A Study of SKB264 for the Treatment of Participants With Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability and objective response rate of SKB264 as combination with therapy in subjects with advanced or metastatic non-small cell lung cancer.

Detailed Description
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This is a multicenter, open-label study of SKB264 as combination therapy in subjects with NSCLC. Approximately up to 296 subjects will be enrolled in this study including around 36 (may expand) subjects for safety run-in period and 200 subjects for expansion period.

Official Title
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A Phase II Study of SKB264 as Monotherapy or as Combination Therapy in Subjects With Advanced or Metastatic Non-small Cell Lung Cancer

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: SKB264
* Drug: Pembrolizumab
* Drug: Carboplatin
* Drug: Osimertinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Subjects must be at least 18 years of age on day of signing informed consent, regardless of gender; Subjects with histologically or cytologically confirmed locally advanced or metastatic NSCLC ; Subjects for NSCLC should be confirmed to be EGFR (Epidermal growth factor receptor) wild-type and ALK (Anaplastic lymphoma kinase) fusion gene negative; or confirmed to harbor EGFR mutation; Locally advanced or metastatic NSCLC subjects without actionable EGFR mutations and ALK fusion genes, no prior systemic treatment; subjects with EGFR mutation, no prior systemic treatment or failed prior EGFR-TKI (Tyrosine kinase inhibitor) treatment; Subjects are able to provide tumor blocks or slides before the first dose of study intervention; Subject must have at least one radiographically measurable lesion as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria; Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1; Life expectancy at least 3 months for the subject; Adequate organ function; Subjects must have recovered from all toxicities led by prior treatment; Contraceptive methods used by male and female subjects must comply with contraceptive methods of local regulations for clinical study subjects; Subjects should voluntarily participate in the study, sign the ICF, and will be able to comply with the protocol-specified visits and relevant procedures. Exclusion Criteria Subjects with mixed SCLC histopathological features; Subjects with a known history of prior malignancy; Subjects with known meningeal metastases, brainstem metastases, spinal cord metastases and/or compression, or active central nervous system (CNS) metastases; Subjects with ≥ Grade 2 peripheral neuropathy; Subjects who had arteriovenous thromboembolic events; Subjects with active inflammatory bowel disease or previous clear history of inflammatory bowel disease; Subjects who suffer from cardiovascular diseases of clinical significance; Subjects with a history of interstitial lung disease (ILD)/non-infectious pneumonitis that required steroids; Subjects with uncontrolled systemic disease as judged by the Investigator; Subjects with active autoimmune disease that required systemic treatment in the past 2 years; Subjects with active hepatitis B or hepatitis C; Subjects with known history of Human Immunodeficiency Virus (HIV) Subjects with known active tuberculosis; Subjects with known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation; Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study; Subjects whose condition deteriorated rapidly, such as severe changes in performance status, during the screening process prior to the first dose of study intervention; Subjects with other circumstances that, in the opinion of the Investigator, are not appropriate for participation in this study.

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: Cohort 1 EGFR wild-type and ALK fusion genes negative (PD-L1 TPS ≥ 1 %)<br>SKB264 (Dose Level 1) + Pembrolizumab | Drug: SKB264<br>* intravenous (IV) infusion (Q2W)<br>Drug: Pembrolizumab<br>* intravenous (IV) infusion (400mg, Q6W)<br>* Other names: MK-3475;|
| Experimental: Cohort 2 EGFR wild-type and ALK fusion genes negative (PD-L1 TPS ≥ 1 %)<br>SKB264 (Dose Level 2) + Pembrolizumab | Drug: SKB264<br>* intravenous (IV) infusion (Q2W)<br>Drug: Pembrolizumab<br>* intravenous (IV) infusion (400mg, Q6W)<br>* Other names: MK-3475;|
| Experimental: Cohort 3 EGFR wild-type and ALK fusion genes negative<br>SKB264 (Dose Level 3) + Pembrolizumab + Carboplatin | Drug: SKB264<br>* intravenous (IV) infusion (Q2W)<br>Drug: Pembrolizumab<br>* intravenous (IV) infusion (400mg, Q6W)<br>* Other names: MK-3475;Drug: Carboplatin<br>* intravenous (IV) infusion (AUC5, Q3W)<br>* Other names: Carboplatin for injection;|
| Experimental: Cohort 4 EGFR wild-type and ALK fusion genes negative<br>SKB264 (Dose Level 1) + Pembrolizumab + Carboplatin | Drug: SKB264<br>* intravenous (IV) infusion (Q2W)<br>Drug: Pembrolizumab<br>* intravenous (IV) infusion (400mg, Q6W)<br>* Other names: MK-3475;Drug: Carboplatin<br>* intravenous (IV) infusion (AUC5, Q3W)<br>* Other names: Carboplatin for injection;|
| Experimental: Cohort 5 EGFR sensitizing mutation<br>SKB264 (Dose Level 3) + Carboplatin | Drug: SKB264<br>* intravenous (IV) infusion (Q2W)<br>Drug: Carboplatin<br>* intravenous (IV) infusion (AUC5, Q3W)<br>* Other names: Carboplatin for injection;|
| Experimental: Cohort 6 EGFR sensitizing mutation<br>SKB264 (Dose Level 1) + Carboplatin | Drug: SKB264<br>* intravenous (IV) infusion (Q2W)<br>Drug: Carboplatin<br>* intravenous (IV) infusion (AUC5, Q3W)<br>* Other names: Carboplatin for injection;|
| Experimental: Cohort 7 EGFR 19del or L858R Mutation<br>SKB264 (Dose Level 1) + Osimertinib | Drug: SKB264<br>* intravenous (IV) infusion (Q2W)<br>Drug: Osimertinib<br>* 80mg, QD<br>* Other names: Osimertinib Mesylate;|
| Experimental: Cohort 8 EGFR 19del or L858R Mutation<br>SKB264 (Dose Level 2) + Osimertinib | Drug: SKB264<br>* intravenous (IV) infusion (Q2W)<br>Drug: Osimertinib<br>* 80mg, QD<br>* Other names: Osimertinib Mesylate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability | Dose-limiting toxicity (DLT); Incidence and severity of adverse events (AEs); Discontinuation of study treatment due to AEs | From subject sign the informed consent form (ICF) to 30 days after the last dose of study treatment, up to approximately 36 months | 
| ORR | Objective response rate (ORR) per RECIST v1.1 | The proportion of subjects with a confirmed complete response (CR) or partial response (PR), up to approximately 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DOR) | For subjects with a confirmed CR or PR, DOR is defined as the time from the first documented evidence of CR or PR until radiographic disease progression or death due to any cause, whichever occurs first | From baseline until disease progression, death, or other protocol defined reason, up to approximately 36 months | 
| Progression-free survival (PFS) | The time from first dose of study intervention to first documentation of radiographic disease progression or death due to any cause, whichever occurs first | From baseline until disease progression, death, or other protocol defined reason, up to approximately 36 months | 
| Overall survival (OS) | the time period from the start of study intervention to death due to any cause. | From baseline until death due to any cause, up to approximately 36 months |