Urothelial Cancer
Conditions
Keywords
Urothelial Cancer, Enfortumab vedotin, metastatic urothelial cancer, pembrolizumab, locally advanced urothelial cancer
Brief summary
This study is being done to see how well two drugs (enfortumab vedotin and pembrolizumab) work together to treat patients with urothelial cancer. The study will compare these drugs to other drugs that are usually used to treat this cancer (standard of care). The patients in this study will have cancer that has spread from their urinary system to other parts of their body.
Detailed description
Japan PMDA has approved enfortumab vedotin (Padcev) for the treatment of advanced urothelial cancer. The study will continue as a post marketing study in Japan. This study is being conducted to evaluate the combination of enfortumab vedotin + pembrolizumab versus standard of care gemcitabine + platinum-containing chemotherapy, in subjects with previously untreated locally advanced or metastatic urothelial cancer. Enfortumab vedotin may be administered for an unlimited number of cycles until a protocol defined reason for study discontinuation occurs. Pembrolizumab may be administered for a maximum of 35 cycles or a protocol-defined reason for study discontinuation occurs, whichever is first. Cisplatin or carboplatin plus gemcitabine may be administered for a maximum of 6 cycles or a protocol-defined reason for study discontinuation occurs, whichever is first.
Interventions
DRUGEnfortumab vedotin
Enfortumab vedotin administered as an IV infusion on Days 1 and 8 of every 3-week cycle
DRUGPembrolizumab
IV infusion on Day 1 of every 3-week cycle
DRUGCisplatin
administered as IV infusion on Day 1 of each 3-week cycle
DRUGCarboplatin
Dosed according to local guidelines and will be administered as IV infusion on Day 1 of each 3-week cycle
DRUGGemcitabine
IV infusion on Days 1 and 8 of every 3 week cycle
Sponsors
Astellas Pharma Global Development, Inc.
Merck Sharp & Dohme LLC
Seagen Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically documented, unresectable locally advanced or metastatic urothelial carcinoma * Measurable disease by investigator assessment according to RECIST v1.1 * Participants with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy * Participants must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions: * Participants that received neoadjuvant chemotherapy with recurrence \>12 months from completion of therapy are permitted * Participants that received adjuvant chemotherapy following cystectomy with recurrence \>12 months from completion of therapy are permitted * Must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator's judgment * Archival tumor tissue comprising muscle-invasive urothelial carcinoma or a biopsy of metastatic urothelial carcinoma must be provided for PD-L1 testing prior to randomization * Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2 * Adequate hematologic and organ function
Exclusion criteria
* Previously received enfortumab vedotin or other monomethyl auristatin E (MMAE)-based antibody-drug conjugate (ADCs) * Received prior treatment with a programmed cell death ligand-1 (PD-(L)-1) inhibitor for any malignancy, including earlier stage urothelial cancer (UC), defined as a PD-1 inhibitor or PD-L1 inhibitor * Received prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor * Received anti-cancer treatment with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion 1-3 that is not completed 4 weeks prior to first dose of study treatment * Uncontrolled diabetes * Estimated life expectancy of less than 12 weeks * Active central nervous system (CNS) metastases * Ongoing clinically significant toxicity associated with prior treatment that has not resolved to ≤ Grade 1 or returned to baseline * Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted. * Known active hepatitis B, active hepatitis C, or human immunodeficiency virus (HIV) infection. * History of another invasive malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy * Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class IV within 6 months prior to randomization * Receipt of radiotherapy within 2 weeks prior to randomization * Received major surgery (defined as requiring general anesthesia and \>24 hour inpatient hospitalization) within 4 weeks prior to randomization * Known severe (≥ Grade 3) hypersensitivity to any enfortumab vedotin excipient contained in the drug formulation of enfortumab vedotin * Active keratitis or corneal ulcerations * History of autoimmune disease that has required systemic treatment in the past 2 years * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan * Prior allogeneic stem cell or solid organ transplant * Received a live attenuated vaccine within 30 days prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Blinded Independent Central Review (BICR) | From the date of randomization to first documentation of PD or death due to any cause, whichever occurred first (maximum exposure to treatment was up to 39.2 months) | PFS was defined as the time from date of randomization to first documentation of disease progression (PD), or to death due to any cause, whichever occurred first. PD: at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter (mm). PD could also be unequivocal progression of non-target lesions or the presence of unequivocal new lesions. Kaplan-Meier method was used for analysis. |
| Overall Survival (OS) | From randomization to date of death due to any cause or censoring date, whichever occurred first (maximum exposure to treatment was up to 39.2 months) | OS was defined as the time from the date of randomization to the date of death from any cause. In the absence of death, OS was censored at the date the participant was last known to be alive. Kaplan-Meier method was used for analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Objective Response Rate (ORR) Per RECIST v1.1 by BICR | From first dose till CR/PR or PD or death, whichever occurred first (maximum up to approximately 7.4 years) | ORR as per RECIST v1.1 by BICR was defined as the percentage of participants with confirmed complete response (CR) or partial response (PR) CR was defined as disappearance of all lesions including non-target lesions (not just target lesions). Any pathological lymph nodes must have reduction in short axis to\<10 mm. PR was defined as at least 30 percent \[%\] decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For a response to be considered as confirmed, the subsequent response needs to be at least 4 weeks after the initial response. |
| Time to Pain Progression (TTPP) | From the date of randomization to date of pain progression (maximum up to approximately 7.4 years) | TTPP was defined as the time from the date of randomization to date of pain progression. Pain progression was defined as a participant reporting either of the following, whichever came first: 1) Increase of 2 or more points from baseline on Brief Pain Inventory - Short Form (BPI-SF) Question 3 (i.e., pain at its worst in the last 24 hours, score range 0 to 10 with higher scores associated with higher pain levels) maintained for at least two consecutive assessments. 2) Initiation of new opioid medication from baseline for pain with usage maintained for at least two consecutive assessments as recorded in BPI-SF Question 7 (i.e., What medications received for pain). |
| Change From Baseline in Worst Pain Using BPI-SF at Week 26 | Baseline, Week 26 | Brief Pain Inventory (BPI-SF) was defined as summary of the worst, least, and average pain experienced in the last 24 hours as well as pain right now and number of pain locations were provided for each treatment arm. BPI-sf worst pain measured the severity of pain based on the pain at its worst in the last 24 hours, score range 0 to 10 with higher scores associated with higher pain levels. |
| PFS Per RECIST v1.1 by Investigator Assessment | From the date of randomization to first documentation of PD or death due to any cause, whichever occurred first (maximum up to approximately 7.4 years) | PFS as per RECIST v1.1 by investigator was defined as the time from date of randomization to first documentation of PD, or to death due to any cause, whichever comes first. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PD could also be unequivocal progression of non-target lesions or the presence of unequivocal new lesions. |
| ORR Per RECIST v1.1 by Investigator Assessment | From first dose till CR/PR or PD or death, whichever occurred first (maximum up to approximately 7.4 years) | ORR as per RECIST v1.1 by investigator was defined as the percentage of participants with confirmed CR or PR. CR was defined as disappearance of all lesions including non-target lesions (not just target lesions). Any pathological lymph nodes must have reduction in short axis to\<10 mm. PR was defined as at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For a response to be considered as confirmed, the subsequent response needs to be at least 4 weeks after the initial response. |
| Duration of Response (DOR) Per RECIST v1.1 by BICR | From the date of first documented response of CR or PR to the first documented disease progression or to death from any cause, whichever occurred first (maximum up to approximately 7.4 years) | DOR was defined as the time from the first objective response (CR or PR that is subsequently confirmed) to the first documented PD per RECIST v1.1 per BICR or death from any cause, whichever occurs first. DOR will only include subjects with a confirmed response (CR or PR per RECIST v1.1). CR was defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to\<10 mm. PR was defined as at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For a response to be considered as confirmed, the subsequent response needs to be at least 4 weeks after the initial response. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
| DOR Per RECIST v1.1 by Investigator Assessment | From the date of first documented response of CR or PR to the first documented disease progression or to death from any cause, whichever occurred first (maximum up to approximately 7.4 years) | DOR was defined as the time from the first objective response (CR or PR that is subsequently confirmed) to the first documented PD per RECIST v1.1 per investigator or death from any cause, whichever occurs first. DOR will only include subjects with a confirmed response (CR or PR per RECIST v1.1). CR was defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to\<10 mm. PR was defined as at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. For a response to be considered as confirmed, the subsequent response needs to be at least 4 weeks after the initial response. |
| Disease Control Rate (DCR) Per RECIST v1.1 by BICR | From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to approximately 7.4 years) | DCR by BICR was defined as the percentage of participants with confirmed response (CR or PR), or SD (or non-CR/non-PD), per RECIST v1.1. Subjects who have no post-baseline response assessments will be considered as non-responders for calculating the DCR. Only response assessments before the first documented PD or subsequent anticancer therapies were considered. CR was defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to\<10 mm. PR was defined as at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For a response to be considered as confirmed, the subsequent response needs to be at least 4 weeks after the initial response. SD was defined as a change in tumor size that is neither radiological response (\>30% shrinkage) nor progression (\>20% growth). |
| DCR Per RECIST v1.1 by Investigator Assessment | From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to approximately 7.4 years) | DCR by BICR was defined as the percentage of participants with confirmed response (CR or PR), or SD (or non-CR/non-PD), per RECIST v1.1. Subjects who have no post-baseline response assessments will be considered as non-responders for calculating the DCR. Only response assessments before the first documented PD or subsequent anticancer therapies were considered. CR was defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to\<10 mm. PR was defined as at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For a response to be considered as confirmed, the subsequent response needs to be at least 4 weeks after the initial response. SD was defined as a change in tumor size that is neither radiological response (\>30% shrinkage) nor progression (\>20% growth). |
| Mean Scores in Patient Reported Outcome (PRO) Assessment Measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L) | End of study (approximately up to 7.4 years) | The EQ-5D-5L is a 5-item self-reported measure of functioning and well-being, which assesses 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression (EQ-5D-5L User Guide, 2019). Each dimension comprises 5 levels (no problems, slight problems, moderate problems, severe problems, and extreme problems). |
| Change From Baseline in PRO Assessment Measured by the EQ-5D-5L | Baseline, End of study (approximately up to 7.4 years) | The EQ-5D-5L is a 5-item self-reported measure of functioning and well-being, which assesses 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression (EQ-5D-5L User Guide, 2019). Each dimension comprises 5 levels (no problems, slight problems, moderate problems, severe problems, and extreme problems). |
| Mean Scores in PRO Assessment Measured by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) | End of study (approximately up to 7.4 years) | EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status (GHS), symptom scales (fatigue, pain, nausea/vomiting), and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea, and financial difficulties). Most questions used 4- point scale (1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores averaged, transformed to 0- 100 scale; higher score=better level of functioning or greater degree of symptoms. |
| Change From Baseline in PRO Assessment Measured by EORTC QLQ-C30 | Baseline, End of study (approximately up to 7.4 years) | EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status (GHS), symptom scales (fatigue, pain, nausea/vomiting), and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea, and financial difficulties). Most questions used 4- point scale (1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores averaged, transformed to 0- 100 scale; higher score=better level of functioning or greater degree of symptoms. Change from baseline=Cycle/Day score minus baseline score. |
| Number of Participants With Treatment Emergent Adverse Events Adverse Events (AEs) | From start of treatment up to 37 days after last dose of study drug (approximately up to 7.4 years) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 37 days after last dose that were absent before treatment or that worsened relative to pretreatment state. |
| Number of Participants With Serious TEAE | From start of treatment up to 37 days after last dose of study drug (approximately up to 7.4 years) | SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/ incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 37 days after last dose that were absent before treatment or that worsened relative to pretreatment state. |
| Number of Participants With Grade 3-5 TEAE | From start of treatment up to 37 days after last dose of study drug (approximately up to 7.4 years) | AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per common terminology criteria for adverse events (CTCAE) version 4, Grade 3= severe AE; Grade 4= life-threatening or disabling AE; Grade 5= death related to an AE. |
| Number of Participants Related to Treatment AEs | From start of treatment up to 37 days after last dose of study drug (approximately up to 7.4 years) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment relatedness was assessed by the investigator. |
| Number of Participants With Laboratory Abnormalities | From start of treatment up to 37 days after last dose of study drug (approximately up to 7.4 years) | Laboratory abnormalities included Hematology and Serum Chemistry. In Hematology (increased : hemoglobin, lymphocytes, leukocytes, and decreased : hemoglobin, lymphocytes, neutrophils, platelets and leukocytes) and In serum chemistry (increased in : alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium corrected for albumin, creatinine, glucose (non-fasting), potassium, sodium, and decreased in albumin, calcium corrected for albumin, glucose (non-fasting), potassium, phosphate and sodium). |
| Number of Participants With Treatment Discontinuation Rate Due to AEs | During study (approximately up to 7.4 years) | — |
Countries
Argentina, Australia, Belgium, Canada, China, Czechia, Denmark, France, Germany, Hungary, Israel, Italy, Japan, Netherlands, Poland, Russia, Singapore, South Korea, Spain, Switzerland, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORZejing Wang, MD, PhD
Seagen Inc.
STUDY_DIRECTORJohn Lu, MD
Seagen Inc.
Participant flow
Recruitment details
Participants with untreated locally advanced or metastatic urothelial cancer (UC) were enrolled in the study.
Pre-assignment details
Results are reported only for primary outcome measures at primary completion date (08-Aug-2023). Remaining secondary outcome measures whose analysis are not final, results would be reported at study completion date.
Participants by arm
| Arm | Count |
|---|---|
| Enfortumab Vedotin + Pembrolizumab Participants received enfortumab vedotin at 1.25 mg/kg as an IV infusion over approximately 30 minutes on Days 1 and 8 of each cycle, and pembrolizumab 200 mg as an IV infusion over approximately 30 minutes on Day 1 of each cycle, after completion of the enfortumab vedotin infusion. 1 cycle = 3 weeks. | 442 |
| Standard of Care Participants received gemcitabine at 1000 mg/m\^2 as an IV infusion on Days 1 and 8 of each cycle, and either cisplatin (70 mg/m\^2) or carboplatin (AUC 4.5, or AUC 5 according to local guidelines) on Day 1 of each cycle, with adequate pre- and post-hydration, by IV infusion per institutional standards. 1 cycle = 3 weeks. | 444 |
| Total | 886 |
Baseline characteristics
| Characteristic | Enfortumab Vedotin + Pembrolizumab | Total | Standard of Care |
|---|---|---|---|
| Age, Continuous | 67.9 Years STANDARD_DEVIATION 9.1 | 67.9 Years STANDARD_DEVIATION 9.2 | 68.0 Years STANDARD_DEVIATION 9.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 52 Participants | 104 Participants | 52 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 359 Participants | 702 Participants | 343 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 31 Participants | 80 Participants | 49 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 2 Participants | 4 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Asian | 99 Participants | 191 Participants | 92 Participants |
| Race/Ethnicity, Customized Race Black or African American | 3 Participants | 10 Participants | 7 Participants |
| Race/Ethnicity, Customized Race Multiple | 0 Participants | 4 Participants | 4 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Not Reported | 22 Participants | 59 Participants | 37 Participants |
| Race/Ethnicity, Customized Race Other | 3 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Unknown | 5 Participants | 15 Participants | 10 Participants |
| Race/Ethnicity, Customized Race White | 308 Participants | 598 Participants | 290 Participants |
| Sex: Female, Male Female | 98 Participants | 206 Participants | 108 Participants |
| Sex: Female, Male Male | 344 Participants | 680 Participants | 336 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 133 / 442 | 226 / 444 |
| other Total, other adverse events | 435 / 440 | 418 / 433 |
| serious Total, serious adverse events | 220 / 440 | 169 / 433 |
Outcome results
Primary
Overall Survival (OS)
OS was defined as the time from the date of randomization to the date of death from any cause. In the absence of death, OS was censored at the date the participant was last known to be alive. Kaplan-Meier method was used for analysis.
Time frame: From randomization to date of death due to any cause or censoring date, whichever occurred first (maximum exposure to treatment was up to 39.2 months)
Population: ITT analysis set included all randomized participants. Participants were analyzed according to the treatment arm assigned at randomization regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enfortumab Vedotin + Pembrolizumab | Overall Survival (OS) | 31.5 Months |
| Standard of Care | Overall Survival (OS) | 16.1 Months |
p-value: <0.0000195% CI: [0.376, 0.582]Log Rank
Primary
Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Blinded Independent Central Review (BICR)
PFS was defined as the time from date of randomization to first documentation of disease progression (PD), or to death due to any cause, whichever occurred first. PD: at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter (mm). PD could also be unequivocal progression of non-target lesions or the presence of unequivocal new lesions. Kaplan-Meier method was used for analysis.
Time frame: From the date of randomization to first documentation of PD or death due to any cause, whichever occurred first (maximum exposure to treatment was up to 39.2 months)
Population: ITT analysis set included all randomized participants. Participants were analyzed according to the treatment arm assigned at randomization regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enfortumab Vedotin + Pembrolizumab | Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Blinded Independent Central Review (BICR) | 12.5 Months |
| Standard of Care | Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Blinded Independent Central Review (BICR) | 6.3 Months |
p-value: <0.0000195% CI: [0.377, 0.538]Log Rank
Secondary
Change From Baseline in PRO Assessment Measured by EORTC QLQ-C30
EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status (GHS), symptom scales (fatigue, pain, nausea/vomiting), and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea, and financial difficulties). Most questions used 4- point scale (1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores averaged, transformed to 0- 100 scale; higher score=better level of functioning or greater degree of symptoms. Change from baseline=Cycle/Day score minus baseline score.
Time frame: Baseline, End of study (approximately up to 7.4 years)
Secondary
Change From Baseline in PRO Assessment Measured by the EQ-5D-5L
The EQ-5D-5L is a 5-item self-reported measure of functioning and well-being, which assesses 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression (EQ-5D-5L User Guide, 2019). Each dimension comprises 5 levels (no problems, slight problems, moderate problems, severe problems, and extreme problems).
Time frame: Baseline, End of study (approximately up to 7.4 years)
Secondary
Change From Baseline in Worst Pain Using BPI-SF at Week 26
Brief Pain Inventory (BPI-SF) was defined as summary of the worst, least, and average pain experienced in the last 24 hours as well as pain right now and number of pain locations were provided for each treatment arm. BPI-sf worst pain measured the severity of pain based on the pain at its worst in the last 24 hours, score range 0 to 10 with higher scores associated with higher pain levels.
Time frame: Baseline, Week 26
Secondary
DCR Per RECIST v1.1 by Investigator Assessment
DCR by BICR was defined as the percentage of participants with confirmed response (CR or PR), or SD (or non-CR/non-PD), per RECIST v1.1. Subjects who have no post-baseline response assessments will be considered as non-responders for calculating the DCR. Only response assessments before the first documented PD or subsequent anticancer therapies were considered. CR was defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to\<10 mm. PR was defined as at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For a response to be considered as confirmed, the subsequent response needs to be at least 4 weeks after the initial response. SD was defined as a change in tumor size that is neither radiological response (\>30% shrinkage) nor progression (\>20% growth).
Time frame: From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to approximately 7.4 years)
Secondary
Disease Control Rate (DCR) Per RECIST v1.1 by BICR
DCR by BICR was defined as the percentage of participants with confirmed response (CR or PR), or SD (or non-CR/non-PD), per RECIST v1.1. Subjects who have no post-baseline response assessments will be considered as non-responders for calculating the DCR. Only response assessments before the first documented PD or subsequent anticancer therapies were considered. CR was defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to\<10 mm. PR was defined as at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For a response to be considered as confirmed, the subsequent response needs to be at least 4 weeks after the initial response. SD was defined as a change in tumor size that is neither radiological response (\>30% shrinkage) nor progression (\>20% growth).
Time frame: From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to approximately 7.4 years)
Secondary
DOR Per RECIST v1.1 by Investigator Assessment
DOR was defined as the time from the first objective response (CR or PR that is subsequently confirmed) to the first documented PD per RECIST v1.1 per investigator or death from any cause, whichever occurs first. DOR will only include subjects with a confirmed response (CR or PR per RECIST v1.1). CR was defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to\<10 mm. PR was defined as at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. For a response to be considered as confirmed, the subsequent response needs to be at least 4 weeks after the initial response.
Time frame: From the date of first documented response of CR or PR to the first documented disease progression or to death from any cause, whichever occurred first (maximum up to approximately 7.4 years)
Secondary
Duration of Response (DOR) Per RECIST v1.1 by BICR
DOR was defined as the time from the first objective response (CR or PR that is subsequently confirmed) to the first documented PD per RECIST v1.1 per BICR or death from any cause, whichever occurs first. DOR will only include subjects with a confirmed response (CR or PR per RECIST v1.1). CR was defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to\<10 mm. PR was defined as at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For a response to be considered as confirmed, the subsequent response needs to be at least 4 weeks after the initial response. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: From the date of first documented response of CR or PR to the first documented disease progression or to death from any cause, whichever occurred first (maximum up to approximately 7.4 years)
Secondary
Mean Scores in Patient Reported Outcome (PRO) Assessment Measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L)
The EQ-5D-5L is a 5-item self-reported measure of functioning and well-being, which assesses 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression (EQ-5D-5L User Guide, 2019). Each dimension comprises 5 levels (no problems, slight problems, moderate problems, severe problems, and extreme problems).
Time frame: End of study (approximately up to 7.4 years)
Secondary
Mean Scores in PRO Assessment Measured by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30)
EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status (GHS), symptom scales (fatigue, pain, nausea/vomiting), and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea, and financial difficulties). Most questions used 4- point scale (1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores averaged, transformed to 0- 100 scale; higher score=better level of functioning or greater degree of symptoms.
Time frame: End of study (approximately up to 7.4 years)
Secondary
Number of Participants Related to Treatment AEs
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment relatedness was assessed by the investigator.
Time frame: From start of treatment up to 37 days after last dose of study drug (approximately up to 7.4 years)
Secondary
Number of Participants With Grade 3-5 TEAE
AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per common terminology criteria for adverse events (CTCAE) version 4, Grade 3= severe AE; Grade 4= life-threatening or disabling AE; Grade 5= death related to an AE.
Time frame: From start of treatment up to 37 days after last dose of study drug (approximately up to 7.4 years)
Secondary
Number of Participants With Laboratory Abnormalities
Laboratory abnormalities included Hematology and Serum Chemistry. In Hematology (increased : hemoglobin, lymphocytes, leukocytes, and decreased : hemoglobin, lymphocytes, neutrophils, platelets and leukocytes) and In serum chemistry (increased in : alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium corrected for albumin, creatinine, glucose (non-fasting), potassium, sodium, and decreased in albumin, calcium corrected for albumin, glucose (non-fasting), potassium, phosphate and sodium).
Time frame: From start of treatment up to 37 days after last dose of study drug (approximately up to 7.4 years)
Secondary
Number of Participants With Serious TEAE
SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/ incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 37 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Time frame: From start of treatment up to 37 days after last dose of study drug (approximately up to 7.4 years)
Secondary
Number of Participants With Treatment Discontinuation Rate Due to AEs
Time frame: During study (approximately up to 7.4 years)
Secondary
Number of Participants With Treatment Emergent Adverse Events Adverse Events (AEs)
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 37 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Time frame: From start of treatment up to 37 days after last dose of study drug (approximately up to 7.4 years)
Secondary
ORR Per RECIST v1.1 by Investigator Assessment
ORR as per RECIST v1.1 by investigator was defined as the percentage of participants with confirmed CR or PR. CR was defined as disappearance of all lesions including non-target lesions (not just target lesions). Any pathological lymph nodes must have reduction in short axis to\<10 mm. PR was defined as at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For a response to be considered as confirmed, the subsequent response needs to be at least 4 weeks after the initial response.
Time frame: From first dose till CR/PR or PD or death, whichever occurred first (maximum up to approximately 7.4 years)
Secondary
Percentage of Participants With Objective Response Rate (ORR) Per RECIST v1.1 by BICR
ORR as per RECIST v1.1 by BICR was defined as the percentage of participants with confirmed complete response (CR) or partial response (PR) CR was defined as disappearance of all lesions including non-target lesions (not just target lesions). Any pathological lymph nodes must have reduction in short axis to\<10 mm. PR was defined as at least 30 percent \[%\] decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For a response to be considered as confirmed, the subsequent response needs to be at least 4 weeks after the initial response.
Time frame: From first dose till CR/PR or PD or death, whichever occurred first (maximum up to approximately 7.4 years)
Secondary
PFS Per RECIST v1.1 by Investigator Assessment
PFS as per RECIST v1.1 by investigator was defined as the time from date of randomization to first documentation of PD, or to death due to any cause, whichever comes first. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PD could also be unequivocal progression of non-target lesions or the presence of unequivocal new lesions.
Time frame: From the date of randomization to first documentation of PD or death due to any cause, whichever occurred first (maximum up to approximately 7.4 years)
Secondary
Time to Pain Progression (TTPP)
TTPP was defined as the time from the date of randomization to date of pain progression. Pain progression was defined as a participant reporting either of the following, whichever came first: 1) Increase of 2 or more points from baseline on Brief Pain Inventory - Short Form (BPI-SF) Question 3 (i.e., pain at its worst in the last 24 hours, score range 0 to 10 with higher scores associated with higher pain levels) maintained for at least two consecutive assessments. 2) Initiation of new opioid medication from baseline for pain with usage maintained for at least two consecutive assessments as recorded in BPI-SF Question 7 (i.e., What medications received for pain).
Time frame: From the date of randomization to date of pain progression (maximum up to approximately 7.4 years)