Brief Title: Study of Efficacy and Safety of Canakinumab as Adjuvant Therapy in Adult Subjects With Stages AJCC/UICC v. 8 II-IIIA and IIIB (T>5cm N2) Completely Resected Non-small Cell Lung Cancer Acronym: CANOPY-A

Study Overview
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Brief Summary
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The primary purpose of the study is to compare the efficacy and safety of canakinumab versus placebo as adjuvant therapy in adult subjects with stages AJCC/UICC v. 8 II -IIIA and the subset of IIIB (T>5cm N2 disease) completely resected (R0) non-small cell lung cancer (NSCLC).

Official Title
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A Phase III, Multicenter, Randomized, Double Blind, Placebo-controlled Study Evaluating the Efficacy and Safety of Canakinumab Versus Placebo as Adjuvant Therapy in Adult Subjects With Stages AJCC/UICC v. 8 II -IIIA and IIIB (T>5cm N2) Completely Resected (R0) Non-small Cell Lung Cancer (NSCLC)

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Canakinumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have completely resected (R0) NSCLC AJCC/UICC v. 8 stage IIA-IIIA and IIIB (N2 disease only) OR have NSCLC Stage IIA-IIIA, IIIB (N2 disease only) and are candidates for complete resection surgery Cisplatin-based chemotherapy is mandatory for all subjects (Exception: In subjects with stage IIA disease with no nodal involvement, cisplatin-based chemotherapy can be administered if recommended by the treating physician). When required, a minimum of two cycles of cisplatin-based chemotherapy is mandatory, after which additional therapies can be given based upon local clinical practice and/or guidelines. Typically, chemotherapy is initiated within 60 days of surgery. Must have recovered from all toxicities related to prior systemic therapy to grade ≤ 1 (CTCAE v 4.03). Exception to this criterion: subjects with any grade of alopecia and grade 2 or less neuropathy are allowed to enter the study Have ECOG performance status (PS) of 0 or 1 Exclusion Criteria: Have unresectable or metastatic disease, positive microscopic margins on the pathology report, and/or gross disease remaining at the time of surgery Have received any neoadjuvant therapy Presence or history of a malignant disease, other than the resected NSCLC, that has been diagnosed and/or required therapy within the past 3 years Exceptions to this exclusion include the following: completely resected basal cell and squamous cell skin cancers, completely resected carcinoma in situ of any type and hormonal maintenance for breast and prostate cancer > 3 years. Have a history of current diagnosis of cardiac disease Have uncontrolled diabetes Have known active or recurrent hepatic disorder including cirrhosis, hepatitis B and C (positive or indeterminate central laboratory results) Subjects must be evaluated for tuberculosis as per local treatment guidelines or clinical practice. Subjects with active tuberculosis are not eligible. Have suspected or proven immunocompromised state as described in the protocol Had Live and attenuated vaccination within 3 months prior to first dose of study drug (e.g. MMR, Yellow Fever, Rotavirus, Smallpox, etc.). Other inclusion/exclusion criteria may apply

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: canakinumab<br>Participants will receive canakinumab for 18 cycles (approximately 54 weeks). | Drug: Canakinumab<br>* Canakinumab will be administered periodically for approximately 54 weeks.<br>* Other names: ACZ885;|
| Placebo Comparator: Placebo<br>Participants will receive canakinumab placebo for 18 cycles (approximately 54 weeks). | Drug: Placebo<br>* Placebo will be administered periodically for approximately 54 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival (DFS) by local investigator | DFS is the time from the date of randomization to the date of the first documented NSCLC disease recurrence as assessed by local investigator radiologically or death due to any cause. | Up to approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall Survival (OS) is the time from the date of randomization to the date of death due to any cause. | Up to approximately 5 years | 
| Disease free survival (DFS) by local investigator in PD-L1 subgroups | DFS is the time from the date of randomization to the date of the first documented NSCLC disease recurrence as assessed by local investigator radiologically or death due to any cause. DFS analysis will be performed by programmed cell death-ligand 1 (PD-L1) status (positive, negative) where a positive status is defined as having ≥ 1% expression and a negative status is defined as having < 1% expression. | Up to approximately 5 years | 
| Disease free survival (DFS) by local investigator in CD8 subgroups | DFS is the time from the date of randomization to the date of the first documented NSCLC disease recurrence as assessed by local investigator radiologically or death due to any cause. DFS analysis will be performed by CD8 subgroups with the median and quartiles of baseline CD8 expression as cut-offs. | Up to approximately 5 years | 
| Overall Survival (OS) by local investigator in PD-L1 subgroups | Overall Survival (OS) is the time from the date of randomization to the date of death due to any cause. OS analysis will be performed by programmed cell death-ligand 1 (PD-L1) status (positive, negative) where a positive status is defined as having ≥ 1% expression and a negative status is defined as having < 1% expression. | up to approximately 5 years | 
| Overall Survival (OS) by local investigator in CD8 subgroups | Overall Survival (OS) is the time from the date of randomization to the date of death due to any cause. OS analysis will be performed by CD8 subgroups with the median and quartiles of baseline CD8 expression as cut-offs. | up to approximately 5 years | 
| Lung Cancer Specific Survival (LCSS) | LCSS is defined as the time from date of randomization to the date of death due to lung cancer. | up to approximately 5 years | 
| Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) of canakinumab | To characterize the pharmacokinetics of canakinumab therapy. AUClast will be calculated from serum concentration-time data. | Up to approximately 5 years | 
| Maximum Observed Plasma Concentration (Cmax) of canakinumab | To characterize the pharmacokinetics of canakinumab therapy. Cmax will be calculated from serum concentration-time data. | Up to approximately 5 years | 
| Trough Concentration (Cmin) of canakinumab | To characterize the pharmacokinetics of canakinumab therapy. Cmin will be calculated from serum concentration-time data. | Up to approximately 5 years | 
| Anti-drug Antibody (ADA) prevalence at baseline | Immunogenicity to canakinumab prior to canakinumab exposure. ADA prevalence at baseline wil be calculated as the proportion of participants who had an ADA positive result at baseline | Baseline | 
| Anti-drug Antibody (ADA) incidence | ADA incidence on treatment will be calculated as the proportion of participants who were treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer) | Up to approximately 5 years | 
| Time to definitive 10 point deterioration symptom scores of pain,cough and dyspnea per EORTC QLQ-LC13 questionnaire | The Lung Cancer module of the EORTC's quality of life questionnaire (EORTC QLQ-LC13) is used in conjunction with the EORTC QLQ-C30 and provides information on an additional 13 items specifically related to lung cancer. The lung cancer module incorporates one multi-item scale to assess dyspnea, and 9 single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All of the domain scores range from 0 to 100. A high score indicates a high level of symptoms. The time to definitive 10 point deterioration symptom scores of pain, cough and dyspnea is defined as the time from the date of randomization to the date of event, which is defined as at least 10 points relative to baseline worsening of the EORTC QLQ-LC13 symptom score with no later change below this thereshold or death due to any cause, whichever occurs earlier | Up to approximately 5 years | 
| Time to definitive 10 point deterioration of global health status/QoL, shortness of breath and pain per EORTC QLQ-C30 questionnaire | The EORTC QLQ-C30 is a questionnaire developed to assess the health-related quality of life of cancer participants. It assesses 15 domains consisting of 5 functional domains (physical, role, emotional, cognitive, social) and 9 symptom domains (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties) and a global health status/quality of life (QoL) scale. All of the domain scores range from 0 to 100. A high score for a functional scale indicates a high and healthy level of functioning but a high score for a symptom scale indicates a high level of symptoms. The time to definitive 10 point deterioration of global health status/QoL, shortness of breath and pain is defined as the time from the date of randomization to the date of event, which is defined as at least 10 points relative to baseline worsening of the EORTC QLQ-C30 score with no later change below this threshold or death due to any cause, whichever occurs earlier. | Up to approximately 5 years | 
| Time to first 10 point deterioration for symptom scores of pain, cough and dyspnea per EORTC QLQ-LC13 questionnaire | The Lung Cancer module of the EORTC's quality of life questionnaire (EORTC QLQ-LC13) is used in conjunction with the EORTC QLQ-C30 and provides information on an additional 13 items specifically related to lung cancer. The lung cancer module incorporates one multi-item scale to assess dyspnea, and 9 single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All of the domain scores range from 0 to 100. A high score indicates a high level of symptoms. The time to first 10 point deterioration symptom scores of pain, cough and dyspnea is defined as the time from the date of randomization to the first onset of at least 10 points absolute increase from baseline (worsening) in symptoms scores or death due to any cause, whichever occurs earlier. | Up to approximately 5 years | 
| Time to first 10 point deterioration of global health status/QoL, shortness of breath and pain per EORTC QLQ-C30 questionnaire | The EORTC QLQ-C30 is a questionnaire developed to assess the health-related quality of life of cancer participants. It assesses 15 domains consisting of 5 functional domains (physical, role, emotional, cognitive, social) and 9 symptom domains (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties) and a global health status/quality of life (QoL) scale. All of the domain scores range from 0 to 100. A high score for a functional scale indicates a high and healthy level of functioning but a high score for a symptom scale indicates a high level of symptoms. The time to first 10 point deterioration of global health status/QoL, shortness of breath and pain scores is defined as the time from the date of randomization to the first onset of at least 10 points absolute increase from baseline (worsening) in symptoms scores or death due to any cause, whichever occurs earlier. | Up to approximately 5 years | 
| Utility scores of the EQ-5D-5L | EQ-5D-5L is a standardized participant completed questionnaire that measures health-related quality of life and translates that score into an index value or utility score. EQ-5D-5L consists of two components: a health state profile and an optional visual analogue scale (VAS). EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, and 5= extreme problems. Higher scores indicated greater levels of problems across each of the five dimensions. | Up to approximately 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Small Cell Lung Cancer, NSCLC, ACZ885, canakinumab, adjuvant, AJCC/UICC v. 8 stages II-IIIA and IIIB (T>5cm N2)