Non-small Cell Lung Cancer
Conditions
Keywords
ACZ885, canakinumab, pembrolizumab, carboplatin, cisplatin, paclitaxel, nab-paclitaxel, pemetrexed, NSCLC, non-small cell lung cancer, non small cell lung cancer, squamous, non-squamous, hsCRP, IL-1β, PD-L1, CANOPY, CANOPY-1, platinum-based doublet chemotherapy, first line therapy, locally advanced, metastatic
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.
Interventions
DRUGcanakinumab
canakinumab 200 mg subcutaneous (s.c.) injection every 3 weeks (squamous and non-squamous)
DRUGcanakinumab-matching placebo
canakinumab placebo every 3 weeks (squamous and non-squamous)
DRUGpembrolizumab
200 mg every 3 weeks (squamous and non-squamous)
DRUGcarboplatin
Area Under the Curve (AUC) 5 mg/mL\*min every 3 weeks (non-squamous) or AUC 6 mg/mL\*min (squamous)
DRUGcisplatin
75 mg/m\^2 every 3 weeks (non-squamous)
DRUGpaclitaxel
200 mg/m\^2 every 3 weeks (squamous)
DRUGnab-paclitaxel
100 mg/m\^2 on Days 1, 8, and 15 of every cycle (squamous)
DRUGpemetrexed
500 mg/m\^2 every 3 weeks (non-squamous)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
Key inclusion criteria: * Histologically confirmed locally advanced stage IIIB or stage IV NSCLC for treatment in the first-line setting * Known PD-L1 status determined by a Novartis designated central laboratory. A newly obtained tissue biopsy or an archival biopsy (block or slides) is required for PD-L1 determination (PD-L1 IHC 22C3 pharmDx assay), prior to study randomization. Note: For the safety run-in part, known PD-L1 status is not required. * Eastern Cooperative oncology group (ECOG) performance status of 0 or 1. * At least 1 measurable lesion by RECIST 1.1 Key
Exclusion criteria
* Previous immunotherapy (e.g. anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways). * Prior treatment with canakinumab or drugs of a similar mechanism of action (IL-1β inhibitor). * Subjects with epidermal growth factor receptor (EGFR) sensitizing mutations (identified in exons 19, 20, or 21), and/or ALK rearrangement by locally approved laboratory testing. * Previously untreated or symptomatic central nervous system (CNS) metastases or lepto-meningeal disease. * Subject with suspected or proven immune-compromised state or infections. * Subject has prior to starting study drug: received live vaccination ≤3 months, had major surgery ≤4 weeks prior to starting study drug, has thoracic radiotherapy: lung fields ≤ 4 weeks, other anatomic sites ≤ 2 weeks, palliative radiotherapy for bone lesions ≤ 2 weeks.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 baseline |
Countries
Argentina, Australia, Austria, Brazil, Canada, Chile, China, Colombia, Czechia, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, Iceland, India, Italy, Japan, Lebanon, Malaysia, Netherlands, Norway, Philippines, Poland, Portugal, Romania, Russia, Singapore, Slovakia, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States, Vietnam
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Pre-assignment details
All inclusion and exclusion criteria were checked at screening.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Cohort A Safety run-in, canakinumab in combination with pembrolizumab, carboplatin, and pemetrexed. | 10 |
| Part 1: Cohort B Safety run-in, canakinumab in combination with pembrolizumab, cisplatin, and pemetrexed. | 11 |
| Part 1: Cohort C Safety run-in, canakinumab in combination with pembrolizumab, carboplatin, and paclitaxel. | 9 |
| Part 2: Canakinumab+Pembro+CTx Double-blind, randomized, placebo-controlled, canakinumab in combination with pembrolizumab and platinum-based doublet chemotherapy. | 320 |
| Part 2: Placebo+Pembro+CTx Double-blind, randomized, placebo-controlled, canakinumab-matching placebo in combination with pembrolizumab and platinum-based doublet chemotherapy. | 323 |
| Total | 673 |
Baseline characteristics
| Characteristic | Part 1: Cohort A | Part 1: Cohort B | Part 1: Cohort C | Part 2: Canakinumab+Pembro+CTx | Part 2: Placebo+Pembro+CTx | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 64.5 years STANDARD_DEVIATION 6.57 | 57.9 years STANDARD_DEVIATION 13.03 | 63.1 years STANDARD_DEVIATION 7.18 | 61.7 years STANDARD_DEVIATION 9.65 | 62.7 years STANDARD_DEVIATION 8.74 | 62.2 years STANDARD_DEVIATION 9.23 |
| Race/Ethnicity, Customized Asian | 5 Participants | 5 Participants | 2 Participants | 115 Participants | 117 Participants | 244 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants | 5 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 3 Participants | 0 Participants | 19 Participants | 20 Participants | 42 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 3 Participants | 7 Participants | 185 Participants | 180 Participants | 380 Participants |
| Sex: Female, Male Female | 0 Participants | 5 Participants | 3 Participants | 93 Participants | 91 Participants | 192 Participants |
| Sex: Female, Male Male | 10 Participants | 6 Participants | 6 Participants | 227 Participants | 232 Participants | 481 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 10 | 1 / 11 | 4 / 9 | 97 / 320 | 102 / 323 | 2 / 6 | 5 / 10 | 3 / 5 | 50 / 223 | 57 / 220 |
| other Total, other adverse events | 10 / 10 | 11 / 11 | 9 / 9 | 309 / 320 | 310 / 322 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 4 / 10 | 3 / 11 | 4 / 9 | 174 / 320 | 167 / 322 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Part 1 (Safety Run-in): Number of Participants With Dose-limiting Toxicities (DLTs)
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.
Time frame: During the first 42 days of dosing
Population: The dose-determining set (DDS) included all participants from the safety set who met the minimum exposure criterion and had sufficient safety evaluations, or experienced a dose-limiting toxicity (DLT) during the first 42 days (6 weeks) of dosing. Data are reported for Part 1 only.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cohort A | Part 1 (Safety Run-in): Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Part 1: Cohort B | Part 1 (Safety Run-in): Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Part 1: Cohort C | Part 1 (Safety Run-in): Number of Participants With Dose-limiting Toxicities (DLTs) | 1 Participants |
Primary
Part 2 (Double-blind, Randomized, Placebo-controlled): Overall Survival (OS) Per Investigator Assessment Using RECIST v1.1
Overall survival is defined as the time from date of randomization to date of death due to any cause.
Time frame: Up to approximately 32 months
Population: The full analysis set (FAS) comprised all participants to whom study treatment was assigned and who received at least one dose of the study treatment. Data are reported for Part 2 only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Overall Survival (OS) Per Investigator Assessment Using RECIST v1.1 | 20.83 months |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Overall Survival (OS) Per Investigator Assessment Using RECIST v1.1 | 20.17 months |
Primary
Part 2 (Double-blind, Randomized, Placebo-controlled): Progression-free Survival (PFS) Per Investigator Assessment Using RECIST v1.1
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.
Time frame: 18 months
Population: The full analysis set (FAS) comprised all participants to whom study treatment was assigned and who received at least one dose of the study treatment. Data are reported for Part 2 only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Progression-free Survival (PFS) Per Investigator Assessment Using RECIST v1.1 | 6.77 months |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Progression-free Survival (PFS) Per Investigator Assessment Using RECIST v1.1 | 6.77 months |
Secondary
Part 1 (Safety Run-in): Antidrug Antibodies (ADA) of Canakinumab
Participants with at least one ADA-positive sample.
Time frame: 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
Secondary
Part 1 (Safety run-in): Antidrug Antibodies (ADAs) of Pembrolizumab
Participants with at least one ADA-positive sample.
Time frame: 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
Secondary
Part 1 (Safety run-in): Disease Control Rate (DCR) Per Investigator Assessment Using RECIST v1.1
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.
Time frame: Up to approximately 14 months
Population: The full analysis set (FAS) comprised all participants to whom study treatment was assigned and who received at least one dose of the study treatment. Data are reported for Part 1 only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Cohort A | Part 1 (Safety run-in): Disease Control Rate (DCR) Per Investigator Assessment Using RECIST v1.1 | 70.0 percentage of participants |
| Part 1: Cohort B | Part 1 (Safety run-in): Disease Control Rate (DCR) Per Investigator Assessment Using RECIST v1.1 | 81.8 percentage of participants |
| Part 1: Cohort C | Part 1 (Safety run-in): Disease Control Rate (DCR) Per Investigator Assessment Using RECIST v1.1 | 77.8 percentage of participants |
Secondary
Part 1 (Safety run-in): Duration of Response (DOR) Per Investigator Assessment Using RECIST v1.1
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.
Time frame: Up to approximately 25 months
Population: The full analysis set (FAS) comprised all participants to whom study treatment was assigned and who received at least one dose of the study treatment. Participants who never achieved a best overall response of CR or PR were excluded from the analysis. Data are reported for responders in Part 1 only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort A | Part 1 (Safety run-in): Duration of Response (DOR) Per Investigator Assessment Using RECIST v1.1 | 7.43 months |
| Part 1: Cohort B | Part 1 (Safety run-in): Duration of Response (DOR) Per Investigator Assessment Using RECIST v1.1 | 18.50 months |
| Part 1: Cohort C | Part 1 (Safety run-in): Duration of Response (DOR) Per Investigator Assessment Using RECIST v1.1 | 8.15 months |
Secondary
Part 1 (Safety Run-in): Overall Response Rate (ORR) Per Investigator Assessment Using RECIST v1.1
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.
Time frame: Up to approximately 14 months
Population: The full analysis set (FAS) comprised all participants to whom study treatment was assigned and who received at least one dose of the study treatment. Data are reported for Part 1 only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Cohort A | Part 1 (Safety Run-in): Overall Response Rate (ORR) Per Investigator Assessment Using RECIST v1.1 | 20.0 percentage of participants |
| Part 1: Cohort B | Part 1 (Safety Run-in): Overall Response Rate (ORR) Per Investigator Assessment Using RECIST v1.1 | 72.7 percentage of participants |
| Part 1: Cohort C | Part 1 (Safety Run-in): Overall Response Rate (ORR) Per Investigator Assessment Using RECIST v1.1 | 44.4 percentage of participants |
Secondary
Part 1 (Safety Run-in): Plasma Carboplatin Concentration
Time frame: Predose (0 h), end of infusion, 1, 2, 4, 8 h post infusion on Cycles 1 and 2 (Cycle length =21 days)
Population: The pharmacokinetic (PK) analysis set -carboplatin included all participants who received at least one dose of carboplatin and had at least one evaluable PK sample for carboplatin. Data are reported for the Part 1 Cohorts A and C arms only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 1, Day 1, Pre-infusion n=8,9 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 1, Day 1, End-of-infusion, n=9,9 | 17400 μg/mL | Geometric Coefficient of Variation 21.9 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 1, Day 1, 1 hour n=9,6 | 10400 μg/mL | Geometric Coefficient of Variation 42.7 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 1, Day 1, 2 hours n=9,9 | 6200 μg/mL | Geometric Coefficient of Variation 34.3 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 1, Day 1, 4 hours n=9,9 | 3380 μg/mL | Geometric Coefficient of Variation 34.6 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 1, Day 1, 8 hours n=9,6 | 1370 μg/mL | Geometric Coefficient of Variation 33.6 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 2, Day 1, Pre-infusion n=9,9 | 125 μg/mL | Geometric Coefficient of Variation 29.7 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 2, Day 1, End-of-infusion n=9,9 | 10300 μg/mL | Geometric Coefficient of Variation 441.8 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 2, Day 1, 1 hour n=8,6 | 13300 μg/mL | Geometric Coefficient of Variation 44.1 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 2, Day 1, 2 hours n=9,9 | 8080 μg/mL | Geometric Coefficient of Variation 38.5 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 2, Day 1, 4 hours n=9,9 | 3590 μg/mL | Geometric Coefficient of Variation 26.8 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 2, Day 1, 8 hours n=9,5 | 1670 μg/mL | Geometric Coefficient of Variation 29.7 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 2, Day 1, 4 hours n=9,9 | 3680 μg/mL | Geometric Coefficient of Variation 26.7 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 1, Day 1, Pre-infusion n=8,9 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 2, Day 1, Pre-infusion n=9,9 | 120 μg/mL | Geometric Coefficient of Variation 16.4 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 1, Day 1, End-of-infusion, n=9,9 | 21700 μg/mL | Geometric Coefficient of Variation 49.8 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 2, Day 1, 2 hours n=9,9 | 6620 μg/mL | Geometric Coefficient of Variation 22.5 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 1, Day 1, 1 hour n=9,6 | 13300 μg/mL | Geometric Coefficient of Variation 46.8 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 2, Day 1, End-of-infusion n=9,9 | 16200 μg/mL | Geometric Coefficient of Variation 32.4 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 1, Day 1, 2 hours n=9,9 | 7380 μg/mL | Geometric Coefficient of Variation 23.5 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 2, Day 1, 8 hours n=9,5 | 1800 μg/mL | Geometric Coefficient of Variation 34.8 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 1, Day 1, 4 hours n=9,9 | 3970 μg/mL | Geometric Coefficient of Variation 29.4 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 2, Day 1, 1 hour n=8,6 | 11400 μg/mL | Geometric Coefficient of Variation 24.5 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Carboplatin Concentration | Cycle 1, Day 1, 8 hours n=9,6 | 1540 μg/mL | Geometric Coefficient of Variation 39.6 |
Secondary
Part 1 (Safety Run-in): Plasma Cisplatin Concentration
Time frame: 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)
Population: The pharmacokinetic (PK) analysis set -cisplatin included all participants who received at least one dose of cisplatin and had at least one evaluable PK sample for cisplatin. Data are reported for the Part 1 Cohort B arm only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Cisplatin Concentration | Cycle 1, Day 1, Pre-infusion n=11 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Cisplatin Concentration | Cycle 1, Day 1, end-of-infusion, n=11 | 3750 μg/mL | Geometric Coefficient of Variation 130.2 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Cisplatin Concentration | Cycle 1, Day 1, 2 hours n=6 | 3690 μg/mL | Geometric Coefficient of Variation 248.2 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Cisplatin Concentration | Cycle 1, Day 1, 4 hours n=11 | 1930 μg/mL | Geometric Coefficient of Variation 35.9 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Cisplatin Concentration | Cycle 1, Day 1, 8 hours n=11 | 1680 μg/mL | Geometric Coefficient of Variation 22.4 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Cisplatin Concentration | Cycle 2, Day 1, Pre-infusion n=10 | 235 μg/mL | Geometric Coefficient of Variation 29.3 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Cisplatin Concentration | Cycle 2, Day 1, End-of-infusion n=10 | 2900 μg/mL | Geometric Coefficient of Variation 45.6 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Cisplatin Concentration | Cycle 2, Day 1, 1.5 hours n=10 | 2100 μg/mL | Geometric Coefficient of Variation 51.9 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Cisplatin Concentration | Cycle 2, Day 1, 2 hours n=5 | 2650 μg/mL | Geometric Coefficient of Variation 20.3 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Cisplatin Concentration | Cycle 2, Day 1, 4 hours n=10 | 2070 μg/mL | Geometric Coefficient of Variation 15.2 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Cisplatin Concentration | Cycle 2, Day 1, 8 hours n=10 | 1750 μg/mL | Geometric Coefficient of Variation 29.9 |
Secondary
Part 1 (Safety Run-in): Plasma Paclitaxel Concentration
Time frame: 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)
Population: The pharmacokinetic (PK) analysis set -paclitaxel included all participants who received at least one dose of paclitaxel and had at least one evaluable PK sample for paclitaxel. Data are reported for the Part 1 Cohort C arm only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Paclitaxel Concentration | Cycle 1, Day 1, Pre-infusion n=9 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Paclitaxel Concentration | Cycle 1, Day 1, End-of-infusion, n=9 | 4440 μg/mL | Geometric Coefficient of Variation 42.5 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Paclitaxel Concentration | Cycle 1, Day 1, 4 hours n=8 | 827 μg/mL | Geometric Coefficient of Variation 111.3 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Paclitaxel Concentration | Cycle 1, Day 1, 8 hours n=9 | 310 μg/mL | Geometric Coefficient of Variation 83.5 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Paclitaxel Concentration | Cycle 1, Day 1, 12 hours n=6 | 130 μg/mL | Geometric Coefficient of Variation 78.3 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Paclitaxel Concentration | Cycle 2, Day 1, Pre-infusion n=7 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Paclitaxel Concentration | Cycle 2, Day 1, End-of-infusion n=7 | 4940 μg/mL | Geometric Coefficient of Variation 35.1 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Paclitaxel Concentration | Cycle 2, Day 1, 4 hours n=7 | 1090 μg/mL | Geometric Coefficient of Variation 89.5 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Paclitaxel Concentration | Cycle 2, Day 1, 6 hours n=8 | 525 μg/mL | Geometric Coefficient of Variation 74.1 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Paclitaxel Concentration | Cycle 2, Day 1, 8 hours n=7 | 333 μg/mL | Geometric Coefficient of Variation 79.8 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Paclitaxel Concentration | Cycle 2, Day 1, 12 hours n=4 | 134 μg/mL | Geometric Coefficient of Variation 89.7 |
Secondary
Part 1 (Safety Run-in): Plasma Pemetrexed Concentration
Time frame: 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)
Population: The pharmacokinetic (PK) analysis set -pemetrexed included all participants who received at least one dose of pemetrexed and had at least one evaluable PK sample for pemetrexed. Data are reported for the Part 1 Cohorts A and B arms only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 1, Day 1, 4 hours n=9,11 | 10300 μg/mL | Geometric Coefficient of Variation 25.1 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 2, Day 1, End-of-infusion n=9,10 | 93300 μg/mL | Geometric Coefficient of Variation 19 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 1, Day 1, 1 hour n=9,11 | 39000 μg/mL | Geometric Coefficient of Variation 23.3 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 2, Day 1, 1 hour n=9,10 | 43600 μg/mL | Geometric Coefficient of Variation 15.7 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 1, Day 1, 8 hours n=9,11 | 3180 μg/mL | Geometric Coefficient of Variation 38.3 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 2, Day 1, 2 hours n=9,9 | 26300 μg/mL | Geometric Coefficient of Variation 19.1 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 1, Day 1, end-of-infusion, n=9,11 | 102000 μg/mL | Geometric Coefficient of Variation 30.2 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 2, Day 1, 4 hours n=9,10 | 11100 μg/mL | Geometric Coefficient of Variation 25.5 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 2, Day 1, Pre-infusion n=8,10 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 2, Day 1, 8 hours n=9,10 | 3920 μg/mL | Geometric Coefficient of Variation 39.1 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 1, Day 1, Pre-infusion n=9,11 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 2, Day 1, 8 hours n=9,10 | 2760 μg/mL | Geometric Coefficient of Variation 55 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 1, Day 1, Pre-infusion n=9,11 | 517 μg/mL | Geometric Coefficient of Variation 1.4 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 1, Day 1, end-of-infusion, n=9,11 | 87800 μg/mL | Geometric Coefficient of Variation 39.5 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 1, Day 1, 1 hour n=9,11 | 39000 μg/mL | Geometric Coefficient of Variation 29.5 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 1, Day 1, 4 hours n=9,11 | 10300 μg/mL | Geometric Coefficient of Variation 29.6 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 1, Day 1, 8 hours n=9,11 | 2340 μg/mL | Geometric Coefficient of Variation 58.8 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 2, Day 1, Pre-infusion n=8,10 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 2, Day 1, End-of-infusion n=9,10 | 92600 μg/mL | Geometric Coefficient of Variation 37.5 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 2, Day 1, 1 hour n=9,10 | 43500 μg/mL | Geometric Coefficient of Variation 16.2 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 2, Day 1, 2 hours n=9,9 | 23400 μg/mL | Geometric Coefficient of Variation 13.9 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Plasma Pemetrexed Concentration | Cycle 2, Day 1, 4 hours n=9,10 | 10800 μg/mL | Geometric Coefficient of Variation 34.3 |
Secondary
Part 1 (Safety Run-in): Serum Canakinumab Concentration
Time frame: 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)
Population: The pharmacokinetic (PK) analysis set - canakinumab included all participants who received at least one dose of canakinumab and had at least one evaluable PK sample for canakinumab. Data are reported for Part 1 only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 12, Day 1, 0 hour n=2,6,4 | 40.6 μg/mL | Geometric Coefficient of Variation 90.4 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 5, Day 1, 168 hour n=5,9,4 | 32.1 μg/mL | Geometric Coefficient of Variation 33.1 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 3, Day 1, 0 hour n=7,9,8 | 16.9 μg/mL | Geometric Coefficient of Variation 31.3 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 1, Day 1, 168 hour n=9,11,9 | 12.1 μg/mL | Geometric Coefficient of Variation 44.5 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 5, Day 1, 0 hour n=4,7,6 | 26.9 μg/mL | Geometric Coefficient of Variation 41.8 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 4, Day 1, 0 hour n=8,8,6 | 23.1 μg/mL | Geometric Coefficient of Variation 29 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 1, Day 1, 0 hour n=9,11,9 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 1, Day 1, 24 hour n=8,11,9 | 4.43 μg/mL | Geometric Coefficient of Variation 72.1 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 8, Day 1, 0 hour n=3,7,4 | 37.7 μg/mL | Geometric Coefficient of Variation 27.5 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 1, Day 1, 336 hour n=8,10,8 | 11.1 μg/mL | Geometric Coefficient of Variation 35 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 16, Day 1, 0 hour n=1,5,4 | 68.2 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 6, Day 1, 0 hour n=3,7,6 | 32.2 μg/mL | Geometric Coefficient of Variation 40 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 2, Day 1, 0 hour n=9,9,7 | 10.2 μg/mL | Geometric Coefficient of Variation 33.6 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 4, Day 1, 0 hour n=8,8,6 | 26.6 μg/mL | Geometric Coefficient of Variation 35 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 1, Day 1, 0 hour n=9,11,9 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 1, Day 1, 24 hour n=8,11,9 | 4.97 μg/mL | Geometric Coefficient of Variation 113.5 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 1, Day 1, 168 hour n=9,11,9 | 14.0 μg/mL | Geometric Coefficient of Variation 61.7 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 1, Day 1, 336 hour n=8,10,8 | 12.3 μg/mL | Geometric Coefficient of Variation 55.2 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 2, Day 1, 0 hour n=9,9,7 | 8.80 μg/mL | Geometric Coefficient of Variation 49.4 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 3, Day 1, 0 hour n=7,9,8 | 20.3 μg/mL | Geometric Coefficient of Variation 40.3 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 5, Day 1, 0 hour n=4,7,6 | 35.6 μg/mL | Geometric Coefficient of Variation 47.6 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 5, Day 1, 168 hour n=5,9,4 | 49.8 μg/mL | Geometric Coefficient of Variation 42.5 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 6, Day 1, 0 hour n=3,7,6 | 36.8 μg/mL | Geometric Coefficient of Variation 47.8 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 8, Day 1, 0 hour n=3,7,4 | 45.8 μg/mL | Geometric Coefficient of Variation 38.6 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 12, Day 1, 0 hour n=2,6,4 | 52.2 μg/mL | Geometric Coefficient of Variation 42.9 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 16, Day 1, 0 hour n=1,5,4 | 41.8 μg/mL | Geometric Coefficient of Variation 67.3 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 5, Day 1, 168 hour n=5,9,4 | 32.7 μg/mL | Geometric Coefficient of Variation 22.7 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 1, Day 1, 336 hour n=8,10,8 | 10.9 μg/mL | Geometric Coefficient of Variation 35.9 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 12, Day 1, 0 hour n=2,6,4 | 32.4 μg/mL | Geometric Coefficient of Variation 41 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 6, Day 1, 0 hour n=3,7,6 | 26.3 μg/mL | Geometric Coefficient of Variation 27.4 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 1, Day 1, 168 hour n=9,11,9 | 12.8 μg/mL | Geometric Coefficient of Variation 33.2 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 1, Day 1, 0 hour n=9,11,9 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 8, Day 1, 0 hour n=3,7,4 | 29.9 μg/mL | Geometric Coefficient of Variation 29.6 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 4, Day 1, 0 hour n=8,8,6 | 19.4 μg/mL | Geometric Coefficient of Variation 29.2 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 3, Day 1, 0 hour n=7,9,8 | 17.1 μg/mL | Geometric Coefficient of Variation 16.4 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 1, Day 1, 24 hour n=8,11,9 | 4.57 μg/mL | Geometric Coefficient of Variation 67.1 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 5, Day 1, 0 hour n=4,7,6 | 22.4 μg/mL | Geometric Coefficient of Variation 39 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 2, Day 1, 0 hour n=9,9,7 | 8.69 μg/mL | Geometric Coefficient of Variation 34.5 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Canakinumab Concentration | Cycle 16, Day 1, 0 hour n=1,5,4 | 31.0 μg/mL | Geometric Coefficient of Variation 35 |
Secondary
Part 1 (Safety Run-in): Serum Pembrolizumab Concentration
Time frame: 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)
Population: The pharmacokinetic (PK) analysis set -pembrolizumab included all participants who received at least one dose of pembrolizumab and had at least one evaluable PK sample for pembrolizumab. Data are reported for Part 1 only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 6, Day 1, 0 hour n=2,7,5 | 30.6 μg/mL | Geometric Coefficient of Variation 68.8 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 2, Day 1, 0 hour n=9,9,7 | 12.2 μg/mL | Geometric Coefficient of Variation 36.3 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 24 hour n=7,11,9 | 40.5 μg/mL | Geometric Coefficient of Variation 26.7 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 5, Day 1, end-of-infusion n=5,7,5 | 77.7 μg/mL | Geometric Coefficient of Variation 19.7 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 3, Day 1, 0 hour n=7,9,7 | 21.0 μg/mL | Geometric Coefficient of Variation 38.2 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 1, Day 1, end-of-infusion, n=9,11,7 | 53.9 μg/mL | Geometric Coefficient of Variation 29.8 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 5, Day 1, 0 hour n=5,7,6 | 28.6 μg/mL | Geometric Coefficient of Variation 31.9 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 4, Day 1, 0 hour n=8,8,6 | 27.8 μg/mL | Geometric Coefficient of Variation 31.4 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 8, Day 1, 0 hour n=3,7,3 | 46.4 μg/mL | Geometric Coefficient of Variation 16.2 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 168 hour n=9,11,9 | 19.0 μg/mL | Geometric Coefficient of Variation 49.4 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 16, Day 1, 0 hour n=1,5,1 | 39.8 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 0 hour n=9,11,9 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 336 hour n=9,11,8 | 15.1 μg/mL | Geometric Coefficient of Variation 28.8 |
| Part 1: Cohort A | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 12, Day 1, 0 hour n=1,7,1 | 76.1 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 6, Day 1, 0 hour n=2,7,5 | 37.0 μg/mL | Geometric Coefficient of Variation 33.6 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 0 hour n=9,11,9 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 1, Day 1, end-of-infusion, n=9,11,7 | 52.9 μg/mL | Geometric Coefficient of Variation 41.9 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 24 hour n=7,11,9 | 43.0 μg/mL | Geometric Coefficient of Variation 35.1 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 168 hour n=9,11,9 | 21.7 μg/mL | Geometric Coefficient of Variation 42.9 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 336 hour n=9,11,8 | 14.7 μg/mL | Geometric Coefficient of Variation 40.6 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 2, Day 1, 0 hour n=9,9,7 | 14.5 μg/mL | Geometric Coefficient of Variation 49.2 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 3, Day 1, 0 hour n=7,9,7 | 22.5 μg/mL | Geometric Coefficient of Variation 46.8 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 4, Day 1, 0 hour n=8,8,6 | 33.0 μg/mL | Geometric Coefficient of Variation 108.5 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 5, Day 1, 0 hour n=5,7,6 | 35.5 μg/mL | Geometric Coefficient of Variation 44.3 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 5, Day 1, end-of-infusion n=5,7,5 | 99.3 μg/mL | Geometric Coefficient of Variation 29.6 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 8, Day 1, 0 hour n=3,7,3 | 45.3 μg/mL | Geometric Coefficient of Variation 43.8 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 12, Day 1, 0 hour n=1,7,1 | 42.9 μg/mL | Geometric Coefficient of Variation 68.8 |
| Part 1: Cohort B | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 16, Day 1, 0 hour n=1,5,1 | 43.4 μg/mL | Geometric Coefficient of Variation 84.5 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 12, Day 1, 0 hour n=1,7,1 | 20.5 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 5, Day 1, end-of-infusion n=5,7,5 | 57.4 μg/mL | Geometric Coefficient of Variation 51.5 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 336 hour n=9,11,8 | 12.5 μg/mL | Geometric Coefficient of Variation 25.5 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 168 hour n=9,11,9 | 18.7 μg/mL | Geometric Coefficient of Variation 17.3 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 6, Day 1, 0 hour n=2,7,5 | 26.6 μg/mL | Geometric Coefficient of Variation 31.2 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 24 hour n=7,11,9 | 41.4 μg/mL | Geometric Coefficient of Variation 23.4 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 0 hour n=9,11,9 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 8, Day 1, 0 hour n=3,7,3 | 35.0 μg/mL | Geometric Coefficient of Variation 52 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 1, Day 1, end-of-infusion, n=9,11,7 | 48.1 μg/mL | Geometric Coefficient of Variation 17.7 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 4, Day 1, 0 hour n=8,8,6 | 23.5 μg/mL | Geometric Coefficient of Variation 37.2 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 3, Day 1, 0 hour n=7,9,7 | 15.5 μg/mL | Geometric Coefficient of Variation 27.2 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 16, Day 1, 0 hour n=1,5,1 | 27.2 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 5, Day 1, 0 hour n=5,7,6 | 28.5 μg/mL | Geometric Coefficient of Variation 82 |
| Part 1: Cohort C | Part 1 (Safety Run-in): Serum Pembrolizumab Concentration | Cycle 2, Day 1, 0 hour n=9,9,7 | 10.5 μg/mL | Geometric Coefficient of Variation 13 |
Secondary
Part 2 (Double-blind, Randomized, Placebo-controlled): Antidrug Antibodies (ADA) of Pembrolizumab
Participants with at least one ADA-positive sample.
Time frame: Up to approximately 26 months
Population: The safety set comprised all participants to whom study treatment was assigned and who received at least one dose of the study treatment. Data are reported for Part 2 only.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Antidrug Antibodies (ADA) of Pembrolizumab | Baseline | 2 Participants |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Antidrug Antibodies (ADA) of Pembrolizumab | On treatment | 7 Participants |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Antidrug Antibodies (ADA) of Pembrolizumab | Baseline | 1 Participants |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Antidrug Antibodies (ADA) of Pembrolizumab | On treatment | 2 Participants |
Secondary
Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire
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
Time frame: 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
Population: The full analysis set (FAS) comprised all participants to whom study treatment was assigned and who received at least one dose of the study treatment. Data are reported for Part 2 only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 66 n=89,79 | 0.026 score on a scale | Standard Deviation 0.2011 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 36 n=129,119 | 0.061 score on a scale | Standard Deviation 0.1767 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 69 n=93,74 | 0.052 score on a scale | Standard Deviation 0.1805 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 21 n=173,176 | 0.016 score on a scale | Standard Deviation 0.2291 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 72 n=87,70 | 0.032 score on a scale | Standard Deviation 0.189 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 39 n=133,119 | 0.037 score on a scale | Standard Deviation 0.2015 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 75 n=78,69 | 0.021 score on a scale | Standard Deviation 0.1797 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 9 n=220,219 | 0.019 score on a scale | Standard Deviation 0.2074 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 78 n=77,64 | 0.027 score on a scale | Standard Deviation 0.1979 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 42 n=124,102 | 0.044 score on a scale | Standard Deviation 0.1794 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 81 n=73,61 | 0.035 score on a scale | Standard Deviation 0.1844 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 24 n=160,164 | 0.027 score on a scale | Standard Deviation 0.2062 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 84 n=63,59 | 0.056 score on a scale | Standard Deviation 0.1923 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 45 n=124,100 | 0.035 score on a scale | Standard Deviation 0.1961 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 87 n=44,43 | 0.049 score on a scale | Standard Deviation 0.1894 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 15 n=194,196 | 0.031 score on a scale | Standard Deviation 0.2103 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 90 n=37,30 | 0.050 score on a scale | Standard Deviation 0.161 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 48 n=111,105 | 0.056 score on a scale | Standard Deviation 0.187 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 93 n=24,24 | 0.082 score on a scale | Standard Deviation 0.1861 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 27 n=157,155 | 0.020 score on a scale | Standard Deviation 0.1929 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 96 n=19,14 | 0.071 score on a scale | Standard Deviation 0.1604 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 51 n=103,95 | 0.026 score on a scale | Standard Deviation 0.1682 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 99 n=15,9 | 0.116 score on a scale | Standard Deviation 0.1755 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 6 n=236,230 | 0.029 score on a scale | Standard Deviation 0.2135 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 102 n=8,4 | 0.144 score on a scale | Standard Deviation 0.173 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 54 n=104,90 | 0.043 score on a scale | Standard Deviation 0.1703 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 105 n=5,2 | 0.073 score on a scale | Standard Deviation 0.1476 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 30 n=140,145 | 0.047 score on a scale | Standard Deviation 0.1928 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 108 n=1,0 | 0.121 score on a scale | — |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Efficacy Follow-up 1 n=9,10 | -0.085 score on a scale | Standard Deviation 0.2034 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 57 n=109,86 | 0.037 score on a scale | Standard Deviation 0.2012 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Efficacy Follow-up 2 n=2,4 | -0.031 score on a scale | Standard Deviation 0.6781 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 18 n=187,198 | 0.020 score on a scale | Standard Deviation 0.2192 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Efficacy Follow-up 3 n=2,1 | 0.406 score on a scale | Standard Deviation 0.4349 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 60 n=94,84 | 0.022 score on a scale | Standard Deviation 0.2119 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 33 n=136,124 | 0.036 score on a scale | Standard Deviation 0.1996 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at CFB at Efficacy Follow-up 5 n=1,0 | -0.144 score on a scale | — |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Post-disease Progression (7 days) n=32,24 | -0.126 score on a scale | Standard Deviation 0.2115 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 63 n=94,76 | 0.034 score on a scale | Standard Deviation 0.2056 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Post-disease Progression (28 days) n=30,30 | -0.031 score on a scale | Standard Deviation 0.2191 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 3 n=254,249 | 0.766 score on a scale | Standard Deviation 0.2138 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 12 n=192,214 | 0.028 score on a scale | Standard Deviation 0.2101 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Post-disease Progression (28 days) n=30,30 | -0.010 score on a scale | Standard Deviation 0.2854 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 3 n=254,249 | 0.768 score on a scale | Standard Deviation 0.2153 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 6 n=236,230 | 0.032 score on a scale | Standard Deviation 0.2317 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 9 n=220,219 | 0.059 score on a scale | Standard Deviation 0.2512 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 12 n=192,214 | 0.044 score on a scale | Standard Deviation 0.2486 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 15 n=194,196 | 0.039 score on a scale | Standard Deviation 0.2512 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 18 n=187,198 | 0.050 score on a scale | Standard Deviation 0.2723 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 21 n=173,176 | 0.041 score on a scale | Standard Deviation 0.2533 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 24 n=160,164 | 0.050 score on a scale | Standard Deviation 0.2824 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 27 n=157,155 | 0.043 score on a scale | Standard Deviation 0.2828 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 30 n=140,145 | 0.046 score on a scale | Standard Deviation 0.2897 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 33 n=136,124 | 0.055 score on a scale | Standard Deviation 0.2595 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 36 n=129,119 | 0.054 score on a scale | Standard Deviation 0.2881 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 39 n=133,119 | 0.071 score on a scale | Standard Deviation 0.2816 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 42 n=124,102 | 0.063 score on a scale | Standard Deviation 0.268 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 45 n=124,100 | 0.065 score on a scale | Standard Deviation 0.2584 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 48 n=111,105 | 0.081 score on a scale | Standard Deviation 0.2603 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 51 n=103,95 | 0.067 score on a scale | Standard Deviation 0.284 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 54 n=104,90 | 0.054 score on a scale | Standard Deviation 0.3086 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 57 n=109,86 | 0.049 score on a scale | Standard Deviation 0.2979 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 60 n=94,84 | 0.069 score on a scale | Standard Deviation 0.2819 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 63 n=94,76 | 0.082 score on a scale | Standard Deviation 0.3043 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 66 n=89,79 | 0.071 score on a scale | Standard Deviation 0.2996 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 69 n=93,74 | 0.061 score on a scale | Standard Deviation 0.2964 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 72 n=87,70 | 0.057 score on a scale | Standard Deviation 0.3176 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 75 n=78,69 | 0.080 score on a scale | Standard Deviation 0.2966 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 78 n=77,64 | 0.056 score on a scale | Standard Deviation 0.3064 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 81 n=73,61 | 0.042 score on a scale | Standard Deviation 0.3529 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 84 n=63,59 | 0.064 score on a scale | Standard Deviation 0.3125 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 87 n=44,43 | 0.057 score on a scale | Standard Deviation 0.3474 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 90 n=37,30 | 0.039 score on a scale | Standard Deviation 0.3502 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 93 n=24,24 | 0.074 score on a scale | Standard Deviation 0.4112 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 96 n=19,14 | 0.018 score on a scale | Standard Deviation 0.3986 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 99 n=15,9 | 0.099 score on a scale | Standard Deviation 0.4211 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 102 n=8,4 | -0.002 score on a scale | Standard Deviation 0.4701 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Week 105 n=5,2 | -0.232 score on a scale | Standard Deviation 0.2489 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Efficacy Follow-up 1 n=9,10 | -0.153 score on a scale | Standard Deviation 0.4494 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Efficacy Follow-up 2 n=2,4 | -0.195 score on a scale | Standard Deviation 0.4873 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Efficacy Follow-up 3 n=2,1 | 0.163 score on a scale | — |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Efficacy Follow-up 4 n=0,1 | 0.292 score on a scale | — |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Change From Baseline in Score as Per the EuroQol 5 Dimension 5 Level (EQ-5D-5L) Questionnaire | CFB at Post-disease Progression (7 days) n=32,24 | -0.048 score on a scale | Standard Deviation 0.2844 |
Secondary
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)
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 baseline
Time frame: 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
Population: The full analysis set (FAS) comprised all participants to whom study treatment was assigned and who received at least one dose of the study treatment. Data are reported for Part 2 only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort A | 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) | CFB at Week 66 n=90,79 | 1.0 score on a scale | Standard Deviation 15.49 |
| Part 1: Cohort A | 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) | CFB at Week 36 n=130,119 | 2.3 score on a scale | Standard Deviation 14.79 |
| Part 1: Cohort A | 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) | CFB at Week 69 n=94,74 | 1.9 score on a scale | Standard Deviation 15.48 |
| Part 1: Cohort A | 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) | CFB at Week 21 n=173,176 | 0.0 score on a scale | Standard Deviation 16.92 |
| Part 1: Cohort A | 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) | CFB at Week 72 n=88,70 | 0.4 score on a scale | Standard Deviation 15.3 |
| Part 1: Cohort A | 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) | CFB at Week 39 n=134,119 | 2.2 score on a scale | Standard Deviation 15.25 |
| Part 1: Cohort A | 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) | CFB at Week 75 n=79,69 | -0.1 score on a scale | Standard Deviation 15.96 |
| Part 1: Cohort A | 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) | CFB at Week 9 n=220,219 | 1.4 score on a scale | Standard Deviation 15.23 |
| Part 1: Cohort A | 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) | CFB at Week 78 n=78,64 | 0.1 score on a scale | Standard Deviation 17.65 |
| Part 1: Cohort A | 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) | CFB at Week 42 n=125,103 | 1.5 score on a scale | Standard Deviation 15.15 |
| Part 1: Cohort A | 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) | CFB at Week 81 n=73,61 | 0.2 score on a scale | Standard Deviation 16.1 |
| Part 1: Cohort A | 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) | CFB at Week 24 n=161,164 | 0.4 score on a scale | Standard Deviation 17.15 |
| Part 1: Cohort A | 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) | CFB at Week 84 n=64,59 | 2.0 score on a scale | Standard Deviation 16.33 |
| Part 1: Cohort A | 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) | CFB at Week 45 n=125,100 | 1.2 score on a scale | Standard Deviation 16.15 |
| Part 1: Cohort A | 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) | CFB at Week 87 n=44,43 | 0.6 score on a scale | Standard Deviation 17.07 |
| Part 1: Cohort A | 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) | CFB at Week 15 n=194,196 | 0.8 score on a scale | Standard Deviation 17.41 |
| Part 1: Cohort A | 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) | CFB at Week 90 n=37,30 | -1.9 score on a scale | Standard Deviation 17.04 |
| Part 1: Cohort A | 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) | CFB at Week 48 n=112,105 | 0.9 score on a scale | Standard Deviation 16.62 |
| Part 1: Cohort A | 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) | CFB at Week 93 n=24,24 | 1.9 score on a scale | Standard Deviation 16.06 |
| Part 1: Cohort A | 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) | CFB at Week 27 n=158,155 | 0.1 score on a scale | Standard Deviation 16.38 |
| Part 1: Cohort A | 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) | CFB at Week 96 n=19,14 | 2.9 score on a scale | Standard Deviation 15.01 |
| Part 1: Cohort A | 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) | CFB at Week 51 n=104,95 | 0.8 score on a scale | Standard Deviation 15.94 |
| Part 1: Cohort A | 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) | CFB at Week 99 n=15,9 | -1.2 score on a scale | Standard Deviation 12.09 |
| Part 1: Cohort A | 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) | CFB at Week 6 n=236,230 | 1.3 score on a scale | Standard Deviation 16.04 |
| Part 1: Cohort A | 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) | CFB at Week 102 n=8,4 | 5.3 score on a scale | Standard Deviation 14.98 |
| Part 1: Cohort A | 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) | CFB at Week 54 n=104,90 | 0.5 score on a scale | Standard Deviation 14.43 |
| Part 1: Cohort A | 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) | CFB at Week 105 n=5,2 | 7.2 score on a scale | Standard Deviation 19.49 |
| Part 1: Cohort A | 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) | CFB at Week 30 n=141,145 | 0.7 score on a scale | Standard Deviation 16.45 |
| Part 1: Cohort A | 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) | CFB at Week 108 n=1,0 | 3.0 score on a scale | — |
| Part 1: Cohort A | 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) | CFB at Efficacy Follow-up 1 n=9,10 | -1.6 score on a scale | Standard Deviation 17.67 |
| Part 1: Cohort A | 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) | CFB at Week 57 n=110,86 | 0.2 score on a scale | Standard Deviation 16.63 |
| Part 1: Cohort A | 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) | CFB at Efficacy Follow-up 2 n=2,4 | 8.5 score on a scale | Standard Deviation 9.19 |
| Part 1: Cohort A | 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) | CFB at Week 18 n=187,198 | 0.4 score on a scale | Standard Deviation 16.76 |
| Part 1: Cohort A | 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) | CFB at Efficacy Follow-up 3 n=2,1 | 12.5 score on a scale | Standard Deviation 19.09 |
| Part 1: Cohort A | 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) | CFB at Week 60 n=95,84 | -1.4 score on a scale | Standard Deviation 16.49 |
| Part 1: Cohort A | 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) | CFB at Week 33 n=137,124 | 0.8 score on a scale | Standard Deviation 14.5 |
| Part 1: Cohort A | 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) | CFB at CFB at Efficacy Follow-up 5 n=1,0 | 0.0 score on a scale | — |
| Part 1: Cohort A | 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) | CFB at Post-disease Progression (7 days) n=32,24 | -10.4 score on a scale | Standard Deviation 18.36 |
| Part 1: Cohort A | 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) | CFB at Week 63 n=95,76 | 0.0 score on a scale | Standard Deviation 17.35 |
| Part 1: Cohort A | 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) | CFB at Post-disease Progression (28 days) n=30,30 | -0.1 score on a scale | Standard Deviation 19.14 |
| Part 1: Cohort A | 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) | CFB at Week 3 n=254,249 | 0.1 score on a scale | Standard Deviation 16.51 |
| Part 1: Cohort A | 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) | CFB at Week 12 n=192,214 | 0.0 score on a scale | Standard Deviation 18.28 |
| Part 1: Cohort B | 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) | CFB at Post-disease Progression (28 days) n=30,30 | -1.4 score on a scale | Standard Deviation 22.92 |
| Part 1: Cohort B | 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) | CFB at Week 3 n=254,249 | 3.2 score on a scale | Standard Deviation 18.35 |
| Part 1: Cohort B | 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) | CFB at Week 6 n=236,230 | 2.6 score on a scale | Standard Deviation 18.18 |
| Part 1: Cohort B | 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) | CFB at Week 9 n=220,219 | 2.5 score on a scale | Standard Deviation 17.22 |
| Part 1: Cohort B | 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) | CFB at Week 12 n=192,214 | 3.3 score on a scale | Standard Deviation 16.78 |
| Part 1: Cohort B | 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) | CFB at Week 15 n=194,196 | 2.7 score on a scale | Standard Deviation 18.72 |
| Part 1: Cohort B | 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) | CFB at Week 18 n=187,198 | 4.4 score on a scale | Standard Deviation 17.66 |
| Part 1: Cohort B | 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) | CFB at Week 21 n=173,176 | 2.3 score on a scale | Standard Deviation 18.49 |
| Part 1: Cohort B | 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) | CFB at Week 24 n=161,164 | 2.3 score on a scale | Standard Deviation 19.4 |
| Part 1: Cohort B | 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) | CFB at Week 27 n=158,155 | 2.8 score on a scale | Standard Deviation 17.65 |
| Part 1: Cohort B | 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) | CFB at Week 30 n=141,145 | 2.5 score on a scale | Standard Deviation 19.08 |
| Part 1: Cohort B | 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) | CFB at Week 33 n=137,124 | 4.1 score on a scale | Standard Deviation 17 |
| Part 1: Cohort B | 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) | CFB at Week 36 n=130,119 | 4.8 score on a scale | Standard Deviation 16.73 |
| Part 1: Cohort B | 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) | CFB at Week 39 n=134,119 | 4.6 score on a scale | Standard Deviation 16.68 |
| Part 1: Cohort B | 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) | CFB at Week 42 n=125,103 | 4.7 score on a scale | Standard Deviation 17.17 |
| Part 1: Cohort B | 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) | CFB at Week 45 n=125,100 | 5.0 score on a scale | Standard Deviation 14.75 |
| Part 1: Cohort B | 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) | CFB at Week 48 n=112,105 | 3.9 score on a scale | Standard Deviation 17.29 |
| Part 1: Cohort B | 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) | CFB at Week 51 n=104,95 | 2.8 score on a scale | Standard Deviation 17.07 |
| Part 1: Cohort B | 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) | CFB at Week 54 n=104,90 | 4.2 score on a scale | Standard Deviation 17.5 |
| Part 1: Cohort B | 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) | CFB at Week 57 n=110,86 | 2.1 score on a scale | Standard Deviation 19.12 |
| Part 1: Cohort B | 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) | CFB at Week 60 n=95,84 | 2.8 score on a scale | Standard Deviation 17.46 |
| Part 1: Cohort B | 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) | CFB at Week 63 n=95,76 | 3.0 score on a scale | Standard Deviation 20.02 |
| Part 1: Cohort B | 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) | CFB at Week 66 n=90,79 | 4.6 score on a scale | Standard Deviation 19.36 |
| Part 1: Cohort B | 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) | CFB at Week 69 n=94,74 | 5.6 score on a scale | Standard Deviation 18.3 |
| Part 1: Cohort B | 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) | CFB at Week 72 n=88,70 | 3.6 score on a scale | Standard Deviation 19.21 |
| Part 1: Cohort B | 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) | CFB at Week 75 n=79,69 | 5.1 score on a scale | Standard Deviation 19.12 |
| Part 1: Cohort B | 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) | CFB at Week 78 n=78,64 | 5.1 score on a scale | Standard Deviation 19.34 |
| Part 1: Cohort B | 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) | CFB at Week 81 n=73,61 | 3.1 score on a scale | Standard Deviation 19.38 |
| Part 1: Cohort B | 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) | CFB at Week 84 n=64,59 | 2.0 score on a scale | Standard Deviation 19.05 |
| Part 1: Cohort B | 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) | CFB at Week 87 n=44,43 | 1.7 score on a scale | Standard Deviation 18.35 |
| Part 1: Cohort B | 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) | CFB at Week 90 n=37,30 | 2.6 score on a scale | Standard Deviation 18.13 |
| Part 1: Cohort B | 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) | CFB at Week 93 n=24,24 | 0.7 score on a scale | Standard Deviation 16.75 |
| Part 1: Cohort B | 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) | CFB at Week 96 n=19,14 | 4.8 score on a scale | Standard Deviation 16.28 |
| Part 1: Cohort B | 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) | CFB at Week 99 n=15,9 | 5.9 score on a scale | Standard Deviation 19.51 |
| Part 1: Cohort B | 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) | CFB at Week 102 n=8,4 | 0.5 score on a scale | Standard Deviation 21.63 |
| Part 1: Cohort B | 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) | CFB at Week 105 n=5,2 | -15.5 score on a scale | Standard Deviation 7.78 |
| Part 1: Cohort B | 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) | CFB at Efficacy Follow-up 1 n=9,10 | -9.8 score on a scale | Standard Deviation 27.85 |
| Part 1: Cohort B | 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) | CFB at Efficacy Follow-up 2 n=2,4 | -5.3 score on a scale | Standard Deviation 17.23 |
| Part 1: Cohort B | 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) | CFB at Efficacy Follow-up 3 n=2,1 | 5.0 score on a scale | — |
| Part 1: Cohort B | 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) | CFB at Efficacy Follow-up 4 n=0,1 | 21.0 score on a scale | — |
| Part 1: Cohort B | 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) | CFB at Post-disease Progression (7 days) n=32,24 | -4.6 score on a scale | Standard Deviation 21.4 |
Secondary
Part 2 (Double-blind, Randomized, Placebo-controlled): Disease Control Rate (DCR) Per Investigator Assessment Using RECIST v1.1
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.
Time frame: Up to approximately 26 months
Population: The full analysis set (FAS) comprised all participants to whom study treatment was assigned and who received at least one dose of the study treatment. Data are reported for Part 2 only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Disease Control Rate (DCR) Per Investigator Assessment Using RECIST v1.1 | 86.9 percentage of participants |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Disease Control Rate (DCR) Per Investigator Assessment Using RECIST v1.1 | 84.8 percentage of participants |
Secondary
Part 2 (Double-blind, Randomized, Placebo-controlled): Duration of Response (DOR) Per Investigator Assessment Using RECIST v1.1
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.
Time frame: Up to approximately 26 months
Population: The full analysis set (FAS) comprised all participants to whom study treatment was assigned and who received at least one dose of the study treatment. Participants who never achieved a best overall response of CR or PR were excluded from the analysis. Data are reported for responders in Part 2 only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Duration of Response (DOR) Per Investigator Assessment Using RECIST v1.1 | 14.26 months |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Duration of Response (DOR) Per Investigator Assessment Using RECIST v1.1 | 13.60 months |
Secondary
Part 2 (Double-blind, Randomized, Placebo-controlled): Number of Participants With Antidrug Antibodies (ADA) of Canakinumab
Participants with at least one ADA-positive sample.
Time frame: Up to approximately 26 months
Population: The safety set comprised all participants to whom study treatment was assigned and who received at least one dose of the study treatment. The data analysis applied to the Part 2 Canakinumab+pembro+CTx arm only.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Number of Participants With Antidrug Antibodies (ADA) of Canakinumab | Baseline | 3 Participants |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Number of Participants With Antidrug Antibodies (ADA) of Canakinumab | On treatment | 2 Participants |
Secondary
Part 2 (Double-blind, Randomized, Placebo-controlled): Overall Response Rate (ORR) Per Investigator Assessment Using RECIST v1.1
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.
Time frame: Up to approximately 26 months
Population: The full analysis set (FAS) comprised all participants to whom study treatment was assigned and who received at least one dose of the study treatment. Data are reported for Part 2 only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Overall Response Rate (ORR) Per Investigator Assessment Using RECIST v1.1 | 45.6 percentage of participants |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Overall Response Rate (ORR) Per Investigator Assessment Using RECIST v1.1 | 45.5 percentage of participants |
Secondary
Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration
Time frame: Predose (0 h), end of infusion, 1, 2, 4, 8 h post infusion on Cycles 1 and 2 (Cycle length =21 days)
Population: The pharmacokinetic (PK) analysis set -carboplatin included all participants who received at least one dose of carboplatin and had at least one evaluable PK sample for carboplatin. Data are reported for Part 2 only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 1, Day 1, Pre-infusion n=17,19 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 1, Day 1, End-of-infusion, n=17,23 | 13800 μg/mL | Geometric Coefficient of Variation 23.4 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 1, Day 1, 1 hour n=14,21 | 9980 μg/mL | Geometric Coefficient of Variation 40.4 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 1, Day 1, 2 hours n=17,23 | 7250 μg/mL | Geometric Coefficient of Variation 25 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 1, Day 1, 4 hours n=16,22 | 3690 μg/mL | Geometric Coefficient of Variation 26.4 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 2, Day 1, Pre-infusion n=11,16 | 145 μg/mL | Geometric Coefficient of Variation 37.2 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 2, Day 1, End-of-infusion n=11,18 | 14300 μg/mL | Geometric Coefficient of Variation 34.8 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 2, Day 1, 1 hour n=10,16 | 8880 μg/mL | Geometric Coefficient of Variation 23.8 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 2, Day 1, 2 hours n=12,18 | 6810 μg/mL | Geometric Coefficient of Variation 35.3 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 2, Day 1, 4 hours n=11,18 | 3990 μg/mL | Geometric Coefficient of Variation 34.4 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 2, Day 1, 1 hour n=10,16 | 9490 μg/mL | Geometric Coefficient of Variation 213.7 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 1, Day 1, Pre-infusion n=17,19 | 668 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 2, Day 1, Pre-infusion n=11,16 | 121 μg/mL | Geometric Coefficient of Variation 8.6 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 1, Day 1, End-of-infusion, n=17,23 | 16900 μg/mL | Geometric Coefficient of Variation 53.6 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 2, Day 1, 4 hours n=11,18 | 3830 μg/mL | Geometric Coefficient of Variation 37.4 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 1, Day 1, 1 hour n=14,21 | 10600 μg/mL | Geometric Coefficient of Variation 35.9 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 2, Day 1, End-of-infusion n=11,18 | 13000 μg/mL | Geometric Coefficient of Variation 183.5 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 1, Day 1, 2 hours n=17,23 | 6930 μg/mL | Geometric Coefficient of Variation 36.3 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 2, Day 1, 2 hours n=12,18 | 7080 μg/mL | Geometric Coefficient of Variation 26.5 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Carboplatin Concentration | Cycle 1, Day 1, 4 hours n=16,22 | 3780 μg/mL | Geometric Coefficient of Variation 46.7 |
Secondary
Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration
Time frame: 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)
Population: The pharmacokinetic (PK) analysis set -cisplatin included all participants who received at least one dose of cisplatin and had at least one evaluable PK sample for cisplatin. Data are reported for Part 2 only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 1, Day 1, end-of-infusion, n=20,18 | 3670 μg/mL | Geometric Coefficient of Variation 49.6 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 2, Day 1, End-of-infusion n=19,13 | 3130 μg/mL | Geometric Coefficient of Variation 92 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 1, Day 1, 4 hours n=17,16 | 1950 μg/mL | Geometric Coefficient of Variation 11.2 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 2, Day 1, 1.5 hours n=16,12 | 2790 μg/mL | Geometric Coefficient of Variation 29.9 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 1, Day 1, 2 hours n=17,18 | 2280 μg/mL | Geometric Coefficient of Variation 27.8 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 2, Day 1, 2 hours n=16,12 | 2550 μg/mL | Geometric Coefficient of Variation 22.7 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 2, Day 1, Pre-infusion n=20,14 | 288 μg/mL | Geometric Coefficient of Variation 58.9 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 2, Day 1, 4 hours n=19,11 | 2340 μg/mL | Geometric Coefficient of Variation 17.4 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 1, Day 1, Pre-infusion n=21,18 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 2, Day 1, 4 hours n=19,11 | 2340 μg/mL | Geometric Coefficient of Variation 13.7 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 1, Day 1, Pre-infusion n=21,18 | 177 μg/mL | Geometric Coefficient of Variation 47.5 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 1, Day 1, end-of-infusion, n=20,18 | 3120 μg/mL | Geometric Coefficient of Variation 20.9 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 1, Day 1, 2 hours n=17,18 | 2180 μg/mL | Geometric Coefficient of Variation 23.5 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 1, Day 1, 4 hours n=17,16 | 1950 μg/mL | Geometric Coefficient of Variation 17.5 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 2, Day 1, Pre-infusion n=20,14 | 296 μg/mL | Geometric Coefficient of Variation 51.7 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 2, Day 1, End-of-infusion n=19,13 | 2820 μg/mL | Geometric Coefficient of Variation 88.2 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 2, Day 1, 1.5 hours n=16,12 | 2410 μg/mL | Geometric Coefficient of Variation 38.3 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Cisplatin Concentration | Cycle 2, Day 1, 2 hours n=16,12 | 2790 μg/mL | Geometric Coefficient of Variation 23.9 |
Secondary
Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration
Time frame: 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)
Population: The pharmacokinetic (PK) analysis set -nab-paclitaxel included all participants who received at least one dose of nab-paclitaxel and had at least one evaluable PK sample for nab-paclitaxel. Data are reported for Part 2 only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 1, Day 1, End-of-infusion, n=10,15 | 2620 μg/mL | Geometric Coefficient of Variation 87.5 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 2, Day 1, End-of-infusion n=7,8 | 1630 μg/mL | Geometric Coefficient of Variation 92.1 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 1, Day 1, 24 hours n=4,9 | 24.2 μg/mL | Geometric Coefficient of Variation 16.7 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 2, Day 1, 4 hours n=6,8 | 83.6 μg/mL | Geometric Coefficient of Variation 45.5 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 1, Day 1, 4 hours n=10,14 | 112 μg/mL | Geometric Coefficient of Variation 38.3 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 2, Day 1, 6 hours n=6,8 | 75.6 μg/mL | Geometric Coefficient of Variation 47.1 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 2, Day 1, Pre-infusion n=7,8 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 2, Day 1, 24 hours n=5,7 | 34.5 μg/mL | Geometric Coefficient of Variation 107.7 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 1, Day 1, Pre-infusion n=9,13 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 2, Day 1, 24 hours n=5,7 | 23.6 μg/mL | Geometric Coefficient of Variation 39.2 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 1, Day 1, Pre-infusion n=9,13 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 1, Day 1, End-of-infusion, n=10,15 | 2520 μg/mL | Geometric Coefficient of Variation 285.4 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 1, Day 1, 4 hours n=10,14 | 117 μg/mL | Geometric Coefficient of Variation 90.2 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 1, Day 1, 24 hours n=4,9 | 23.9 μg/mL | Geometric Coefficient of Variation 47.8 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 2, Day 1, Pre-infusion n=7,8 | 44.6 μg/mL | Geometric Coefficient of Variation 160.1 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 2, Day 1, End-of-infusion n=7,8 | 3440 μg/mL | Geometric Coefficient of Variation 79.1 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 2, Day 1, 4 hours n=6,8 | 96.5 μg/mL | Geometric Coefficient of Variation 63.8 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Nab-paclitaxel Concentration | Cycle 2, Day 1, 6 hours n=6,8 | 86.1 μg/mL | Geometric Coefficient of Variation 55.2 |
Secondary
Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration
Time frame: 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)
Population: The pharmacokinetic (PK) analysis set -paclitaxel included all participants who received at least one dose of paclitaxel and had at least one evaluable PK sample for paclitaxel. Data are reported for Part 2 only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 1, Day 1, End-of-infusion, n=13,12 | 4620 μg/mL | Geometric Coefficient of Variation 97.3 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 2, Day 1, End-of-infusion n=10,9 | 3930 μg/mL | Geometric Coefficient of Variation 41.8 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 1, Day 1, 24 hours n=10,8 | 102 μg/mL | Geometric Coefficient of Variation 38.9 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 2, Day 1, 4 hours n=9,9 | 1450 μg/mL | Geometric Coefficient of Variation 26.6 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 1, Day 1, 4 hours n=12,11 | 1880 μg/mL | Geometric Coefficient of Variation 43.5 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 2, Day 1, 6 hours n=7,8 | 920 μg/mL | Geometric Coefficient of Variation 45.7 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 2, Day 1, Pre-infusion n=9,8 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 2, Day 1, 24 hours n=10,7 | 101 μg/mL | Geometric Coefficient of Variation 23.6 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 1, Day 1, Pre-infusion n=12,11 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 2, Day 1, 24 hours n=10,7 | 81.4 μg/mL | Geometric Coefficient of Variation 27.7 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 1, Day 1, Pre-infusion n=12,11 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 1, Day 1, End-of-infusion, n=13,12 | 3380 μg/mL | Geometric Coefficient of Variation 116.8 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 1, Day 1, 4 hours n=12,11 | 1900 μg/mL | Geometric Coefficient of Variation 88.4 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 1, Day 1, 24 hours n=10,8 | 114 μg/mL | Geometric Coefficient of Variation 47.4 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 2, Day 1, Pre-infusion n=9,8 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 2, Day 1, End-of-infusion n=10,9 | 3660 μg/mL | Geometric Coefficient of Variation 75.1 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 2, Day 1, 4 hours n=9,9 | 1180 μg/mL | Geometric Coefficient of Variation 62.6 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Paclitaxel Concentration | Cycle 2, Day 1, 6 hours n=7,8 | 775 μg/mL | Geometric Coefficient of Variation 55 |
Secondary
Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration
Time frame: 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)
Population: The pharmacokinetic (PK) analysis set -pemetrexed included all participants who received at least one dose of pemetrexed and had at least one evaluable PK sample for pemetrexed. Data are reported for Part 2 only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 1, Day 1, end-of-infusion, n=19,20 | 92000 μg/mL | Geometric Coefficient of Variation 21.9 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 2, Day 1, End-of-infusion n=15,17 | 89200 μg/mL | Geometric Coefficient of Variation 40.8 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 1, Day 1, 4 hours n=19,20 | 11700 μg/mL | Geometric Coefficient of Variation 33.3 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 2, Day 1, 1 hour n=15,17 | 47600 μg/mL | Geometric Coefficient of Variation 30.9 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 1, Day 1, 1 hour n=19,20 | 42900 μg/mL | Geometric Coefficient of Variation 23.5 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 2, Day 1, 2 hours n=15,17 | 26900 μg/mL | Geometric Coefficient of Variation 28.7 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 2, Day 1, Pre-infusion n=15,16 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 2, Day 1, 4 hours n=14,17 | 12500 μg/mL | Geometric Coefficient of Variation 38.2 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 1, Day 1, Pre-infusion n=18,18 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 2, Day 1, 4 hours n=14,17 | 9880 μg/mL | Geometric Coefficient of Variation 55.8 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 1, Day 1, Pre-infusion n=18,18 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 1, Day 1, end-of-infusion, n=19,20 | 86400 μg/mL | Geometric Coefficient of Variation 46.6 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 1, Day 1, 1 hour n=19,20 | 36900 μg/mL | Geometric Coefficient of Variation 29.4 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 1, Day 1, 4 hours n=19,20 | 9390 μg/mL | Geometric Coefficient of Variation 48.5 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 2, Day 1, Pre-infusion n=15,16 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 2, Day 1, End-of-infusion n=15,17 | 97000 μg/mL | Geometric Coefficient of Variation 32.3 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 2, Day 1, 1 hour n=15,17 | 37300 μg/mL | Geometric Coefficient of Variation 20.6 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Plasma Pemetrexed Concentration | Cycle 2, Day 1, 2 hours n=15,17 | 20900 μg/mL | Geometric Coefficient of Variation 41.9 |
Secondary
Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Canakinumab Concentration
Time frame: 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)
Population: The pharmacokinetic (PK) analysis set - canakinumab included all participants who received at least one dose of canakinumab and had at least one evaluable PK sample for canakinumab. Data are reported for the Part 2 Canakinumab+pembro+CTx arm only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Canakinumab Concentration | Cycle 1, Day 1, 0 hour n=291 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Canakinumab Concentration | Cycle 1, Day 1, 24 hour n=263 | 5.36 μg/mL | Geometric Coefficient of Variation 99.3 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Canakinumab Concentration | Cycle 1, Day 1, 168 hour n=271 | 12.3 μg/mL | Geometric Coefficient of Variation 52.1 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Canakinumab Concentration | Cycle 1, Day 1, 336 hour n=272 | 10.8 μg/mL | Geometric Coefficient of Variation 47.2 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Canakinumab Concentration | Cycle 2, Day 1, 0 hour n=228 | 8.82 μg/mL | Geometric Coefficient of Variation 46.8 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Canakinumab Concentration | Cycle 3, Day 1, 0 hour n=181 | 15.2 μg/mL | Geometric Coefficient of Variation 40.1 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Canakinumab Concentration | Cycle 4, Day 1, 0 hour n=166 | 18.6 μg/mL | Geometric Coefficient of Variation 44.4 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Canakinumab Concentration | Cycle 5, Day 1, 0 hour n=154 | 22.5 μg/mL | Geometric Coefficient of Variation 42.9 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Canakinumab Concentration | Cycle 5, Day 1, 168 hour n=174 | 33.8 μg/mL | Geometric Coefficient of Variation 42.2 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Canakinumab Concentration | Cycle 6, Day 1, 0 hour n=181 | 25.0 μg/mL | Geometric Coefficient of Variation 47.5 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Canakinumab Concentration | Cycle 8, Day 1, 0 hour n=144 | 29.0 μg/mL | Geometric Coefficient of Variation 46.9 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Canakinumab Concentration | Cycle 12, Day 1, 0 hour n=124 | 32.3 μg/mL | Geometric Coefficient of Variation 49.8 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Canakinumab Concentration | Cycle 16, Day 1, 0 hour n=91 | 33.0 μg/mL | Geometric Coefficient of Variation 49 |
Secondary
Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration
Time frame: 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)
Population: The pharmacokinetic (PK) analysis set -pembrolizumab included all participants who received at least one dose of pembrolizumab and had at least one evaluable PK sample for pembrolizumab. Data are reported for Part 2 only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 0 hours n=29,28 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 1, Day 1, end-of-infusion, n=27,27 | 53.5 μg/mL | Geometric Coefficient of Variation 55.1 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 24 hours n=29,31 | 45.9 μg/mL | Geometric Coefficient of Variation 23.6 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 168 hours n=28,29 | 21.5 μg/mL | Geometric Coefficient of Variation 30.1 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 336 hours n=23,25 | 14.5 μg/mL | Geometric Coefficient of Variation 33.8 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 2, Day 1, 0 hours n=19,25 | 11.5 μg/mL | Geometric Coefficient of Variation 46.6 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 3, Day 1, 0 hours n=12,20 | 22.7 μg/mL | Geometric Coefficient of Variation 39.8 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 4, Day 1, 0 hours n=12,20 | 24.7 μg/mL | Geometric Coefficient of Variation 42.5 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 5, Day 1, 0 hours n=15,22 | 28.6 μg/mL | Geometric Coefficient of Variation 38.6 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 5, Day 1, end-of-infusion n=18,21 | 66.3 μg/mL | Geometric Coefficient of Variation 42.6 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 6, Day 1, 0 hours n=14,17 | 34.0 μg/mL | Geometric Coefficient of Variation 69 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 8, Day 1, 0 hours n=16,17 | 36.0 μg/mL | Geometric Coefficient of Variation 53.2 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 12, Day 1, 0 hours n=10,9 | 47.6 μg/mL | Geometric Coefficient of Variation 27.6 |
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 16, Day 1, 0 hours n=9,8 | 42.9 μg/mL | Geometric Coefficient of Variation 39.4 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 6, Day 1, 0 hours n=14,17 | 32.2 μg/mL | Geometric Coefficient of Variation 71.5 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 0 hours n=29,28 | 0 μg/mL | Geometric Coefficient of Variation 0 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 4, Day 1, 0 hours n=12,20 | 27.2 μg/mL | Geometric Coefficient of Variation 55 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 1, Day 1, end-of-infusion, n=27,27 | 50.9 μg/mL | Geometric Coefficient of Variation 36 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 12, Day 1, 0 hours n=10,9 | 41.9 μg/mL | Geometric Coefficient of Variation 44.7 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 24 hours n=29,31 | 43.7 μg/mL | Geometric Coefficient of Variation 51.8 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 5, Day 1, 0 hours n=15,22 | 26.5 μg/mL | Geometric Coefficient of Variation 55 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 168 hours n=28,29 | 21.4 μg/mL | Geometric Coefficient of Variation 42.2 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 8, Day 1, 0 hours n=16,17 | 30.1 μg/mL | Geometric Coefficient of Variation 57.4 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 1, Day 1, 336 hours n=23,25 | 14.9 μg/mL | Geometric Coefficient of Variation 39.9 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 5, Day 1, end-of-infusion n=18,21 | 70.9 μg/mL | Geometric Coefficient of Variation 41.5 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 2, Day 1, 0 hours n=19,25 | 12.9 μg/mL | Geometric Coefficient of Variation 39.3 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 16, Day 1, 0 hours n=9,8 | 47.0 μg/mL | Geometric Coefficient of Variation 38 |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Serum Pembrolizumab Concentration | Cycle 3, Day 1, 0 hours n=12,20 | 20.6 μg/mL | Geometric Coefficient of Variation 50 |
Secondary
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
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.
Time frame: Up to approximately 25 months
Population: The full analysis set (FAS) comprised all participants to whom study treatment was assigned and who received at least one dose of the study treatment. Data are reported for Part 2 only.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Cohort A | 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 | Chest Pain n=65,96 | NA months |
| Part 1: Cohort A | 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 | Cough n=63,94 | NA months |
| Part 1: Cohort A | 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 | Dyspnea n=111,149 | 19.61 months |
| Part 1: Cohort B | 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 | Chest Pain n=65,96 | 22.14 months |
| Part 1: Cohort B | 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 | Cough n=63,94 | 23.06 months |
| Part 1: Cohort B | 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 | Dyspnea n=111,149 | 11.50 months |
Comparison: Chest painp-value: 0.0016495% CI: [0.45, 0.86]Log Rank
Comparison: Coughp-value: 0.0006995% CI: [0.43, 0.82]Log Rank
Comparison: Dyspneap-value: 0.0004595% CI: [0.51, 0.84]Log Rank
Secondary
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
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.
Time frame: Up to approximately 25 months
Population: The full analysis set (FAS) comprised all participants to whom study treatment was assigned and who received at least one dose of the study treatment. Data are reported for Part 2 only.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Cohort A | 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 | Quality of Life n=119, 129 | 17.54 months |
| Part 1: Cohort A | 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 | Shortness of Breath n=83,115 | NA months |
| Part 1: Cohort A | 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 | Pain n=117,122 | 20.07 months |
| Part 1: Cohort B | 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 | Quality of Life n=119, 129 | 15.90 months |
| Part 1: Cohort B | 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 | Shortness of Breath n=83,115 | 19.29 months |
| Part 1: Cohort B | 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 | Pain n=117,122 | 17.91 months |
Comparison: Quality of Lifep-value: 0.11395% CI: [0.66, 1.1]Log Rank
Comparison: Shortness of Breathp-value: 0.0043395% CI: [0.51, 0.91]Log Rank
Comparison: Painp-value: 0.29495% CI: [0.72, 1.2]Log Rank
Secondary
Part 2 (Double-blind, Randomized, Placebo-controlled): Time to Response (TTR) Per Investigator Assessment Using RECIST v1.1
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.
Time frame: Up to approximately 26 months
Population: The full analysis set (FAS) comprised all participants to whom study treatment was assigned and who received at least one dose of the study treatment. Data are reported for responders in Part 2 only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort A | Part 2 (Double-blind, Randomized, Placebo-controlled): Time to Response (TTR) Per Investigator Assessment Using RECIST v1.1 | NA months |
| Part 1: Cohort B | Part 2 (Double-blind, Randomized, Placebo-controlled): Time to Response (TTR) Per Investigator Assessment Using RECIST v1.1 | NA months |
Post Hoc
All Collected Deaths
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.
Time frame: 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.
Population: The full analysis set (FAS) comprised all participants to whom study treatment was assigned and who received at least one dose of the study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Cohort A | All Collected Deaths | Pre-treatment deaths | 0 Participants |
| Part 1: Cohort A | All Collected Deaths | All deaths | 6 Participants |
| Part 1: Cohort A | All Collected Deaths | Post-treatment survival follow-up deaths | 2 Participants |
| Part 1: Cohort A | All Collected Deaths | On-treatment deaths | 4 Participants |
| Part 1: Cohort B | All Collected Deaths | All deaths | 6 Participants |
| Part 1: Cohort B | All Collected Deaths | On-treatment deaths | 1 Participants |
| Part 1: Cohort B | All Collected Deaths | Pre-treatment deaths | 0 Participants |
| Part 1: Cohort B | All Collected Deaths | Post-treatment survival follow-up deaths | 5 Participants |
| Part 1: Cohort C | All Collected Deaths | Post-treatment survival follow-up deaths | 3 Participants |
| Part 1: Cohort C | All Collected Deaths | All deaths | 7 Participants |
| Part 1: Cohort C | All Collected Deaths | Pre-treatment deaths | 0 Participants |
| Part 1: Cohort C | All Collected Deaths | On-treatment deaths | 4 Participants |
| Part 2: Canakinumab+Pembro+CTx | All Collected Deaths | Pre-treatment deaths | 0 Participants |
| Part 2: Canakinumab+Pembro+CTx | All Collected Deaths | On-treatment deaths | 97 Participants |
| Part 2: Canakinumab+Pembro+CTx | All Collected Deaths | Post-treatment survival follow-up deaths | 50 Participants |
| Part 2: Canakinumab+Pembro+CTx | All Collected Deaths | All deaths | 147 Participants |
| Part 2: Placebo+Pembro+CTx | All Collected Deaths | All deaths | 159 Participants |
| Part 2: Placebo+Pembro+CTx | All Collected Deaths | Pre-treatment deaths | 0 Participants |
| Part 2: Placebo+Pembro+CTx | All Collected Deaths | On-treatment deaths | 102 Participants |
| Part 2: Placebo+Pembro+CTx | All Collected Deaths | Post-treatment survival follow-up deaths | 57 Participants |