Study of AK119 and AK112 With or Without Chemotherapy for NSCLC Patients

Study Overview
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Brief Summary
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This is a phase Ib/II study to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of AK119 and AK112 With or Without Chemotherapy for NSCLC patients.

Official Title
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A Multicenter, Open-Label, Phase Ib/II Study of AK119 and AK112 With or Without Chemotherapy in Patients With EGFR-mutant Locally Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer Who Have Failed to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) Treatment

Conditions
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NSCLC

Intervention / Treatment
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* Drug: AK119
* Drug: AK112
* Drug: Pemetrexed
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be able to understand and voluntarily sign the written informed consent, which must be signed before the designated research procedure. Age ≥ 18 and ≤ 75, male or female. Local advanced or metastatic non-squamous NSCLC confirmed by histology or cytology according to eighth edition of the TNM classification for lung cancer. EGFR activating mutation confirmed by tumor histology, cytology or hematology. Failed to previous EGFR-TKI treatment. ECOG performance status 0 to1. Life expectancy ≥3 months. At least one measurable lesion according to RECIST v1.1. Adequate organ function. Exclusion Criteria: Histological or cytological pathology confirmed the presence of small cell carcinoma or squamous cell carcinoma. Have suffered from the second primary active malignant tumor in the past 3 years. There are other driving gene mutations that can obtain effective treatment. Receipt of the following treatments or procedures: immunotherapy, including immunocheckpoint inhibitors, immunocheckpoint agonists, immunocellular therapy, and any other treatment targeting tumor immune mechanism; systematic chemotherapy in the advanced stage (IIIB-IV); anti-angiogenesis drugs, except for small molecule anti-angiogenesis drugs with drug withdrawal more than 4 weeks; extensive radiotherapy within 4 weeks; EGFR-TKIs within 2 weeks. Symptomatic central nervous system metastases. The toxicity of previous anti-tumor therapy has not been alleviated. Uncontrolled massive ascites, pleural effusion or pericardial effusion. Active autoimmune diseases in the past 2 years. History of interstitial lung disease or noninfectious pneumonitis. Suffering from clinically significant cardiovascular or cerebrovascular diseases. History of severe bleeding tendency or coagulation dysfunction. History of deep vein thrombosis, pulmonary embolism or any other serious thromboembolism in the past 3 months. Serious infection in the past 4 weeks. Acute exacerbation of chronic obstructive pulmonary disease or asthma in the past 4 weeks. History of human immunodeficiency virus (HIV) infection. History of severe hypersensitivity reactions to other mAbs. History of organ transplantation. Any other conditions that, in the opinion of the investigator, may increase the risk when receiving the investigational product.

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AK119 + AK112<br>Subjects will receive AK119 plus AK112 via intravenously (IV) Q3W, up to 2 years. | Drug: AK119<br>* AK119 IV every 3 weeks.<br>Drug: AK112<br>* AK112 IV every 3 weeks.<br>|
| Experimental: AK119 + AK112 + Pemetrexed + Carboplatin<br>Subjects will receive AK119 and AK112 plus pemetrexed and carboplatin via intravenously (IV) Q3W, up to 4 cycles. Afterward, AK119 and AK112 plus pemetrexed will continue to be treated up to 2 years. | Drug: AK119<br>* AK119 IV every 3 weeks.<br>Drug: AK112<br>* AK112 IV every 3 weeks.<br>Drug: Pemetrexed<br>* Pemetrexed IV every 3 weeks.<br>Drug: Carboplatin<br>* Carboplatin IV every 3 weeks.<br>|
| Experimental: AK112<br>Subjects will receive AK112 monotherapy via intravenously (IV) Q3W, up to 2 years. | Drug: AK112<br>* AK112 IV every 3 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with dose limiting toxicities (DLTs) | DLTs will be assessed during the first 3 weeks of treatment. DLTs are defined as toxicities that meet pre-defined severity criteria, and assessed as having a suspected relationship to study drug, and unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the DLT observation period. | During the first 3 weeks | 
| Number of subjects with adverse events (AEs) | AE refers to any untoward medical occurrence or deterioration of existing medical event after the subject signed the ICF, whether or not considered related to the study treatment. | From the time of informed consent signed through 90 days after the last dose of study drug | 
| Objective response rate (ORR) | ORR is defined as the proportion of subjects with confirmed CR or confirmed PR. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | PFS is defined as the time from the start of treatment until the first documentation of disease progression or death due to any cause, whichever occurs first (based on RECIST Version 1.1). | Up to 2 years | 
| Disease control rate (DCR) | DCR is defined as the proportion of subjects with CR, PR, or SD (based on RECIST Version 1.1). | Up to 2 years | 
| Duration of response (DoR) | DoR is defined as the duration from the first documentation of objective response to the first documented disease progression (based on RECIST Version 1.1) or death due to any cause, whichever occurs first. | Up to 2 years | 
| Time to response (TTR) | TTR is defined as the time from the start of the treatment to the first objective tumor response observed for patients who achieved CR or PR (based on RECIST Version 1.1). | Up to 2 years | 
| Overall survival (OS) | OS defined as the time from the first dose to death from any cause. | Up to 2 years | 
| Maximum observed concentration (Cmax) of AK119 and AK112 | The PK parameters include serum concentrations of AK119 and AK112 at different timepoints after study drug administration. | From first dose of study drug through last dose | 
| Number of subjects who develop detectable anti-drug antibodies (ADAs) | The immunogenicity of AK119 and AK112 will be assessed by summarizing the number of subjects who develop detectable antidrug antibodies (ADAs). | From first dose of study drug through last dose |