thrombolysis or anticoagulation treatment; 7. HBV DNA> 2000 copies/ml and HCV RNA>1000 after antiviral treatment; 8. Have a history of esophagogastric varices, with significant clinically significant bleeding symptoms or a clear tendency to appear within 3 months before enrollment; 9. Active infection requiring systemic treatment and treatment; patients with active tuberculosis infection within 1 year before enrollment; a history of active tuberculosis infection more than 1 year before enrollment, have not received regular anti-TB treatment or tuberculosis Still in the active period; 10. Human immunodeficiency virus (HIV, HIV1/2 antibody) positive; 11. Have a history of psychotropic substance abuse, alcohol or drug abuse; 12. Known to have a history of severe allergies to any monoclonal antibodies, anti-angiogenic targeted drugs, and platinum or gemcitabine; 13. Other factors that may affect the safety of subjects or test compliance as judged by the investigator. Such as serious illness (including mental illness) requiring combined treatment, severe laboratory abnormalities, or other family or social factors.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Arm1: toripalimab combined with lenvatinib， Arm 2: lenvatinib combined with Gemox
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Toripalimab combined with lenvatinib<br>Toripalimab: 240 mg, intravenous infusion, Q3W; Lenvatinib: 8mg (body weight <60kg) or 12mg (body weight ≥60kg), qd; | Drug: Toripalimab combined with lenvatinib<br>* Toripalimab combined with lenvatinib<br>|
| Other: Lenvatinib combined with gemox<br>Lenvatinib: 8mg (body weight <60kg) or 12mg (body weight ≥60kg), qd Gemox chemotherapy D1: Oxaliplatin 85mg / m2, Gemcitabine 1g / m2 D8: Gemcitabine 1g / m2 Three weeks are a course, a total of 6-8 courses | Drug: Lenvatinib combined with gemox<br>* Arm2: Lenvatinib + gemox<br>* Other names: gemox chemotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | Objective response rate of advanced and unresectable intrahepatic cholangiocarcinoma | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: the potential side effects | The potential side effects | 12 months | 
| Overall survival | From the beginning date of combined therapy to the date of death | 12 months | 
| Progression free survival | From the beginning date of combined therapy to disease progression or death, whichever occurs first. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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intrahepatic Cholangiocarcinoma, Lenvatinib, Gemox chemotherapy, Programmed cell death protein 1 antibody