Gut Microbial Metabolites Inosine Combined With PD-1/PD-L1 Inhibitor for Patients With Malignant Advanced Solid Tumors

Study Overview
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Brief Summary
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We conducted a single-center, prospective randomized ,Parallel controls, open labels Clinical Studies,The study is about Gut Microbial Metabolites Inosine Combined With PD-1/PD-L1 Inhibitor for Patients with malignant Advanced Solid Tumors .One group was the inosine group , the other group was the non-inosine group.The treatment regimen of inosine group : inosine + PD-1/PD-L1 inhibitor ± chemotherapy/targeting, and the treatment regimen of non-inosine group : PD-1/PD-L1 inhibitor ± chemotherapy/targeting.The primary study endpoints were overall survival (OS) and progression-free survival PFS, and the secondary study endpoints were objective remission rate (ORR) and disease control rate (DCR) comparing the two groups.

Detailed Description
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We conducted a single-center, prospective randomized ,Parallel controls, open labels Clinical Studies,,The study is about Gut Microbial Metabolites Inosine Combined With PD-1/PD-L1 Inhibitor for Patients with malignant Advanced Solid Tumors.One group was the inosine group , the other group was the non-inosine group. A total of 172 patients with advanced malignant solid tumors were collected from Capital Medical University Beijing Friendship Hospital, and randomly assigned to two groups according to 1:1, 86 patients in the inosine group and 86 patients in the non-inosine group. The regimen of inosine treatment group was: inosine + PD-1/PD-L1 inhibitor ± chemotherapy/targeting, and the treatment regimen of non-inosine treatment group was: PD-1/PD-L1 inhibitor ±chemotherapy/targeting,every 2 or 3 weeks protocol ,until the subject's disease progresses, death, intolerable adverse events, the investigator determines that there is no benefit from continued treatment or other termination criteria are met (pregnancy, individual patient reasons or co-morbidities), the subject requests withdrawal from the study, withdrawal of informed consent, and loss of visit.Anti-tumor efficacy is evaluated every 2/3 cycles (every 6 weeks) based on computed tomography (CT) or magnetic resonance imaging (MRI) results and their tumor markers, according to RECIST v1.1 criteria. Inosine tablets were purchased from Tianjin Jinshi, dosage: 0.2g orally 3 times/day, PD-1/PD-L1 inhibitors, chemotherapy and targeted combination therapy regimens were developed by the investigators according to the NCCN guidelines and CSCO guidelines and the patient's condition and its staging.

Official Title
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Gut Microbial Metabolites Inosine Combined With PD-1/PD-L1 Inhibitor for Patients With Malignant Advanced Solid Tumors

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: Inosine 0.2g orally 3 times/day
* Drug: PD-1/PD-L1 inhibitor ,chemotherapy/targeting


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathologically confirmed unresectable locally advanced, recurrent or metastatic solid tumors Age 18 years old - 75 years old ECOG score of ≤ 2 Time to end of palliative treatment for localized lesions (non-target lesions) was >3 weeks from randomization start time, At least one measurable lesion or assessable lesion according to RECIST v1.1 Can provide archived pathological tissues or fresh pathological tissues for PD-L1, MMR/MSI, TMB testing within 6 months from the signing of the informed consent for screening and can obtain the test results Adequate organ and bone marrow function, defined as follows: 1) Blood count: absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count (PLT) ≥ 100 × 109/L, hemoglobin level (HGB) ≥ 9.0 g/dL. 2) Liver function: patients without liver metastases require: serum total bilirubin (TBIL) ≤ 1.5 × upper limit of normal ( ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN. patients with liver metastases required: TBIL ≤1.5×ULN; ALT and AST ≤5×ULN. 3) renal function: creatinine clearance (Ccr) ≥50mL/min (calculated using the Cockcroft/Gault formula): female: Ccr = (140-years-old) × body weight (kg) × 0.85; men: Ccr = (140-years-old) × body weight (kg) × 1.00. 4) Adequate coagulation function, defined as international normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN Expected survival time ≥ 12 weeks Female subjects of childbearing age or male subjects whose sexual partners are women of childbearing age are required to use effective contraception throughout the treatment period and for 6 months after the treatment period Sign the written informed consent Exclusion Criteria: Signs of active bleeding or perforation History of intestinal obstruction or the following diseases: inflammatory bowel disease or extensive bowel resection, Crohn's disease, ulcerative colitis Hepatic metastatic focal load of approximately 50% or more of the entire liver volume Antibiotic was used within 2 weeks before study treatment Received systemic antitumor therapy with herbs or immunomodulatory drugs (including thymidine, interferon, interleukin, etc.) within 2 weeks before the first dose. immunosuppressive drugs was used within 4 weeks before study treatment, excluding topical glucocorticoids or physiologic doses of systemic glucocorticoids (i.e., no more than 10mg/day of prednisone or equivalent doses of other glucocorticoids) of nasal spray, inhalation, or other routes, or glucocorticoid for the prevention of contrast allergy Interstitial lung disease requiring glucocorticoid therapy Active, known or suspected autoimmune disease or history of the disease within the last 2 years (patients with vitiligo, psoriasis, alopecia or Grave's disease not requiring systemic treatment within the last 2 years, hypothyroidism requiring only thyroid hormone replacement therapy, and type I diabetes requiring only insulin replacement therapy may be enrolled) Symptomatic congestive heart failure (New York Heart Association class -≥3) or symptomatic or poorly controlled arrhythmias standard treatment could not uncontrollarterial hypertension (systolic blood pressure ≥ 160 or diastolic blood pressure ≥ 100). Any arterial thromboembolic event, including myocardial infarction, unstable angina, cerebrovascular accident or transient ischemic attack, within 6 months prior to enrollment in treatment History of deep vein thrombosis, pulmonary embolism, or any other serious thromboembolism within 3 months prior to enrollment Known active tuberculosis Known history of case type immunodeficiency virus infection Positive hepatitis B surface antigen and peripheral blood hepatitis B virus deoxyribonucleic acid (HBV DNA) titer test ≥ 1×104 copies/mL (or HBV-DNA quantification ≥ 2000 units/ml); active hepatitis C History of other primary malignancies, except: malignancies in complete remission for at least 5 years prior to enrollment and requiring no other treatment during the study period; adequately treated non-melanoma skin cancer or malignant freckled nevus with no evidence of disease recurrence; adequately treated carcinoma in situ with no evidence of disease recurrence Patients who, in the judgment of the investigator, are otherwise likely to interfere with the conduct of the clinical study, who may not be able to comply with the protocol or who are unable to cooperate, or who are a risk to the study This study was approved by the Clinical Investigation Ethics Committee of Beijing Friendship Hospital, Capital Medical University, and was conducted in accordance with the Declaration of Helsinki. All patients signed informed consent forms for data collection and study purposes

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: inosine group<br>Participants will receive inosine + PD-1/PD-L1 inhibitor ± chemotherapy/targeting,every 2 or 3 weeks, until the subject's disease progresses, death, intolerable adverse events, the investigator determines that there is no benefit from continued treatment or other termination criteria are met (pregnancy, individual patient reasons or co-morbidities), the subject requests withdrawal from the study, withdrawal of informed consent, and loss of visit | Drug: Inosine 0.2g orally 3 times/day<br>* inosine + PD-1/PD-L1 inhibitor ± chemotherapy/targeting,<br>* Other names: chemotherapy/targeting;|
| Active Comparator: non-inosine group<br>Participants will receive PD-1/PD-L1 inhibitor ± chemotherapy/targeting, every 2 or 3 weeks .until the subject's disease progresses, death, intolerable adverse events, the investigator determines that there is no benefit from continued treatment or other termination criteria are met (pregnancy, individual patient reasons or co-morbidities), the subject requests withdrawal from the study, withdrawal of informed consent, and loss of visit | Drug: PD-1/PD-L1 inhibitor ,chemotherapy/targeting<br>* PD-1/PD-L1 inhibitor ± chemotherapy/targeting<br>* Other names: chemotherapy/targeting;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival (OS) | Time from randomization grouping to death from any cause | 36 months | 
| progression-free survival (PFS) | Time from randomization grouping to the first recorded disease progression or death from any cause | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| objective remission rate(ORR) [ Time Frame: Up to 36 months ] | Proportion of subjects with best overall efficacy assessed as CR and PR | 36 months | 
| disease control rate (DCR) | Proportion of subjects with best overall efficacy assessed as CR, PR and SD | 36 months |