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
- Registration Number
- NCT03447769
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
The primary purpose of the study was to compare the efficacy and safety of canakinumab versus placebo as adjuvant therapy in adult subjects with stages II -IIIA according to the 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) and the subset of IIIB (T\>5cm N2 disease) completely resected (R0) non-small cell lung cancer (NSCLC).
- Detailed Description
This was a phase III, multicenter, randomized, double-blind study to evaluate the efficacy and safety of canakinumab as adjuvant therapy in adult patients with stages AJCC/UICC v.8 II-IIIA and IIIB (T\>5 cm N2) completely resected (R0) NSCLC.
Approximately 1500 patients were planned to be randomized 1:1 to canakinumab, 200 mg subcutaneously (s.c.) every 3 weeks or matching placebo s.c. every 3 weeks. Patients were planned to continue their assigned treatment until they completed 18 cycles (cycle= 21 days) or experienced any one of the following: non-small cell lung cancer (NSCLC) disease recurrence as determined by Investigator; unacceptable toxicity that precluded further treatment; treatment discontinuation at the discretion of the Investigator or patient; start of a new antineoplastic therapy; death, or loss to follow-up, whichever occurred first. All patients who discontinued from the study treatment were to be followed up every 12 weeks for survival until the final OS analysis or death, loss to follow-up or withdrawal of consent for survival follow-up.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 1382
- Had completely resected (R0) NSCLC AJCC/UICC v. 8 stage IIA-IIIA and IIIB (N2 disease only) OR had NSCLC Stage IIA-IIIA, IIIB (N2 disease only) and were candidates for complete resection surgery.
- Cisplatin-based chemotherapy was mandatory for all subjects (Exception: In subjects with stage IIA disease with no nodal involvement, cisplatin-based chemotherapy could be administered if recommended by the treating physician). When required, a minimum of two cycles of cisplatin-based chemotherapy was mandatory, after which additional therapies could be given based upon local clinical practice and/or guidelines. Typically, chemotherapy was initiated within 60 days of surgery.
- Radiation therapy was allowed if indicated as per local guidelines or practice.
- Had recovered from all toxicities related to prior systemic therapy to grade ≤ 1 (CTCAE v 5.0). Exception to this criterion: subjects with any grade of alopecia and grade 2 or less neuropathy were allowed to enter the study
- Had ECOG performance status (PS) of 0 or 1
Key
- Had unresectable or metastatic disease, positive microscopic margins on the pathology report, and/or gross disease remaining at the time of surgery
- Had received any neoadjuvant therapy
- Had presence or history of a malignant disease, other than the resected NSCLC, that had been diagnosed and/or required therapy within the past 3 years Exceptions to this exclusion included 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.
- Had a history of current diagnosis of cardiac disease
- Had uncontrolled diabetes
- Had known active or recurrent hepatic disorder including cirrhosis, hepatitis B and C (positive or indeterminate central laboratory results)
- Subjects had to be evaluated for tuberculosis as per local treatment guidelines or clinical practice. Subjects with active tuberculosis were not eligible.
- Had 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.).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Participants received canakinumab placebo subcutaneously every 3 weeks for up to 18 cycles (approximately 54 weeks) canakinumab Canakinumab Participants received 200mg of canakinumab subcutaneously every 3 weeks for up to 18 cycles (approximately 54 weeks)
- Primary Outcome Measures
Name Time Method Disease Free Survival (DFS) by Local Investigator Up to approximately 4 years 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. Disease recurrence included diagnoses of new primary lung malignancies. Clinical deterioration was not considered as a recurrence of disease. In case of non-conclusive radiological evidence, a biopsy assessment was performed to confirm NSCLC recurrence.
The median DFS was estimated using the Kaplan-Meier method. DFS was censored if no DFS event was observed prior to the analysis cut-off date or subjects who received any subsequent anti-neoplastic therapy for NSCLC. The censoring date was the date of last assessment before the cut-off date or NSCLC related anti-neoplastic therapy date.
- Secondary Outcome Measures
Name Time Method Disease Free Survival (DFS) by Local Investigator in PD-L1 Subgroups Up to approximately 4 years 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. Disease recurrence included diagnoses of new primary lung malignancies. Clinical deterioration was not considered as a recurrence of disease. In case of non-conclusive radiological evidence, a biopsy assessment was performed to confirm NSCLC recurrence.
The median DFS was estimated using the Kaplan-Meier method. DFS was censored if no DFS event was observed prior to the analysis cut-off date or subjects who received any subsequent anti-neoplastic therapy for NSCLC. The censoring date was the date of last assessment before the cut-off date or NSCLC related anti-neoplastic therapy date.
DFS analysis was performed by baseline programmed cell death-ligand 1 (PD-L1) expression status: PD-L1 \<1%, PD-L1 ≥1% and \<49%, and PD-L1 ≥50%.Lung Cancer Specific Survival (LCSS) Up to approximately 4.3 years LCSS is defined as the time from date of randomization to the date of death due to lung cancer. The LCSS distribution was estimated using the Kaplan-Meier method, and Kaplan-Meier medians and 95% confidence intervals of the medians were presented for each treatment group.
Canakinumab Serum Concentrations Cycle 1 on day 1 (pre-dose), day 8 and 15; Cycle 2, 4, 6, 9 and 12 on day 1 (pre-dose). Cycle=21 days Serum concentrations of canakinumab were determinded using an ELISA method.
Time to Definitive 10 Point Deterioration Symptom Scores of Pain,Cough and Dyspnea Per European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ)- Lung Cancer (LC) 13 Questionnaire From baseline up to approximately 4 years The Lung Cancer module of the EORTC's quality of life questionnaire (EORTC QLQ-LC13) was used in conjunction with the EORTC QLQ-C30 and provided information on an additional 13 items specifically related to lung cancer. The lung cancer module incorporated 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 ranged from 0 to 100. A high score indicated a high level of symptoms.
The time to definitive 10 point deterioration symptom scores of pain, cough and dyspnea was defined as the time from the date of randomization to the date of event, which was defined as at least 10 points relative to baseline worsening of the EORTC QLQ-LC13 symptom score with no later change below this threshold or death due to any cause, whichever occurred earlier.Overall Survival (OS) in PD-L1 Subgroups Up to approximately 4.3 years Overall Survival (OS) is the time from the date of randomization to the date of death due to any cause. The OS was censored at the latest date the subject was known to be alive. The OS distribution was estimated using the Kaplan-Meier method, and Kaplan-Meier curves, medians and 95% confidence intervals of the medians were presented for each treatment group. OS analysis was performed by programmed cell death-ligand 1 (PD-L1) expression status: PD-L1 \<1%, PD-L1 ≥1% and \<49%, and PD-L1 ≥50%.
Disease Free Survival (DFS) by Local Investigator in CD8 Subgroups Up to approximately 4 years 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. Disease recurrence included diagnoses of new primary lung malignancies. Clinical deterioration was not considered as a recurrence of disease. In case of non-conclusive radiological evidence, a biopsy assessment was performed to confirm NSCLC recurrence.
The median DFS was estimated using the Kaplan-Meier method. DFS was censored if no DFS event was observed prior to the analysis cut-off date or subjects who received any subsequent anti-neoplastic therapy for NSCLC. The censoring date was the date of last assessment before the cut-off date or NSCLC related anti-neoplastic therapy date.
DFS analysis was performed by CD8 subgroups with the median of baseline CD8 expression as cut-off.Canakinumab Anti-drug Antibody (ADA) Prevalence at Baseline Baseline Canakinumab ADA prevalence at baseline was calculated as the percentage of participants who had an ADA positive result at baseline
Change From Baseline in the Utility Score of the EuroQoL- 5 Dimension- 5 Level (EQ-5D-5L) Baseline, every 3 weeks for 14 months; end of treatment; every 4 weeks up to 130 days post-treatment; at 18,24,30,36 and 48 months post-randomization (if no recurrence); 7 and 28 days post-disease progression, up to approx. 4 years. EQ-5D-5L was a standardized questionnaire that measured health-related QoL. EQ-5D-5L consisted of 2 components: a health state profile and a visual analogue scale. The health state profile included five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, each with five levels ranging from 1 (no problems) to 5 (extreme problems).
The EQ-5D-5L health state profile responses were converted into single index utility score, ranging from -1 to 1, where lower scores representing a higher level of dysfunction. Published weights are available enabling the calculation of the utility score. A positive change from baseline indicated improvement. This endpoint was assessed throughout the study, including safety and efficacy follow-up (FU) visits. Safety FU visits: every 4 weeks after end of treatment up to 130 days post-last dose. Efficacy FU visits: at 18, 24, 30, 36 and 48 months post-randomization (if no recurrence observed during treatment or safety FU)Overall Survival (OS) Up to approximately 4.3 years Overall Survival (OS) is the time from the date of randomization to the date of death due to any cause. The OS was censored at the latest date the subject was known to be alive. The OS distribution was estimated using the Kaplan-Meier method, and Kaplan-Meier medians and 95% confidence intervals of the medians were presented for each treatment group.
Overall Survival (OS) in CD8 Subgroups up to approximately 4.3 years Overall Survival (OS) is the time from the date of randomization to the date of death due to any cause. The OS was censored at the latest date the subject was known to be alive. The OS distribution was estimated using the Kaplan-Meier method, and Kaplan-Meier medians and 95% confidence intervals of the medians were presented for each treatment group. OS analysis was performed by CD8 subgroups with the median of baseline CD8 expression as cut-off.
Canakinumab ADA Incidence From baseline up to 130 days after end of treatment, assessed up to approx. 1.5 years Canakinumab ADA incidence on-treatment was calculated as the percentage 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 was at least the fold titer change greater than the ADA-positive baseline titer)
Time to First 10 Point Deterioration for Symptom Scores of Pain, Cough and Dyspnea Per EORTC QLQ-LC13 Questionnaire From baseline up to approximately 4 years The Lung Cancer module of the EORTC's quality of life questionnaire (EORTC QLQ-LC13) was used in conjunction with the EORTC QLQ-C30 and provided information on an additional 13 items specifically related to lung cancer. The lung cancer module incorporated 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 ranged from 0 to 100. A high score indicated a high level of symptoms.
The time to first 10 point deterioration symptom scores of pain, cough and dyspnea was 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 occurred earlier.Time to Definitive 10 Point Deterioration of Global Health Status/Quality of Life (QoL), Shortness of Breath and Pain Per EORTC QLQ-C30 Questionnaire From baseline up to approximately 4 years The EORTC QLQ-C30 was a questionnaire developed to assess the health-related quality of life of cancer participants. It assessed 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/QoL scale. All domain scores ranged from 0 to 100. A high score for the functional or global health status scales indicated a high level of functioning or QoL; a high score for a symptom scale indicated a high level of symptoms.
The time to definitive 10 point deterioration of global health status/QoL, shortness of breath and pain was defined as the time from the date of randomization to the date of event, which was 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 occured earlier.Time to First 10 Point Deterioration of Global Health Status/QoL, Shortness of Breath and Pain Per EORTC QLQ-C30 Questionnaire From baseline up to approximately 4 years The EORTC QLQ-C30 was a questionnaire developed to assess the health-related quality of life of cancer participants. It assessed 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/QoL scale. All domain scores ranged from 0 to 100. A high score for the functional or global health status scales indicated a high level of functioning or QoL; a high score for a symptom scale indicated a high level of symptoms.
The time to first 10 point deterioration of global health status/QoL, shortness of breath and pain scores was 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 occurred earlier.
Trial Locations
- Locations (21)
Cancer Center of Kansas Dept.ofCancerCtr.ofKansas
🇺🇸Wichita, Kansas, United States
Florida Cancer Specialists
🇺🇸West Palm Beach, Florida, United States
Advanced Medical Specialties Drug Ship - 2
🇺🇸Miami, Florida, United States
Rocky Mountain Cancer Centers Denver-Mdtn(Bone&MarrowTransp)
🇺🇸Longmont, Colorado, United States
Sansum Clinic
🇺🇸Santa Barbara, California, United States
Rush University Medical Center Regulatory
🇺🇸Chicago, Illinois, United States
Louis Stokes Cleveland Department of Veterans Affairs MC .
🇺🇸Cleveland, Ohio, United States
Chattanooga Oncology and Hematology Associates PC Chattanooga Oncology
🇺🇸Chattanooga, Tennessee, United States
Sarah Cannon Research Institute
🇺🇸Nashville, Tennessee, United States
Virginia Cancer Specialists Fairfax Northern Virginia
🇺🇸Fairfax, Virginia, United States
Highlands Oncology Group .
🇺🇸Fayetteville, Arkansas, United States
Cancer and Blood Specialty Clinic
🇺🇸Los Alamitos, California, United States
University of California at Los Angeles
🇺🇸Los Angeles, California, United States
VA Palo Alto Health Care System CRLX030A2301
🇺🇸Palo Alto, California, United States
Florida Cancer Specialists North
🇺🇸Saint Petersburg, Florida, United States
Florida Cancer Affiliates of Ocala
🇺🇸Ocala, Florida, United States
Oncology Associates of Oregon, PC
🇺🇸Eugene, Oregon, United States
Texas Oncology MamieMcFaddenWardCtr
🇺🇸Dallas, Texas, United States
Novartis Investigative Site
🇻🇳Hanoi, Vietnam
Oncology and Hematology Associates of Southwest Virginia Inc .
🇺🇸Salem, Virginia, United States
VA Nebraska-W IA Health Care System .
🇺🇸Omaha, Nebraska, United States