A Study of Tislelizumab (BGB-A317) Plus Chemoradiotherapy Followed by Tislelizumab Monotherapy in Newly Diagnosed, Stage III Subjects With Locally Advanced, Unresectable Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This is a Phase 3, randomized, double-blind, placebo-controlled multicenter global study designed to compare the efficacy and safety of tislelizumab in combination with concurrent chemoradiotherapy (cCRT) followed by tislelizumab monotherapy versus cCRT alone, and tislelizumab given sequentially after cCRT versus cCRT alone, in newly diagnosed stage III subjects with locally advanced, unresectable non-small cell lung cancer (NSCLC). The primary endpoint is centrally-assessed progression free survival (PFS) in the intent-to-treat (ITT) population. .

Official Title
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A PHASE 3, RANDOMIZED, BLINDED, PLACEBO-CONTROLLED STUDY OF TISLELIZUMAB (BGB-A317) PLUS CHEMORADIOTHERAPY FOLLOWED BY TISLELIZUMAB MONOTHERAPY IN NEWLY DIAGNOSED, STAGE III SUBJECTS WITH LOCALLY ADVANCED, UNRESECTABLE NON-SMALL CELL LUNG CANCER

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Tislelizumab
* Drug: Concurrent chemoradiotherapy (cCRT)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed, histologically confirmed, locally advanced, stage III unresectable non small cell lung cancer (NSCLC). Staging will be confirmed at screening by positron emission tomography-computed tomography (PET/CT) and brain imaging by magnetic resonance imaging (MRI) or computed tomography (CT) with contrast. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) gene translocation status available prior to randomization. Provision of fresh or archival tumor tissue or discussion with Sponsor. Adequate hematologic and end-organ function. Exclusion Criteria: Prior therapies including those targeting PD-1 or PD-L1 or chemotherapy, radiation, targeted therapy, biologic therapy, immunotherapy or investigational agent used to control non-small cell lung cancer (NSCLC). History of severe hypersensitivity reactions to other monoclonal antibodies or any contraindication to the planned chemotherapy regimen. History of, or ongoing, interstitial lung disease; pneumonitis requiring steroids; or clinically significant pericardial effusion. Any active malignancy less than or equal to 2 years before randomization, with the exception of non-small cell lung cancer (NSCLC) and any locally recurring cancer that has been treated curatively. Severe chronic or active infections including those requiring systemic antibacterial, antifungal or antiviral therapy; known human immunodeficiency virus (HIV) infection; untreated chronic hepatitis B or chronic hepatitis B virus carries or active hepatitis C; or active autoimmune disease. Prior allogeneic stem cell transplantation or organ transplantation. Significant cardiovascular disease or other condition which places the patient at risk.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1:Tislelizumab + cCRT followed by tislelizumab monotherapy<br>Tislelizumab 200 mg is administered by intravenous (IV) administration and given together upfront with concurrent platinum-based chemoradiotherapy (cCRT) for the first 6 weeks, followed by tislelizumab 200 mg by IV adminstration monotherapy. The standard platinum-based chemotherapy options include carboplatin/ paclitaxel and cisplatin/etoposide | Drug: Tislelizumab<br>* PD-1 inhibitor (monoclonal antibody against PD-1)<br>* Other names: BGB-A317;Drug: Concurrent chemoradiotherapy (cCRT)<br>* Chemotherapy options include carboplatin/paclitaxel and cisplatin/etoposide per standard of care. Radiotherapy will also be given concurrently with chemotherapy.<br>|
| Experimental: Arm 2: Placebo + cCRT followed by tislelizumab monotherapy<br>Placebo is given with concurrent platinum-based chemoradiotherapy (cCRT) for the first 6 weeks, followed by tislelizumab 200 mg by IV administration monotherapy. The standard platinum-based chemotherapy options include carboplatin/paclitaxel and cisplatin/etoposide. | Drug: Tislelizumab<br>* PD-1 inhibitor (monoclonal antibody against PD-1)<br>* Other names: BGB-A317;Drug: Concurrent chemoradiotherapy (cCRT)<br>* Chemotherapy options include carboplatin/paclitaxel and cisplatin/etoposide per standard of care. Radiotherapy will also be given concurrently with chemotherapy.<br>Other: Placebo<br>* Placebo<br>|
| Placebo Comparator: Arm 3: Placebo + cCRT followed by placebo monotherapy<br>Placebo is given with concurrent platinum-based chemoradiotherapy (cCRT) for the first 6 weeks, followed by placebo monotherapy. The standard platinum-based chemotherapy options include carboplatin/paclitaxel and cisplatin/etoposide. | Drug: Concurrent chemoradiotherapy (cCRT)<br>* Chemotherapy options include carboplatin/paclitaxel and cisplatin/etoposide per standard of care. Radiotherapy will also be given concurrently with chemotherapy.<br>Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Progression-free survival was defined as the time from the date of randomization to the date of the first objectively tumor progression as assessed by the blinded independent central review per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria (documented by radiological assessment) or death (any cause) on or prior to the clinical cut-off date, which ever occurred first. Stable disease-neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for Progressive disease (PD)• Progressive Disease- At least a 20% increase in the sum of diameters of target lesions from nadir. | Up to approximately 5 years; date of randomization to the date of tumor progression or death; until study withdrawal date of 26 June 2019 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival was defined as the time between randomization of treatment and death from any cause. | Up to approximately 5 years; date of randomization to date of death from any cause. | 
| Overall Survival at 24 Months | Overall survival was defined as the time between randomization of treatment and death from any cause. | Up to approximately 24 months | 
| Percentage of Participants Who Achieved a Best Overall Response of Complete Response or Partial Response | Overall Response was defined as percentage of participants who had a radiologic confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) guidelines, between Day 1 of treatment and subsequent anti-cancer therapy, death or study discontinuation. Complete response was defined as the disappearance of all target lesions; partial response (PR) is defined as at least a 30% decrease in the sum of diameters of target lesions from baseline; stable disease-neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for progressive disease (PD). | Up to approximately 5 years | 
| Duration of Response | Duration of Response is defined as the time from the first occurrence of a documented objective response to the time of relapse, as determined by blinded independent central review per RECIST v1.1, or death from any cause, whichever comes first. | Up to approximately 5 years | 
| Percentage of Participants Alive and Progression-Free at 12 Months (APF12) | Progression-free survival was defined as the time from the date of randomization to the date of the first objectively tumor progression as assessed by the blinded independent central review per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria (documented by radiological assessment) or death (any cause) on or prior to the clinical cut-off date, which ever occurred first | Up to 12 months | 
| Percentage of Participants Alive and Progression-free at 18 Months (APF18) | Progression-free survival was defined as the time from the date of randomization to the date of the first objectively tumor progression as assessed by the blinded independent central review per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria (documented by radiological assessment) or death (any cause) on or prior to the clinical cut-off date, which ever occurred first | Up to approximately 18 months | 
| Time to Distant Metastasis (TTDM) | TTDM was defined as the time from the date of randomization until the first date of distant metastasis or death in the absence of distant metastasis. Distant metastasis was defined as any new lesion that is outside of the radiation field according to RECIST v1.1 or proven by biopsy. | Up to approximately 5 years | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAEs include any adverse events (AEs) that had an onset date or a worsening in severity from baseline on or after the first dose of study drug up to 30 days following study drug discontinuation or initiation of new anticancer therapy, whichever occurred first. TEAEs also included all immune-related AEs recorded up to 90 days after the last dose of tislelizumab or placebo, regardless of whether or not the particpant started a new anticancer therapy. In addition, any serious AE with an onset date more than 30 days after the last dose of study drug that is assessed by the investigator as related to study drug were considered a TEAE. | From first dose of study drug up to study withdrawal date of 26 June 2019; 15 days. | 
| Number of Participants With Lung Cancer Symptoms Assessed by the Corresponding Domains of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC-QLQ-C30) and Lung-Cancer Specific QLQ-LC13 | The EORTC QLQ-C30 is a 30-item, questionnaire assessing quality of life (QoL), psychosocial burden and physical symptoms. It is classified into 15 domains: 5 functional subscales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning); 3 multi-item symptom subscales (fatigue, nausea/vomiting, and pain); each item is measured on a 4 point response scale; (not at all, a little, quite a bit, very much), with the exception of the 2 items measuring global health and QoL, (measured on a 7-point response scale). Scores are linearly transformed to 0 to 100 scores. Scores vary from 0 (worst) to 100 (best) for the functional dimensions and GHS, and from 0 (best) to 100 (worst) for the symptom dimensions; higher scores = better QoL, better functioning, or more severe symptoms, respectively. The LC13 covers 13 typical symptoms of lung cancer patients, such as coughing, pain, dyspnea, sore mouth, peripheral neuropathy, and hair loss. | Up to approximately 5 years | 
| Percentage of Participants Who Would Have Continued on to Monotherapy Phase | Included the percentage of participants who would have received at least one dose of tislelizumab or placebo in the monotherapy phase before progression. | Up to approximately 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Locally Advanced, Unresectable Non-Small Cell Lung Cancer, Non-Small Cell Lung Cancer, NSCLC, Randomized, BGB-A317, Tislelizumab, PD-1