Tislelizumab Plus Anlotinib for Immunotherapy Resistant Gastrointestinal Cancer

Study Overview
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Brief Summary
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Immunotherapy acquired resistance was observed in clinical practice. The investigators intended to add anlotinib to PD-1 inhibitors, hoping reverse the resistance.

Detailed Description
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Anti-angiogenesis seems have positive effects on tumor immune microenvironment. the combination of PD-1/PD-L1 inhibitors and TKIs exhibited favorable efficacy on gastrointestinal malignancies. Here the investigators want to examine the efficacy and survival benefit from the combination therapy to PD-1 acquired resistance patients, which turns out to be critical issues in recent years.

Official Title
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Efficacy and Safety of Tislelizumab Plus Anlotinib in PD-1/PD-L1 Resistant Metastatic Gastric or Colorectal Cancer: a Single Arm Phase II Clinical Trial

Conditions
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Gastric Cancer, Colo-rectal Cancer

Intervention / Treatment
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* Drug: Tislelizumab
* Drug: Anlotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ECOG scored 0 or 1, ≥18 years old, expected OS≥3 months; Histology confirmed unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma or colorectal cancer; ≥1 evaluable lesion based on RECIST 1.1; Patients received PD-1/PD-L1 in the last treatment line, and should meet following conditions: i) there was no severe immune-related adverse events, ii) the duration between tumor progression and screening should be 3-12 weeks, iii) the best evaluation results should be PR or CR when receiving PD-1/PD-L1 treatment but progression was confirmed in the latest evaluation, iv) patients were diagnosed with special pathology subtypes, that are sensitive to immunotherapy, such as dMMR, MSI-H tumors, or gastric cancer with PD-L1 CPS≥10, PFS≥6 months in the last treatment line; laboratory test should meet following standard: i) HB≥90g/l, neutrophils≥1.5*10^9/L, plt≥100*10^9, ii) ALT and AST<2.5xULN (5ULN for liver metastatic patients), TBIL≤2×ULN, Cr≤1.5×ULN, and Ccr>50μmol/L iii) APTT, INR and PT≤1.5×ULN iv) LVEF≥50% for female participants, Hcg should be negative and both male and female participants should have contraception measures participants should be informed consent, and voluntary. Exclusion Criteria: received anlotinib or other TKIs previously; allergic to other monoclonal antibody before the treatment; diagnosed with other malignancy in last five years (cured skin basal carcinoma, prostate cancer or cervical caner in situ were excluded) concurrent with other active autoimmune disease; any condition that require immune suppressor, such as cortisol (>10mg/d prednisone equally), CTX; conditions affect oral absorption (eg: dysphagia, intestinal obstruction; chronic diarrhea); uncontrolled pleural effusion, hydropericardium and seroperitoneum; brain metastasis; received other anti-tumor treatment in past 3 weeks, eg: surgery, radiotherapy, target therapy, immunotherapy, and traditional Chinese therapy (target therapy less than 5 half-life period, 5-Fu less than 14 days were excluded); concurrent with uncontrolled other diseases, i) hypertension (>150/90mmHg) ii) unstable angina pectoris, ≥ level 2 heart failure, arrhythmia within last 6 months; iii) clinical meaningful liver disease, eg: active HBV/HCV hepatitis; iv) HIV positive; v) uncontrolled diabetes; vi) urine protein ≥++ or 24h urine protein >1g; injected vaccine in past 4 weeks, or administrated with antibiotics; investigator assumed improper conditions, such as mental disease, family or society factors.

Ages Eligible for Study
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Minimum Age: 18 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: tislelizumab+anlotinib<br>patients will be administrate with dual drugs, tislelizumab plus anlotinib. | Drug: Tislelizumab<br>* For included participants, tislelizumab would be administrated 200mg q3w iv.<br>Drug: Anlotinib<br>* Patients will be administrated with Anlotinib 12mg p.o. d1-d14 q3w.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| objective response rate | the rate of patients reached PR or CR based on RECIST 1.1 | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression-free survival | the time from recruiting to death or progression | Up to 2 years | 
| overall survival | the time from recruiting to death | Up to 2 years |