A Study of Anti-PD-1 AK105 in Patients With Metastatic Squamous Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This is a phase III, randomized, double-blinded, multicenter clinical study to evaluate the efficiency and safety of AK105 (Anti-PD1 antibody) plus paclitaxel and carboplatin vs placebo plus paclitaxel and carboplatin as First-line Therapy in patients with metastatic squamous non-small cell lung cancer.

Official Title
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A Phase III, Randomized, Double-blinded, Multicenter Study of AK105 Combined With Carboplatin and Paclitaxel vs Placebo Combined With Carboplatin and Paclitaxel as First-line Therapy in Patients With Metastatic Squamous Non-small Cell Lung Cancer

Conditions
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Lung Cancer Non-small Cell Stage IV, Squamous Cell Lung Cancer

Intervention / Treatment
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* Biological: AK105
* Drug: Paclitaxel
* Drug: Carboplatin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent form voluntarily. Age over 18 years old (inclusive) and not more than 75 years old (inclusive), when signing the ICF. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1. Expected life expectance ≥ 3 months. Histologically or cytologically confirmed diagnosis of stage IV squamous NSCLC. No prior systemic chemotherapy for advanced or metastatic NSCLC. Subjects who have received prior adjuvant chemotherapy or neoadjuvant chemotherapy with curative intent, or definitive chemoradiotherapy for advanced disease, will be eligible provided that progression has occurred >6 months from last treatment. At least one measurable tumor lesion per RECIST 1.1 criteria. A lesion previously irradiated will not be considered a target lesion. Subjects must provide an available tumor tissue sample taken < 6 months prior to first dose of study treatment. Adequate organ function. Females of childbearing potential who are sexually active with a nonsterilized male partner must use at least one highly effective method of contraception. Nonsterilized males who are sexually active with a female partner of childbearing potential must use highly effective method of contraception from Day 1 and for 120 days after the last dose of investigational product. Exclusion Criteria: Subjects who are diagnosed as NSCLC that harbors an EGFR-sensitizing mutation or ALK gene translocation. Subjects with other histological types of NSCLC, including mixed squamous cell carcinoma and adenocarcinoma, and mixed carcinoma containing small cell lung carcinoma or neuroendocrine carcinoma. Received prior treatment with EGFR inhibitors or ALK inhibitors. Receipt of last radiotherapy or any anti-tumor treatment [chemotherapy, targeted therapy, immunotherapy, Chinese patent drugs with antitumor indications, or immunomodulators or tumor embolization] within 3 weeks prior to the first dose of study treatment. Prior exposure to any anti-PD-1, anti-PD-L1, anti-CTLA-4 antibody, or any other antibody or drug therapy for T cell co-stimulatory or checkpoint pathways, such as ICOS or agonists (e.g. CD40, CD137, GITR and OX40 etc). Other invasive malignancies within 5 years, except for locally treatable (manifested as cured) malignancies, such as basal or skin squamous cell carcinoma, superficial bladder cancer, cervical or breast carcinoma in situ. Subjects with active, known or suspected autoimmune disease, or a medical history of autoimmune disease, with the exceptions of the following: vitiligo, alopecia, Grave disease, psoriasis or eczema not requiring systemic treatment within the last 2 years, hypothyroidism (caused by autoimmune thyroiditis) only requiring steady doses of hormone replacement therapy and type I diabetes only requiring steady doses of insulin replacement therapy, or completely relieved childhood asthma that requires no intervention in adulthood, or primary diseases that will not relapse unless triggered by external factors. Active or previously documented inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis or chronic diarrhea). Subjects who require systemic corticosteroids (a dose equivalent to >10 mg/day prednisone) or other immunosuppressive drugs within 14 days prior to the first dose of study drug. Major surgery (as defined by the investigator) within 28 days prior to the first dose of study drug. Subjects who received non-thoracic radiotherapy >30 Gy within 4 weeks prior to the first dose, or thoracic radiotherapy >30 Gy within 24 weeks prior to the first dose study drug. History of gastrointestinal perforation and/ or fistula within 6 months prior to the first dose of study drug. Known history of primary immunodeficiency virus infection. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation. Known history of interstitial lung disease. Known history of active tuberculosis (TB). Serious infections within 4 weeks prior to the first dose of study drug, including but not limited to complications requiring hospitalization, sepsis or severe pneumonia. An active infection requiring systemic therapy. Subjects with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) DNA exceeding 500 IU/ mL or active hepatitis C virus (HCV) should be excluded. Subjects with non-active HBsAg carriers, treated and stable hepatitis B (HBV DNA <500 IU/ mL) , and cured hepatitis C can be enrolled. Subjects with positive HCV antibodies are eligible only if the HCV RNA test results are negative. Known history of testing positive for human immunodeficiency virus (HIV). Presence of central nervous system (CNS) metastasis, meningeal metastasis, spinal cord compression, or leptomeningeal disease. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage. Clinically active hemoptysis, active diverticulitis, peritoneal abscess, or gastrointestinal obstruction. Clinically significant bleeding symptoms or significant bleeding tendency such as gastrointestinal bleeding, hemorrhagic gastric ulcer or vasculitis within 1 month prior to the first dose of study treatment. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to NCI CTCAE v4.03 Grade 0 or 1, or to levels dictated in the inclusion/exclusion criteria, with the exception of alopecia. Receipt of live or attenuated vaccination within 30 days prior to the first dose of study treatment, or plan to receive live or attenuated vaccine during the study. Known history of server hypersensitivity to other monoclonal antibodies. Known severe allergic reactions to paclitaxel, carboplatin, or their preventive medications. Grade 2 or greater peripheral neuropathy (based on NCI CTCAE v4.03 criteria) Known allergic reactions to any ingredients of AK105. Pregnant or lactating women. Any conditions that, in the investigator's opinion, may put subjects treated with the study drug at risks, or interfere with the evaluation of study drug or subject safety, or the interpretation of study results.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AK105 plus Carboplatin and Paclitaxel<br>Subjects receive AK105 200 mg intravenously (IV) plus Paclitaxel 175mg/m^2 IV and carboplatin area under the curve (AUC) 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by AK105 200 mg IV Q3W until progression. | Biological: AK105<br>* IV infusion<br>Drug: Paclitaxel<br>* IV infusion<br>Drug: Carboplatin<br>* IV infusion<br>|
| Placebo Comparator: placebo plus Carboplatin and Paclitaxel<br>Subjects receive placebo intravenously (IV) plus Paclitaxel 175mg/m^2 IV and carboplatin area under the curve (AUC) 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by AK105 200 mg IV Q3W until progression. | Drug: Paclitaxel<br>* IV infusion<br>Drug: Carboplatin<br>* IV infusion<br>Drug: Placebo<br>* IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) in intent-to-treat (ITT) population, assessed by Independent Radiologist Review Committee(IRRC) in accordance with RECIST v1.1 | PFS is defined as the time from the date of randomization till the first documentation of disease progression (per RECIST v1.1 criteria) assessed by IRRC or death due to any cause (whichever occurs first). | Up to approximately 2 years | 
| PFS in PD-L1-selected population, assessed by IRRC in accordance with RECIST v1.1 | PFS is defined as the time from the date of randomization till the first documentation of disease progression (per RECIST v1.1 criteria) assessed by IRRC or death due to any cause (whichever occurs first). | Up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) in ITT population | OS is the time from the date of randomization to death due to any cause. | Up to approximately 2 years | 
| Overall survival (OS) in PD-L1-selected population | OS is the time from the date of randomization to death due to any cause. | Up to approximately 2 years | 
| PFS assessed by the investigator in accordance with RECIST v1.1 | PFS is defined as the time from the date of randomization till the first documentation of disease progression (per RECIST v1.1 criteria) assessed by the investigator or death due to any cause (whichever occurs first). | Up to approximately 2 years | 
| Objective Response Rate (ORR) | ORR is the proportion of subjects with CR or PR , based on RECIST v1.1. | Up to approximately 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 or death due to any cause, whichever occurs first. | Up to approximately 2 years | 
| Disease control rate (DCR) | DCR is defined as the proportion of subjects with CR, PR, or SD, based on RECIST v1.1. | Up to approximately 2 years | 
| Incidence and severity of treatment-emergent adverse events (TEAEs) | An adverse event (AE) is any untoward medical occurrence or the deterioration of existing medical event in a clinical study subject administered an investigational drug, which does not necessarily have an unequivocal causal relationship with the investigational product. | From the time of informed consent signed through 90 days after last dose of AK105 | 
| Observed concentrations of AK105 | The endpoints for assessment of PK of AK105 include serum concentrations of AK105 at different timepoints after AK105 administration. | From first dose of AK105 through 90 days after last dose of AK105 | 
| Number of subjects who develop detectable anti-drug antibodies (ADAs) | The immunogenicity of AK105 will be assessed by summarizing the number of subjects who develop detectable anti-drug antibodies (ADAs). | From first dose of AK105 through 90 days after last dose of AK105 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immuno-oncology, NSCLC, Anti-PD-1 Antibody, immunotherapy