Study of Efficacy and Safety of Pembrolizumab Plus Platinum-based Doublet Chemotherapy With or Without Canakinumab in Previously Untreated Locally Advanced or Metastatic Non-squamous and Squamous NSCLC Subjects
- Conditions
- Non-small Cell Lung Cancer
- Interventions
- Drug: canakinumab-matching placebo
- Registration Number
- NCT03631199
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
This was a Phase III study of pembrolizumab plus platinum-based doublet chemotherapy with or without canakinumab in previously untreated locally advanced or metastatic non-squamous and squamous NSCLC participants.
- Detailed Description
The study primarily assessed the safety and tolerability (safety run-in Part A) of pembrolizumab plus platinum-based doublet chemotherapy with canakinumab, and then, the efficacy (double-blind, randomized, placebo-controlled Part B) of pembrolizumab plus platinum-based doublet chemotherapy with or without canakinumab.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 673
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part 1: Cohort A canakinumab Safety run-in, canakinumab in combination with pembrolizumab, carboplatin, and pemetrexed. Part 1: Cohort A pembrolizumab Safety run-in, canakinumab in combination with pembrolizumab, carboplatin, and pemetrexed. Part 1: Cohort A carboplatin Safety run-in, canakinumab in combination with pembrolizumab, carboplatin, and pemetrexed. Part 1: Cohort A pemetrexed Safety run-in, canakinumab in combination with pembrolizumab, carboplatin, and pemetrexed. Part 1: Cohort B canakinumab Safety run-in, canakinumab in combination with pembrolizumab, cisplatin, and pemetrexed. Part 1: Cohort B pembrolizumab Safety run-in, canakinumab in combination with pembrolizumab, cisplatin, and pemetrexed. Part 1: Cohort B cisplatin Safety run-in, canakinumab in combination with pembrolizumab, cisplatin, and pemetrexed. Part 1: Cohort C canakinumab Safety run-in, canakinumab in combination with pembrolizumab, carboplatin, and paclitaxel. Part 2: Canakinumab+pembro+CTx nab-paclitaxel Double-blind, randomized, placebo-controlled, canakinumab in combination with pembrolizumab and platinum-based doublet chemotherapy. Part 2: Placebo+pembro+CTx canakinumab-matching placebo Double-blind, randomized, placebo-controlled, canakinumab-matching placebo in combination with pembrolizumab and platinum-based doublet chemotherapy. Part 2: Placebo+pembro+CTx nab-paclitaxel Double-blind, randomized, placebo-controlled, canakinumab-matching placebo in combination with pembrolizumab and platinum-based doublet chemotherapy. Part 2: Placebo+pembro+CTx pembrolizumab Double-blind, randomized, placebo-controlled, canakinumab-matching placebo in combination with pembrolizumab and platinum-based doublet chemotherapy. Part 2: Canakinumab+pembro+CTx cisplatin Double-blind, randomized, placebo-controlled, canakinumab in combination with pembrolizumab and platinum-based doublet chemotherapy. Part 1: Cohort C paclitaxel Safety run-in, canakinumab in combination with pembrolizumab, carboplatin, and paclitaxel. Part 1: Cohort B pemetrexed Safety run-in, canakinumab in combination with pembrolizumab, cisplatin, and pemetrexed. Part 1: Cohort C pembrolizumab Safety run-in, canakinumab in combination with pembrolizumab, carboplatin, and paclitaxel. Part 1: Cohort C carboplatin Safety run-in, canakinumab in combination with pembrolizumab, carboplatin, and paclitaxel. Part 2: Canakinumab+pembro+CTx pembrolizumab Double-blind, randomized, placebo-controlled, canakinumab in combination with pembrolizumab and platinum-based doublet chemotherapy. Part 2: Canakinumab+pembro+CTx canakinumab Double-blind, randomized, placebo-controlled, canakinumab in combination with pembrolizumab and platinum-based doublet chemotherapy. Part 2: Canakinumab+pembro+CTx carboplatin Double-blind, randomized, placebo-controlled, canakinumab in combination with pembrolizumab and platinum-based doublet chemotherapy. Part 2: Canakinumab+pembro+CTx paclitaxel Double-blind, randomized, placebo-controlled, canakinumab in combination with pembrolizumab and platinum-based doublet chemotherapy. Part 2: Canakinumab+pembro+CTx pemetrexed Double-blind, randomized, placebo-controlled, canakinumab in combination with pembrolizumab and platinum-based doublet chemotherapy. Part 2: Placebo+pembro+CTx carboplatin Double-blind, randomized, placebo-controlled, canakinumab-matching placebo in combination with pembrolizumab and platinum-based doublet chemotherapy. Part 2: Placebo+pembro+CTx cisplatin Double-blind, randomized, placebo-controlled, canakinumab-matching placebo in combination with pembrolizumab and platinum-based doublet chemotherapy. Part 2: Placebo+pembro+CTx paclitaxel Double-blind, randomized, placebo-controlled, canakinumab-matching placebo in combination with pembrolizumab and platinum-based doublet chemotherapy. Part 2: Placebo+pembro+CTx pemetrexed Double-blind, randomized, placebo-controlled, canakinumab-matching placebo in combination with pembrolizumab and platinum-based doublet chemotherapy.
- Primary Outcome Measures
Name Time Method Part 1 (Safety Run-in): Number of Participants With Dose-limiting Toxicities (DLTs) During the first 42 days of dosing A DLT was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.
Part 2 (Double-blind, Randomized, Placebo-controlled): Progression-free Survival (PFS) Per Investigator Assessment Using RECIST v1.1 18 months Progression free survival was defined as the time from randomization to the date of the first documented radiological progression using RECIST 1.1 (Response evaluation criteria in solid tumor) or death due to any cause.
Part 2 (Double-blind, Randomized, Placebo-controlled): Overall Survival (OS) Per Investigator Assessment Using RECIST v1.1 Up to approximately 32 months Overall survival is defined as the time from date of randomization to date of death due to any cause.
- Secondary Outcome Measures
Name Time Method Part 1 (Safety Run-in): Overall Response Rate (ORR) Per Investigator Assessment Using RECIST v1.1 Up to approximately 14 months ORR was defined as the percentage of participants with confirmed best overall response of complete response (CR) or partial response (PR), as per investigator's assessment by RECIST 1.1. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Part 2 (Double-blind, Randomized, Placebo-controlled): Overall Response Rate (ORR) Per Investigator Assessment Using RECIST v1.1 Up to approximately 26 months ORR was defined as the percentage of participants with confirmed best overall response of complete response (CR) or partial response (PR), as per investigator's assessment by RECIST 1.1. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Part 1 (Safety run-in): Disease Control Rate (DCR) Per Investigator Assessment Using RECIST v1.1 Up to approximately 14 months Disease control rate was defined as the percentage of participants with complete response (CR) or partial response (PR) or participants with stable disease (SD) as per investigator assessment according to RECIST 1.1 criteria. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters; SD=Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
Part 2 (Double-blind, Randomized, Placebo-controlled): Disease Control Rate (DCR) Per Investigator Assessment Using RECIST v1.1 Up to approximately 26 months Disease control rate was defined as the percentage of participants with complete response (CR) or partial response (PR) or participants with stable disease (SD) as per investigator assessment according to RECIST 1.1 criteria. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters; SD=Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
Part 1 (Safety run-in): Duration of Response (DOR) Per Investigator Assessment Using RECIST v1.1 Up to approximately 25 months Duration of response was defined as the time from first documented response of CR or PR to date of first documented progression or death due to any cause, according to RECIST 1.1 criteria. DOR only applied to participants whose best overall response was CR or PR based on tumor response data per local review. If a participant did not have an event, DOR was censored at the date of last adequate tumor assessment. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Part 2 (Double-blind, Randomized, Placebo-controlled): Duration of Response (DOR) Per Investigator Assessment Using RECIST v1.1 Up to approximately 26 months Duration of response was defined as the time from first documented response of CR or PR to date of first documented progression or death due to any cause, according to RECIST 1.1 criteria. DOR only applied to participants whose best overall response was CR or PR based on tumor response data per local review. If a participant did not have an event, DOR was censored at the date of last adequate tumor assessment. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Part 2 (Double-blind, Randomized, Placebo-controlled): Time to Response (TTR) Per Investigator Assessment Using RECIST v1.1 Up to approximately 26 months Time to response (TTR) was defined as duration of time between the date of randomization and the date of first documented response of either CR or PR, according to RECIST 1.1 criteria. Duration of response was defined as the time from first documented response of CR or PR to date of first documented progression or death due to any cause, according to RECIST 1.1 criteria. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Part 1 (Safety Run-in): Antidrug Antibodies (ADA) of Canakinumab Predose (0 hours (h)) on Day 1 of Cycles 1, 4, 8, 12, 16 (Cycle length =21 days), at end of treatment & then at 26, 78 and 130 days after last dose Participants with at least one ADA-positive sample.
Part 2 (Double-blind, Randomized, Placebo-controlled): Number of Participants With Antidrug Antibodies (ADA) of Canakinumab Up to approximately 26 months Participants with at least one ADA-positive sample.
Part 1 (Safety run-in): Antidrug Antibodies (ADAs) of Pembrolizumab Predose (0 h) on Day 1 of Cycles 1, 2, 4, 8, 12, 16 (Cycle length =21 days), at end of treatment & then at 26 days after last dose Participants with at least one ADA-positive sample.
Part 2 (Double-blind, Randomized, Placebo-controlled): Antidrug Antibodies (ADA) of Pembrolizumab Up to approximately 26 months Participants with at least one ADA-positive sample.
Part 1 (Safety Run-in): Serum Canakinumab Concentration Predose (0 h) on Day 1 of Cycles 1-6, 8, 12, 16, Postdose on day 2, 8, 15 of Cycle 1, Post dose on Cycle 5 day 8, at end of treatment & then at 26, 78 and 130 days after last dose (Cycle length =21 days) Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Canakinumab Concentration Predose (0 h) on Day 1 of Cycles 1-6, 8, 12, 16, Postdose on day 2, 8, 15 of Cycle 1, Post dose on Cycle 5 day 8, at end of treatment & then at 26, 78 and 130 days after last dose (Cycle length =21 days) Part 1 (Safety Run-in): Serum Pembrolizumab Concentration Predose (0 h) on Day 1 of Cycles 1-6, 8, 12, 16, Postdose on day 2, 8, 15 of Cycle 1, at end of treatment & then at 26 days after last dose (Cycle length =21 days) Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration Predose (0 h) on Day 1 of Cycles 1-6, 8, 12, 16, Postdose on day 2, 8, 15 of Cycle 1, at end of treatment & then at 26 days after last dose (Cycle length =21 days) Part 1 (Safety Run-in): Plasma Pemetrexed Concentration Predose (0 h) and end of infusion on Cycle 1 and 2; 1, 4, 8 h post infusion on Cycle 1; 1, 2, 4, 8h post infusion on Cycle 2 (Cycle length =21 days) Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration Predose (0 h) and end of infusion on Cycle 1 and 2; 1, 4, 8 h post infusion on Cycle 1; 1, 2, 4, 8h post infusion on Cycle 2 (Cycle length =21 days) Part 1 (Safety Run-in): Plasma Cisplatin Concentration Predose (0 h) and end of infusion on Cycle 1 and 2; 2, 4, 8 h post infusion on Cycle 1; 1.5, 2, 4, 8 h post infusion on Cycle 2 (Cycle length =21 days) Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration Predose (0 h) and end of infusion on Cycle 1 and 2; 2, 4, 8 h post infusion on Cycle 1; 1.5, 2, 4, 8 h post infusion on Cycle 2 (Cycle length = 21 days) Part 1 (Safety Run-in): Plasma Carboplatin Concentration Predose (0 h), end of infusion, 1, 2, 4, 8 h post infusion on Cycles 1 and 2 (Cycle length =21 days) Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration Predose (0 h), end of infusion, 1, 2, 4, 8 h post infusion on Cycles 1 and 2 (Cycle length =21 days) Part 1 (Safety Run-in): Plasma Paclitaxel Concentration Predose (0 h) and end of infusion on Cycle 1 and 2; 4, 8, 12 h post infusion on Cycle 1; 4, 6, 8, 12 h post infusion on Cycle 2 (Cycle length =21 days) Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration Predose (0 h) and end of infusion on Cycle 1 and 2; 4, 8, 12 h post infusion on Cycle 1; 4, 6, 8, 12 h post infusion on Cycle 2 (Cycle length =21 days) Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration Predose (0 h) and end of infusion on Cy 1 and 2, 4, 8, 12 h post infusion on Cy 1, 4, 6, 8, 12 h post infusion on Cy 2 (Cy length =21 days) Part 2 (Double-blind, Randomized, Placebo-controlled): Time to Definitive 10-point Deterioration (TTDD) Symptom Scores of Pain, Cough and Dyspnea Per EORTC QLQ-LC13 Questionnaire Up to approximately 25 months The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13) comprises both multi-item and single-item measures of lung cancer-associated symptoms (ie, coughing, dyspnea, and chest pain). Scores for each scale and single-item range from 0 to 100, with higher scores indicating higher level of symptoms. TTDD for chest pain, cough and dyspnea was defined as the time from randomization to the date of event, which was defined as at least 10 points absolute worsening from baseline of the corresponding scale score, with no later change below this threshold ie.\<10 points was observed, or if this worsening was observed at the last assessment for the subject, or death due to any cause (whichever occurred earlier). If a subject did not have an event, TTDD was censored at the last adequate assessment.
Part 2 (Double-blind, Randomized, Placebo-controlled): Time to Definitive Deterioration in Global Health Status/Quality of Life, Shortness of Breath and Pain Per EORTC QLQ-C30 Questionnaire Up to approximately 25 months The European Organization for Research and Treatment of Cancer quality of life (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/QoL scale. All domain scores range from 0 to 100. A high score for the functional or global health status scales indicates a high level of functioning or QoL; a high score for a symptom scale indicates a high level of symptoms.
Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire Assessed every 3 weeks from Week 3 through Week 108, at follow-up visits 1, 2, 3, 4, and 5 (follow-up visits occurred every 26 days from week 108), and at 7 and 28 days post-disease progression, all up to a maximum of 3.5 years The EQ-5D-5L questionnaire is a standardized measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L measures 5 items on mobility, self-care, usual activities, pain/discomfort, anxiety/depression, measured on 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. A utility index can be computed from the EQ 5D-5L descriptive system with utility scores ranging from -0.281 (worst imaginable health state) to 1 (best imaginable health state), with -0.281 representing an "unconscious" health state. A single index value is analyzed for the EQ-5D-5L score. An increase from baseline in the EQ-ED-5L utility index is indicative of an improvement.). CFB = change from baseline
Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire - Visual Analog Scale (VAS) Assessed every 3 weeks from Week 3 through Week 108, at follow-up visits 1, 2, 3, 4, and 5 (follow-up visits occurred every 26 days from week 108), and at 7 and 28 days post-disease progression, all up to a maximum of 3.5 years The EQ-5D-5L is a standardized questionnaire used to assess health-related quality of life, and it includes a Visual Analog Scale (VAS). The VAS score is obtained by asking the individual to rate their current health status on a scale from 0 to 100, where 0 represents the worst possible health state and 100 represents the best possible health state.
The change from baseline in EQ-5D-5L VAS score was calculated. A positive change from baseline indicates improvement in the health status. CFB = change from baselineAll Collected Deaths On-treatment deaths: Up to approximately 29 months in Part 1 or approximately 25 months in Part 2. Post-treatment survival follow-up deaths: Up to an additional 130 days. On-treatment deaths due to any cause were collected from first dose of study medication to 30 days after the last dose of study treatment. Post-treatment survival follow-up deaths were collected from Day 31 after last dose of study medication to the data cut-off date.
Trial Locations
- Locations (5)
Pacific Shores Medical Group .
🇺🇸Long Beach, California, United States
USC Kenneth Norris Comprehensive Cancer Center .
🇺🇸Los Angeles, California, United States
Advent Health Cancer Institute
🇺🇸Orlando, Florida, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Novartis Investigative Site
🇻🇳Hanoi, Vietnam