Intraperitoneal Immune Checkpoint Inhibitor for Malignant Ascites

Study Overview
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Brief Summary
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This projectis aim to evaluate the efficacy of immune checkpoint inhibitor (pembrolizumab or nivolumab) on the malignant ascites of patients with advanced gastric, pancreatic and biliary tract cancers.

Detailed Description
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Malignant ascites appear when cancer cells metastasize to peritoneal cavity and interfere the circulation of lymph and blood. Patients with malignant ascites suffer from abdominal fullness, abdominal pain, poor intake, decreased nutrition, disability, and eventually inability to further anticancer treatment. Malignant ascites put a heavy burden on patient, their family, society and health care system. Malignant ascites from cancers of stomach, pancreas and biliary tract are more refractory to intravenous chemotherapy or intraperitoneal chemotherapy than ascites from ovarian or chemo-naïve colorectal cancers because of the inherent nature of chemoresistance. Paracentesis is a treatment with immediate effect but the ascites regrow rapidly and repetitive paracentesis puts patients on the risk of intraabdominal infection. Intraperitoneal infusion of OK-432 can reduce malignant ascites but with intolerable adverse effects of fever, chills, pain, vomiting and septation of ascites which limit the further paracentesis. Cumulating clinical experience suggests a tolerable safety profile of immune checkpoint inhibitors compared to chemotherapy for patients with malignancy. One theoretical advantage of intraperitoneal administration of immune checkpoint inhibitors is the existence of abundant inflammatory cells, immune cells and mesothelial cells dispersed in the malignant ascites. In addition, both pembrolizumab and nivolumab have been administrated intraperitoneally without obvious toxicities in murine tumor models At China Medical University Hospital, one hundred gastric cancer patients, 50 pancreatic cancer patients and 50 biliary tract cancer patients are registered and treated each year. Among them, more than 20 patients suffer from malignant ascites which will ultimately be managed by repeated paracentesis with increasing frequency. Till now, there is no reported or ongoing clinical trial to investigate the efficacy of intraperitoneal checkpoint inhibitor on the malignant ascites.

Official Title
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The Effect of Intraperitoneal Immune Checkpoint Inhibitor on Malignant Ascites of Patients With Gastric, Pancreatic or Biliary Tract Cancer

Conditions
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Malignant Ascites

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients have cyto-/histologically confirmed malignant ascites from gastric, pancreatic or biliary tract adenocarcinoma Patients have malignant ascites more than 1000ml Patients have no history of prior intraperitoneal therapy for malignant ascites Patients have life expectancy of at least 4 weeks Patients have adequate platelet count ≥ 50,000/ul Women or men of reproductive potential should agree to use an effective contraceptive method All patients must be informed of the investigational nature of this study and must sign written informed consents. Exclusion Criteria: Patients have ascites which is related to causes other than the malignancies Patients who are receiving intraperitoneal treatment for their malignant ascites including therapeutic paracentesis Patients with active infection Patients with bleeding disorders Patient with active cardiopulmonary disease or history of ischemic heart disease Patients have intolerant abdominal pain Patients who have serious concomitant systemic disorders incompatible with the study, i.e. poorly controlled diabetes mellitus, auto-immune disorders, cirrhosis of the liver, and the rest will be at the discretion of in-charged investigator

Ages Eligible for Study
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Minimum Age: 20 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Checkpoint inhibitor (nivolumab or pembrolizumab)<br>Patients with malignant ascites will received either nivolumab or pembrolizumab intraperitoneally. | Drug: Nivolumab<br>* Intraperitoneal administration of nivolumab Nivolumab 20 mg in normal saline 100ml will be infused intraperitoneally through a temporary catheter in 10 minutes after paracentesis in a weekly interval.<br>* Other names: Opdivo;Drug: Pembrolizumab<br>* Intraperitoneal administration of pembrolizumab Pembrolizumab 20 mg in normal saline 100ml will be infused intraperitoneally through a temporary catheter in 10 minutes after paracentesis in a weekly interval.<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Control of ascites Rate of ascites control = number of patients who have less ascites determinded by five-point method and subjective symptoms / all patients | From the date of registration until the end of treatment, up to 2 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse effects | Adverse effect of intraperitoneal immune checkpoint inhibitor Incidence of adverse effect = number of patients who develop a kind of adverse effect / all patients | From the date of registration until treatment termination, up to 2 years. |