Efficacy and Safety of IBI110 in Combination With Sintilimab Versus Sintilimab Alone in Neoadjuvant and Adjuvant Therapy of Radically Resectable Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the neoadjuvant therapy efficacy of IBI110 in combination with sintilimab versus sintilimab alone based on pathologic complete response (pCR) rate in stage IIB (primary tumor > 4 cm ) to IIIB (N2 only) subjects with radically resectable NSCLC.

Official Title
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A Randomized, Open-label, Phase Ib Clinical Study to Evaluate the Efficacy and Safety of IBI110 in Combination With Sintilimab Versus Sintilimab Alone in Neoadjuvant and Adjuvant Therapy of Radically Resectable Non-small Cell Lung Cancer

Conditions
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Non-small Cell Lung Cancer (NSCLC)

Intervention / Treatment
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* Drug: IBI110
* Drug: sintilimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have NSCLC that has been classified as stage IIB (primary tumor > 4 cm), IIIA, or IIIB (N2 only) per the 8th edition of TNM staging system of International Association for the Study of Lung Cancer (IASLC) and the American Joint Committee on Cancer (AJCC). Subjects with non-squamous NSCLC should undergo genetic testing to confirm the absence of epidermal growth factor receptor (EGFR) sensitizing mutations or anaplastic lymphoma kinase (ALK) rearrangements; Eligible for radical resection (R0 resection) at the thoracic surgeon's discretion, and the lung function meets the criteria for planned surgery; Have at least one measurable lesion per RECIST v1.1 criteria; Have a performance scale of 0 or 1 on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Exclusion Criteria: Have pathological evidence for small cell carcinoma, neuroendocrine carcinoma, sarcoma, lymphoepithelial rumen carcinoma, salivary gland tumor, or mesenchymal tumor from the biopsy. Have been previously exposed to immune-mediated therapies, including but not limited to LAG-3 antibody drugs, anti-cytotoxic T lymphocyte antigen-4 (CTLA-4), anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IBI110+sintilimab<br>IBI110 and sintilimab will be administered as intravenous (IV) infusion on Day 1 of each 21-day cycle (every 3 weeks) for 3 cycles during the neoadjuvant treatment phase. IBI110 and sintilimab will be administered as IV infusion 3 weeks during the post-operative adjuvant phase up to 1 year. | Drug: IBI110<br>* R2PD d1 IV every 3 weeks<br>Drug: sintilimab<br>* 200mg d1 IV every 3 weeks<br>|
| Active Comparator: sintilimab<br>Sintilimab will be administered as intravenous (IV) infusion on Day 1 of each 21-day cycle (every 3 weeks) for 3 cycles during the neoadjuvant treatment phase. Sintilimab will be administered as IV infusion 3 weeks during the post-operative adjuvant phase up to 1 year. | Drug: sintilimab<br>* 200mg d1 IV every 3 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pCR | defined as having no residual visible tumor cells in the surgically resected primary tumor and lymph node samples (ypT0N0) | Approximately 21 to 28 days after operation | 
| Incidence of serious adverse events (SAEs), treatment-emergent AEs (TEAEs) and immune-related AEs (irAEs) | An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is an important medical event that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before. A TEAE will be defined as any new AE that begins, or any pre-existing condition that worsens in severity, after at least 1 dose of study treatment has been administered. irAEs will be assessed. | up to 90 days after the last administration | 
| Number of participants with abnormality in vital signs | Blood pressure, pulse, respiratory rate, and temperature will be assessed. | up to 90 days after the last administration | 
| Number of participants with abnormality in hematology parameters | Blood samples will be collected to evaluate hemoglobin, mean corpuscular volume (MCV), white blood cell (WBC) count, platelets, 5-part differential white cell count, mean platelet volume and coagulation factors including international normalized ratio (INR), activated partial thromboplastin time (aPTT) and prothrombin time (PT). | up to 90 days after the last administration | 
| Number of participants with abnormality in clinical chemistry parameters | Blood samples will be collected to evaluate sodium, potassium, calcium, magnesium, chloride, glucose, creatinine, urea or blood urea nitrogen (BUN), bicarbonate, amylase, bilirubin, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein, albumin, lactate dehydrogenase and lipase. | up to 90 days after the last administration | 
| Number of participants with abnormality in clinical chemistry parameters | Blood samples will be collected to evaluate sodium, potassium, calcium, magnesium, chloride, glucose, creatinine, urea or BUN, bicarbonate, amylase, bilirubin, alkaline phosphatase, AST, ALT, total protein, albumin, lactate dehydrogenase and lipase. | up to 90 days after the last administration | 
| Number of participants with abnormality in routine urinalysis parameters | Urine samples will be collected to evaluate specific gravity, leucocyte esterase, nitrite, blood, bilirubin, protein, glucose, ketones and urobilinogen. | up to 90 days after the last administration | 
| Number of participants with abnormality in ECG parameters | 12-lead ECG will be obtained using an ECG machine. Participants will be in supine or a semi-recumbent position (about 30 degrees of elevation) and rested for approximately 2 minutes before ECGs are recorded. | up to 90 days after the last administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EFS （Event Free Survival） | defined as time from randomization to any of the following events: progression of disease that precludes surgery, local or distant recurrence, or death due to any cause | up to 3 years | 
| major pathological response (MPR) rate | defined as ≤ 10% residual viable tumor cells in the surgically resected primary tumor and lymph nodes | Approximately 21 to 28 days after operation | 
| radical resection (R0 resection) rate | defined as free resection margins, systematic node dissection or sampling, and the highest mediastinal node negative for tumor | Approximately 21 to 28 days after operation | 
| ORR （Objective Response rate,） | defined as the ratio of subjects who have achieved investigator assessed complete response (CR) and partial response (PR) per RECIST v1.1 | Within 7 days before surgery | 
| OS （Overall Survival） | defined as the time from randomization to death from any cause | up to 3 years | 
| Immunogenicity | includes the positive rate of anti-drug antibody (ADA) and neutralizing antibody (NAb) in subjects | From date of randomization to 30 days after last dose of the drug | 
| maximum concentrations (Cmax ) | Maximum serum concentration that IBI110 and Sintilimab achieves in the body after the drug has been administered and before the administration of a second dose. | from first administration of IBI110 to 3 days before the operation | 
| the area under the drug plasma concentration-time curve (AUC) | Area under the concentration-time curve from time zero to last measurable concentration (AUC) | from first administration of IBI110 to 3 days before the operation | 
| half-life (t1/2) | defined as the time it takes for the concentration of IBI110 and Sintilimab in the plasma or the total amount in the body to be reduced by 50%. | from first administration of IBI110 to 3 days before the operation | 
| clearance (CL) | a pharmacokinetic measurement of the volume of plasma from which IBI110 and Sintilimab are completely removed per unit time | from first administration of IBI110 to 3 days before the operation | 
| volume of distribution (V). | calculated by the amount of the drug in the body divided by the plasma concentration. | from first administration of IBI110 to 3 days before the operation |