Efficacy and Safety of IBI351 in Combination With Sintilimab ± Chemotherapy in Advanced Non-squamous Non-small Cell Lung Cancer Subjects With KRAS G12C Mutation

Study Overview
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Brief Summary
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This Phase Ib/III study evaluates the efficacy and safety of IBI351 in combination with Sintilimab± chemotherapy in advanced non-squamous NSCLC with KRAS G12C mutation.

Detailed Description
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This Phase Ib/III study evaluates the efficacy and safety of IBI351 in combination with Sintilimab± chemotherapy. There will be four cohorts of subjects, all of whom have KRAS G12C mutation and have advanced or metastatic NSCLC. Three cohorts (A, C and D) are treated with IBI351+Sintilimab, IBI351+Sintilimab+pemetrexed, or IBI351+Sintilimab+pemetrexed+cis-platinum/carboplatin, respectively, as first-line therapy. Cohort B enrolles subjects who is intolerant or has failed in standard-of care treatment,and is treated with IBI351+Cetuximab. IBI351 is an orally available small molecule inhibitor of KRAS G12C.

Official Title
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An Open-label, Multi-center Phase Ib/III Study Evaluating the Efficacy and Safety of IBI351 in Combination With Sintilimab ± Chemotherapy in Advanced Non-squamous Non-small Cell Lung Cancer Subjects With KRAS G12C Mutation

Conditions
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Advanced Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: pemetrexed
* Drug: cis-platinum
* Drug: Sintilimab
* Drug: IBI351
* Drug: carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of nonsquamous NSCLC with KRAS G12C mutation Unresectable or metastatic disease Adequate organ function Exclusion Criteria: History of intestinal disease or major gastric surgery or inability to swallow oral medications Prior therapy with agents targeting KRAS G12C mutation (e.g., AMG 510). Active brain metastases.

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: IBI351 in combination with Sintilimab and pemetrexed<br> | Drug: pemetrexed<br>* 500mg/m^2, Q3W, day1, i.v.<br>Drug: Sintilimab<br>* 200mg, Q3W, day1, i.v.<br>* Other names: IBI308;Drug: IBI351<br>* recommended dose, po<br>* Other names: GFH925;|
| Experimental: IBI351 in combination with Sintilimab pemetrexed and cis-platinum/carboplatin<br> | Drug: pemetrexed<br>* 500mg/m^2, Q3W, day1, i.v.<br>Drug: cis-platinum<br>* 75mg/m^2, Q3W, day1, i.v.<br>Drug: Sintilimab<br>* 200mg, Q3W, day1, i.v.<br>* Other names: IBI308;Drug: IBI351<br>* recommended dose, po<br>* Other names: GFH925;Drug: carboplatin<br>* AUC=5, Q3W, day1, i.v.<br>|
| Experimental: IBI351 monotherapy<br> | Drug: IBI351<br>* recommended dose, po<br>* Other names: GFH925;|
| Experimental: IBI351 in combination with Sintilimab<br> | Drug: Sintilimab<br>* 200mg, Q3W, day1, i.v.<br>* Other names: IBI308;Drug: IBI351<br>* recommended dose, po<br>* Other names: GFH925;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with dose limiting toxicity | Number of participants with dose limiting toxicity in the dose escalation period | 12 months | 
| Evaluate clinical efficacy of IBI351 in combination with other therapeutic agents | Objective response rate per RECIST v1.1 | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate plasma peak concentration of IBI351 | Cmax | 12 months | 
| Evaluate area under the plasma concentration-time curve (AUC) of IBI351 | AUC | 12 months | 
| Evaluate terminal half-life (t1/2) of IBI351 | t1/2 | 12 months | 
| Evaluate clearance of IBI351 from the plasma | CL/F | 12 months | 
| Evaluate distribution of IBI351 | V/F | 12 months | 
| Evaluate clinical efficacy of IBI351 in combination with other therapeutic agents with other index | PFS, DCR,DOR, TTR per RECIST v1.1; OS | 24 months | 
| Number of subjects with adverse events of interest | AE | 24 months | 
| Number of subjects with treatment-related adverse events | TRAE | 24 months | 
| Number of subjects with serious adverse events | SAE | 24 months | 
| Number of subjects with treatment-emergent adverse events | TEAE | 24 months |