Non-small Cell Lung Cancer
Conditions
Keywords
lung cancer, cancer, non-small cell lung cancer, non small cell lung cancer, NSCLC, Encorafenib, Binimetinib, Phase 2, Open Label, BRAF mutation, BRAF V600E, Array, Stage IV NSCLC, Metastatic NSCLC, PDL1, PD-LI, Immunotherapy, First line platinum based chemotherapy, BRAF inhibitor, V600
Brief summary
This is an open-label, multicenter, non-randomized, Phase 2 study to determine the safety, tolerability and efficacy of encorafenib given in combination with binimetinib in patients with BRAFV600E-mutant metastatic non-small cell lung cancer (NSCLC). Patients who are either treatment-naïve, OR who have received 1) first-line treatment with standard platinum-based chemotherapy, OR 2) first-line treatment with an anti-programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) inhibitor given alone or in combination with platinum-based chemotherapy will be enrolled.
Interventions
DRUGencorafenib
self-administered orally
DRUGbinimetinib
self-administered orally
Sponsors
Pfizer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Histologically confirmed diagnosis of non-small cell lung cancer (NSCLC) that is currently Stage IV. * Presence of a BRAFV600E mutation in lung cancer tissue as determined by a local laboratory assay or the presence of other BRAFV600 mutations other than V600E (i.e. K or D) will be considered * Patients who are either treatment-naïve (e.g., no prior systemic therapy for advanced/metastatic disease), OR who have received 1) first-line platinum-based chemotherapy OR 2) first-line treatment with an anti-programmed cell death protein 1 (PD-1)/ programmed cell death protein ligand 1(PD-L1) inhibitor given alone or in combination with platinum-based chemotherapy. * Presence of measurable disease based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). * Eastern Cooperation Oncology Group (ECOG) performance status of 0 or 1. * Adequate bone marrow function characterized by the following at screening: * absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; * Platelets ≥ 100 × 10⁹/L; * Hemoglobin ≥ 8.5 g/dL (with or without blood transfusions). * Adequate hepatic and renal function characterized by the following at screening: * Total bilirubin ≤ 1.5 × upper limit of normal (ULN) * alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN in presence of liver metastases; Serum creatinine ≤ 1.5 × ULN; or calculated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula; or estimated glomerular filtration rate \> 50 mL/min/1.73m². Key
Exclusion criteria
* Patients who have documentation of any of the following: * epidermal growth factor receptor (EGFR) mutation * anaplastic lymphoma kinase (ALK) fusion oncogene or * ROS1 rearrangement * Patients who have received more than 1 prior line of systemic therapy in the advanced/metastatic setting. * Previous treatment with any BRAF inhibitor (e.g., dabrafenib, vemurafenib, XL281/BMS-908662, etc.), or any mitogen-activated protein kinase (MEK) inhibitor (e.g., trametinib, cobimetinib, selumetinib, RDEA119, etc.) prior to screening and enrollment. * Impaired cardiovascular function or clinically significant cardiovascular diseases * History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to the first dose of study treatment. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e. massive or sub-massive) deep vein thrombosis or pulmonary emboli. * History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); history of retinal degenerative disease. * Concurrent neuromuscular disorder that is associated with the potential of elevated creatine (phospho)kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy). * Patients with symptomatic brain metastasis, leptomeningeal disease or other active central nervous system (CNS) metastases are not eligible.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Confirmed Objective Response (OR) as Determined by Independent Radiology Review (IRR) | From date of the first dose of study intervention until documented progressive disease (PD) or start of new anticancer therapy (up to 36 months) | Objective Response Rate (ORR) was defined as the percentage of participants who had achieved a confirmed best overall response (Complete Response \[CR\] or Partial Response \[PR\]) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. CR was defined by the disappearance of all non-lymph node target lesions (where all target lesions were recorded with a length of 0 mm, and any pathological lymph nodes \[recorded as target lesion\] must have reduction in short axis to \<10 mm) and complete disappearance of all non-target lesions (where all non-target lesions were marked "Absent", and all lymph nodes must be non-pathological in size \[\<10 mm in short axis\]). PR was defined by a 30% or more decrease in sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. ORR was calculated with the exact 2-sided Clopper-Pearson 95% CI. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Confirmed Objective Response (OR) by Investigator Assessment | From date of the first dose of study intervention until documented PD or start of new anticancer therapy (up to 36 months) | ORR was defined as the percentage of participants who had achieved a confirmed best overall response (CR or PR) per RECIST version 1.1. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. CR was defined by the disappearance of all non-lymph node target lesions (where all target lesions were recorded with a length of 0 mm, and any pathological lymph nodes \[recorded as target lesion\] must have reduction in short axis to \<10 mm) and the complete disappearance of all non-target lesions (where all non-target lesions were marked "Absent", and all lymph nodes must be non-pathological in size \[\<10 mm in short axis\]). PR was defined by a 30% or more decrease in SOD of target lesions, taking as reference the baseline SOD. ORR according to derived investigator assessment was calculated with the exact 2-sided Clopper-Pearson 95% CI. |
| Duration of Response (DoR) by IRR and Investigator Assessments | From the date of the first confirmed documented response (CR or PR) to the earliest date of disease progression or death due to any cause (up to 36 months) | DoR, based on IRR and Investigator assessments was defined as the time from the date of the first documented confirmed response (CR or PR) (by IRR and by Investigator, respectively) to the earliest date of disease progression, as determined by Investigator review of radiographic disease assessments and IRR per RECIST version 1.1, or death due to any cause. If a participant with a CR or PR had neither progressed nor died at the time of the analysis cutoff or at the start of any new anticancer therapy, the participant was censored at the date of last adequate tumor assessment. CR was defined by the disappearance of all non-lymph node target lesions and complete disappearance of all non-target lesions. PR was defined by a 30% or more decrease in SOD of target lesions, taking as reference the baseline SOD. DoR was calculated for participants who had achieved a confirmed overall response (CR or PR). The estimate of the DoR survival function was constructed using the Kaplan-Meier method. |
| Disease Control Rate (DCR) by IRR and Investigator Assessments | After 24 Weeks (≥168 days) from the date of first dose of study intervention | DCR was defined as the percentage of participants who had achieved a confirmed overall response of CR, PR or stable disease (SD), as determined by Investigator review of radiographic disease assessments and IRR per RECIST version 1.1 after 24 weeks (≥168 days) from the date of first dose of study intervention. CR was defined by the disappearance of all non-lymph node target lesions and complete disappearance of all non-target lesions. PR was defined by a 30% or more decrease in SOD of target lesions, taking as reference the baseline SOD. SD was assigned when neither sufficient shrinkage to qualify for CR or PR, nor sufficient increase to qualify for PD was observed, taking as reference the nadir. DCR was calculated along with the exact 2-sided Clopper-Pearson 95% CI. |
| Progression-free Survival (PFS) by IRR and Investigator Assessments | From the date of first dose of study drug to the earliest date of disease progression, or death due to any cause (up to 36 months) | PFS was defined as the time from the date of first dose of study intervention to the earliest date of disease progression, as determined by IRR and Investigator review of radiographic disease assessments per RECIST version 1.1, or death due to any cause, whichever occurred first. PD was defined by a 20% or more increase in the SOD of target lesions relative to nadir (smallest SOD considering baseline and all assessments prior to the time point under evaluation), with a minimum absolute increase of 5 mm relative to nadir; PD was assigned if any non-target lesion was marked "unequivocal progression". If a participant had not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment. PFS (months) = \[(date of event or censoring - date of first dose) +1\]/30.4375. The survival distribution function for PFS was estimated using the Kaplan-Meier method. |
| Time to Response (TTR) by IRR and Investigator Assessments | From the date of first dose to the first documentation of confirmed objective response (CR or PR) (up to 36 months) | TTR based on IRR and Investigator assessments was defined, for participants with an objective response, as the time, in months, from the date of first dose to the first documentation of objective response (CR or PR) which was subsequently confirmed (by IRR and by Investigator, respectively). TTR was calculated for the subgroup of participants with a confirmed objective tumor response. |
| Kaplan-Meier Estimates of Overall Survival (OS) | The time from the date of first dose of study intervention to the date of death due to any cause (up to 36 months) | OS was defined as the time from the date of first dose of study intervention to the date of death due to any cause. If a death had not been observed by the date of the analysis cutoff, OS was censored at the date of last contact. The survival distribution function for OS was estimated using the Kaplan-Meier method. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From the time the participant provided informed consent, through and including a minimum of 30 calendar days, after the last administration of the study intervention, and the safety follow-up visit (30 days [±7 days] after the EOT visit) (up to 36 months) | TEAE was a treatment-emergent adverse event that occurred during the on-treatment period. The on-treatment period was defined as the time from the first dose date of study intervention to the last dose of study drug administration date (when both drugs were permanently discontinued) +30 days or the earliest date of subsequent anti-cancer drug therapy minus 1 day, whichever occurred first. Relatedness to study intervention was determined by the investigator. The investigator made an assessment of intensity for each AE reported during the study according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03: Grade 3 events = severe AEs; Grade 4 events = life-threatening consequences, urgent intervention indicated; Grade 5 events = death related to AEs. |
| Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Screening, Cycle 1 Day 1, Cycle 2 Day 1 ±3 Days, Day 1 ±3 Days in Subsequent Cycles, End of Treatment (EOT) ±3 Days and Safety Follow-up Visit (30 Days [±7 Days] After the EOT Visit) (Up to 36 Months) | Blood and urine samples for the laboratory tests. A central laboratory will perform all clinical laboratory assessments. Baseline was the last available assessment performed prior to the study intervention start date/time. Grade 4 was not applicable for the parameters of anemia, hemoglobin increased, leukocytosis and lymphocyte count increased as Grade 4 was not defined for these 4 parameters per CTCAE version 4.03. |
| Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Screening, Cycle 1 Day 1, Cycle 2 Day 1 ±3 Days, Day 1 ±3 Days in Subsequent Cycles, EOT ±3 Days and Safety Follow-up Visit (30 Days [±7 Days] After the EOT Visit) (Up to 36 Months) | Blood and urine samples for the laboratory tests. A central laboratory will perform all clinical laboratory assessments. Baseline was the last available assessment performed prior to the study intervention start date/time. Grade 4 was not applicable for the parameters of hyperglycemia and hypoalbuminemia as Grade 4 was not defined for these 2 parameters per CTCAE version 4.03. |
| Number of Participants With Notable Abnormal Vital Signs | Screening, Cycle 1 Day 1, Cycle 2 Day 1 ±3 Days, Day 1 ±3 Days of Subsequent Cycles, EOT ±3 Days, and Safety Follow-up Visit (30 Days [±7 Days] After the EOT Visit) (Up to 36 Months) | Vital sign measurements were taken before blood collection for laboratory tests or at least 30 minutes after blood collection for laboratory tests, and were measured per institutional standards. Vital sign assessments included temperature, pulse rate, respiratory rate, and blood pressure (assessed in a recumbent, semi recumbent, or sitting position). The criteria of notably abnormal vital signs are listed below: Systolic blood pressure (mmHg): high: ≥160 mmHg with increase from baseline of ≥20 mmHg; low: ≤90 mmHg with decrease from baseline of ≥20 mmHg. Diastolic blood pressure (mmHg): high: ≥100 mmHg with increase from baseline of ≥15 mmHg; low: ≤50 mmHg with decrease from baseline of ≥15 mmHg. Pulse rate (bpm): high: ≥120 bpm with increase from baseline of ≥15 bpm; low: ≤50 bpm with decrease from baseline of ≥15 bpm. Weight (kg): high: ≥10% increase from baseline; low: ≥20% decrease from baseline. Temperature (°C): high: ≥37.5 °C; low: ≤36 °C. |
| Number of Participants With Notable ECG (QTcF) Values | Screening, Cycle 1 Day 1, Cycle 2 Day 1 ±3 Days, Every 12 Weeks ±7 Days, and EOT ±3 Days (Up to 36 Months) | The QTcF increase from baseline \>30/60 msec and new QTcF \>450/480/500 msec were defined as clinically notable ECG criteria. Triplicate ECG measurements were obtained. For new abnormal post-baseline values, the table below presents the number of participants with both non-missing baseline and post-baseline values, and baseline values not meeting the criteria. For abnormal changes from baseline, the table below presents the number of participants with both non-missing baseline and post-baseline evaluations. Baseline was defined as the average of the machine-read triplicate ECG measurements taken pre-dose on Day 1. Change from baseline was post-baseline - baseline values. |
| Number of Participants With the Worst Post-baseline Left Ventricular Ejection Fraction (LVEF) Values Based on CTCAE Grade | Screening, Cycle 2 Day 1 ±3 Days, Every 12 Weeks ±7 Days, and EOT ±3 Days (Up to 36 Months) | Cardiac ejection fraction was assessed by transthoracic echocardiogram (ECHO) or multigated acquisition (MUGA). Participants who developed signs/symptoms of congestive heart failure (CHF) at any point during the study were required to have an evaluation of LVEF measurements by ECHO or MUGA and were monitored per institutional guidelines. Participants were considered as having a LVEF abnormality if the worst post-value was CTCAE Grade 2, 3 or 4 according to the following classification: Grade 0: Non-missing value below Grade 2. Grade 2: LVEF between 40% and 50%, inclusive, or absolute change from baseline between -10% and \< -20%. Grade 3: LVEF between 20% and 39%, inclusive, or absolute change from baseline ≤ -20%. Grade 4: LVEF lower than 20%. Baseline was defined as the last available and valid assessment before or on the start date of study intervention. |
Countries
Italy, Netherlands, South Korea, Spain, United States
Contacts
STUDY_DIRECTORPfizer CT.gov Call Center
Pfizer
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment-Naive Treatment-naïve participants with BRAF V600E-mutant metastatic NSCLC were enrolled to receive encorafenib 450 mg QD and binimetinib 45 mg BID in 28-day (±3 days) cycles and continued until the participants met the protocol-defined criteria for treatment withdrawal. | 59 |
| Previously Treated Patients who had received 1) first-line treatment with standard platinum-based chemotherapy, or 2) first-line treatment with an anti-PD-1/PD-L1 inhibitor given alone, or in combination with platinum-based chemotherapy, or in combination with immunotherapy (eg, ipilimumab) with or without platinum-based chemotherapy were enrolled to receive encorafenib 450 mg QD and binimetinib 45 mg BID was to be administered in 28-day (±3 days) cycles and continued until the participants met the protocol-defined criteria for treatment withdrawal. | 39 |
| Total | 98 |
Baseline characteristics
| Characteristic | Treatment-Naive | Previously Treated | Total |
|---|---|---|---|
| Age, Continuous | 68 Years | 71 Years | 69.5 Years |
| Eastern Cooperation Oncology Group (ECOG) Performance Status Grade 0 | 19 Participants | 7 Participants | 26 Participants |
| Eastern Cooperation Oncology Group (ECOG) Performance Status Grade 1 | 40 Participants | 32 Participants | 72 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 53 Participants | 33 Participants | 86 Participants |
| Sex: Female, Male Female | 33 Participants | 19 Participants | 52 Participants |
| Sex: Female, Male Male | 26 Participants | 20 Participants | 46 Participants |
| Smoking Status Current Smoking | 8 Participants | 5 Participants | 13 Participants |
| Smoking Status Former Smoking | 33 Participants | 23 Participants | 56 Participants |
| Smoking Status Never Smoking | 18 Participants | 11 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 59 | 7 / 39 | 12 / 98 |
| other Total, other adverse events | 59 / 59 | 38 / 39 | 97 / 98 |
| serious Total, serious adverse events | 25 / 59 | 17 / 39 | 42 / 98 |
Outcome results
Primary
Percentage of Participants With Confirmed Objective Response (OR) as Determined by Independent Radiology Review (IRR)
Objective Response Rate (ORR) was defined as the percentage of participants who had achieved a confirmed best overall response (Complete Response \[CR\] or Partial Response \[PR\]) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. CR was defined by the disappearance of all non-lymph node target lesions (where all target lesions were recorded with a length of 0 mm, and any pathological lymph nodes \[recorded as target lesion\] must have reduction in short axis to \<10 mm) and complete disappearance of all non-target lesions (where all non-target lesions were marked Absent, and all lymph nodes must be non-pathological in size \[\<10 mm in short axis\]). PR was defined by a 30% or more decrease in sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. ORR was calculated with the exact 2-sided Clopper-Pearson 95% CI.
Time frame: From date of the first dose of study intervention until documented progressive disease (PD) or start of new anticancer therapy (up to 36 months)
Population: Analysis population included all participants who received at least 1 dose of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment-Naive | Percentage of Participants With Confirmed Objective Response (OR) as Determined by Independent Radiology Review (IRR) | 74.6 Percentage of Participants |
| Previously Treated | Percentage of Participants With Confirmed Objective Response (OR) as Determined by Independent Radiology Review (IRR) | 46.2 Percentage of Participants |
Secondary
Disease Control Rate (DCR) by IRR and Investigator Assessments
DCR was defined as the percentage of participants who had achieved a confirmed overall response of CR, PR or stable disease (SD), as determined by Investigator review of radiographic disease assessments and IRR per RECIST version 1.1 after 24 weeks (≥168 days) from the date of first dose of study intervention. CR was defined by the disappearance of all non-lymph node target lesions and complete disappearance of all non-target lesions. PR was defined by a 30% or more decrease in SOD of target lesions, taking as reference the baseline SOD. SD was assigned when neither sufficient shrinkage to qualify for CR or PR, nor sufficient increase to qualify for PD was observed, taking as reference the nadir. DCR was calculated along with the exact 2-sided Clopper-Pearson 95% CI.
Time frame: After 24 Weeks (≥168 days) from the date of first dose of study intervention
Population: Analysis population included all participants who received at least 1 dose of study intervention.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment-Naive | Disease Control Rate (DCR) by IRR and Investigator Assessments | DCR After 24 Weeks by IRR | 64.4 Percentage of Participants |
| Treatment-Naive | Disease Control Rate (DCR) by IRR and Investigator Assessments | DCR After 24 Weeks by Investigator Assessment | 67.8 Percentage of Participants |
| Previously Treated | Disease Control Rate (DCR) by IRR and Investigator Assessments | DCR After 24 Weeks by IRR | 41.0 Percentage of Participants |
| Previously Treated | Disease Control Rate (DCR) by IRR and Investigator Assessments | DCR After 24 Weeks by Investigator Assessment | 48.7 Percentage of Participants |
Secondary
Duration of Response (DoR) by IRR and Investigator Assessments
DoR, based on IRR and Investigator assessments was defined as the time from the date of the first documented confirmed response (CR or PR) (by IRR and by Investigator, respectively) to the earliest date of disease progression, as determined by Investigator review of radiographic disease assessments and IRR per RECIST version 1.1, or death due to any cause. If a participant with a CR or PR had neither progressed nor died at the time of the analysis cutoff or at the start of any new anticancer therapy, the participant was censored at the date of last adequate tumor assessment. CR was defined by the disappearance of all non-lymph node target lesions and complete disappearance of all non-target lesions. PR was defined by a 30% or more decrease in SOD of target lesions, taking as reference the baseline SOD. DoR was calculated for participants who had achieved a confirmed overall response (CR or PR). The estimate of the DoR survival function was constructed using the Kaplan-Meier method.
Time frame: From the date of the first confirmed documented response (CR or PR) to the earliest date of disease progression or death due to any cause (up to 36 months)
Secondary
Kaplan-Meier Estimates of Overall Survival (OS)
OS was defined as the time from the date of first dose of study intervention to the date of death due to any cause. If a death had not been observed by the date of the analysis cutoff, OS was censored at the date of last contact. The survival distribution function for OS was estimated using the Kaplan-Meier method.
Time frame: The time from the date of first dose of study intervention to the date of death due to any cause (up to 36 months)
Secondary
Number of Participants With Notable Abnormal Vital Signs
Vital sign measurements were taken before blood collection for laboratory tests or at least 30 minutes after blood collection for laboratory tests, and were measured per institutional standards. Vital sign assessments included temperature, pulse rate, respiratory rate, and blood pressure (assessed in a recumbent, semi recumbent, or sitting position). The criteria of notably abnormal vital signs are listed below: Systolic blood pressure (mmHg): high: ≥160 mmHg with increase from baseline of ≥20 mmHg; low: ≤90 mmHg with decrease from baseline of ≥20 mmHg. Diastolic blood pressure (mmHg): high: ≥100 mmHg with increase from baseline of ≥15 mmHg; low: ≤50 mmHg with decrease from baseline of ≥15 mmHg. Pulse rate (bpm): high: ≥120 bpm with increase from baseline of ≥15 bpm; low: ≤50 bpm with decrease from baseline of ≥15 bpm. Weight (kg): high: ≥10% increase from baseline; low: ≥20% decrease from baseline. Temperature (°C): high: ≥37.5 °C; low: ≤36 °C.
Time frame: Screening, Cycle 1 Day 1, Cycle 2 Day 1 ±3 Days, Day 1 ±3 Days of Subsequent Cycles, EOT ±3 Days, and Safety Follow-up Visit (30 Days [±7 Days] After the EOT Visit) (Up to 36 Months)
Population: Analysis population included all participants who received at least 1 dose of study intervention and had baseline and post-baseline vital sign values. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of categories.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment-Naive | Number of Participants With Notable Abnormal Vital Signs | Temperature - high | 8 Participants |
| Treatment-Naive | Number of Participants With Notable Abnormal Vital Signs | Systolic blood pressure - low | 5 Participants |
| Treatment-Naive | Number of Participants With Notable Abnormal Vital Signs | Pulse rate - high | 2 Participants |
| Treatment-Naive | Number of Participants With Notable Abnormal Vital Signs | Temperature - low | 25 Participants |
| Treatment-Naive | Number of Participants With Notable Abnormal Vital Signs | Weight - low | 1 Participants |
| Treatment-Naive | Number of Participants With Notable Abnormal Vital Signs | Pulse rate - low | 1 Participants |
| Treatment-Naive | Number of Participants With Notable Abnormal Vital Signs | Diastolic blood pressure - low | 2 Participants |
| Treatment-Naive | Number of Participants With Notable Abnormal Vital Signs | Systolic blood pressure - high | 10 Participants |
| Treatment-Naive | Number of Participants With Notable Abnormal Vital Signs | Weight - high | 17 Participants |
| Treatment-Naive | Number of Participants With Notable Abnormal Vital Signs | Diastolic blood pressure - high | 5 Participants |
| Previously Treated | Number of Participants With Notable Abnormal Vital Signs | Weight - high | 4 Participants |
| Previously Treated | Number of Participants With Notable Abnormal Vital Signs | Weight - low | 0 Participants |
| Previously Treated | Number of Participants With Notable Abnormal Vital Signs | Diastolic blood pressure - high | 1 Participants |
| Previously Treated | Number of Participants With Notable Abnormal Vital Signs | Temperature - high | 3 Participants |
| Previously Treated | Number of Participants With Notable Abnormal Vital Signs | Systolic blood pressure - high | 4 Participants |
| Previously Treated | Number of Participants With Notable Abnormal Vital Signs | Temperature - low | 10 Participants |
| Previously Treated | Number of Participants With Notable Abnormal Vital Signs | Diastolic blood pressure - low | 2 Participants |
| Previously Treated | Number of Participants With Notable Abnormal Vital Signs | Pulse rate - high | 6 Participants |
| Previously Treated | Number of Participants With Notable Abnormal Vital Signs | Systolic blood pressure - low | 2 Participants |
| Previously Treated | Number of Participants With Notable Abnormal Vital Signs | Pulse rate - low | 1 Participants |
| Total | Number of Participants With Notable Abnormal Vital Signs | Temperature - low | 35 Participants |
| Total | Number of Participants With Notable Abnormal Vital Signs | Systolic blood pressure - low | 7 Participants |
| Total | Number of Participants With Notable Abnormal Vital Signs | Diastolic blood pressure - high | 6 Participants |
| Total | Number of Participants With Notable Abnormal Vital Signs | Diastolic blood pressure - low | 4 Participants |
| Total | Number of Participants With Notable Abnormal Vital Signs | Pulse rate - high | 8 Participants |
| Total | Number of Participants With Notable Abnormal Vital Signs | Pulse rate - low | 2 Participants |
| Total | Number of Participants With Notable Abnormal Vital Signs | Weight - high | 21 Participants |
| Total | Number of Participants With Notable Abnormal Vital Signs | Weight - low | 1 Participants |
| Total | Number of Participants With Notable Abnormal Vital Signs | Temperature - high | 11 Participants |
| Total | Number of Participants With Notable Abnormal Vital Signs | Systolic blood pressure - high | 14 Participants |
Secondary
Number of Participants With Notable ECG (QTcF) Values
The QTcF increase from baseline \>30/60 msec and new QTcF \>450/480/500 msec were defined as clinically notable ECG criteria. Triplicate ECG measurements were obtained. For new abnormal post-baseline values, the table below presents the number of participants with both non-missing baseline and post-baseline values, and baseline values not meeting the criteria. For abnormal changes from baseline, the table below presents the number of participants with both non-missing baseline and post-baseline evaluations. Baseline was defined as the average of the machine-read triplicate ECG measurements taken pre-dose on Day 1. Change from baseline was post-baseline - baseline values.
Time frame: Screening, Cycle 1 Day 1, Cycle 2 Day 1 ±3 Days, Every 12 Weeks ±7 Days, and EOT ±3 Days (Up to 36 Months)
Population: Safety Analysis Set included all participants who received at least 1 dose of study intervention. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of categories.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment-Naive | Number of Participants With Notable ECG (QTcF) Values | QTcF Increase from baseline >30 msec | 20 Participants |
| Treatment-Naive | Number of Participants With Notable ECG (QTcF) Values | New QTcF >500 msec | 1 Participants |
| Treatment-Naive | Number of Participants With Notable ECG (QTcF) Values | New QTcF >450 msec | 12 Participants |
| Treatment-Naive | Number of Participants With Notable ECG (QTcF) Values | New QTcF >480 msec | 5 Participants |
| Treatment-Naive | Number of Participants With Notable ECG (QTcF) Values | QTcF Increase from baseline >60 msec | 3 Participants |
| Previously Treated | Number of Participants With Notable ECG (QTcF) Values | New QTcF >500 msec | 1 Participants |
| Previously Treated | Number of Participants With Notable ECG (QTcF) Values | New QTcF >450 msec | 7 Participants |
| Previously Treated | Number of Participants With Notable ECG (QTcF) Values | New QTcF >480 msec | 5 Participants |
| Previously Treated | Number of Participants With Notable ECG (QTcF) Values | QTcF Increase from baseline >30 msec | 9 Participants |
| Previously Treated | Number of Participants With Notable ECG (QTcF) Values | QTcF Increase from baseline >60 msec | 4 Participants |
| Total | Number of Participants With Notable ECG (QTcF) Values | QTcF Increase from baseline >60 msec | 7 Participants |
| Total | Number of Participants With Notable ECG (QTcF) Values | QTcF Increase from baseline >30 msec | 29 Participants |
| Total | Number of Participants With Notable ECG (QTcF) Values | New QTcF >450 msec | 19 Participants |
| Total | Number of Participants With Notable ECG (QTcF) Values | New QTcF >500 msec | 2 Participants |
| Total | Number of Participants With Notable ECG (QTcF) Values | New QTcF >480 msec | 10 Participants |
Secondary
Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade
Blood and urine samples for the laboratory tests. A central laboratory will perform all clinical laboratory assessments. Baseline was the last available assessment performed prior to the study intervention start date/time. Grade 4 was not applicable for the parameters of hyperglycemia and hypoalbuminemia as Grade 4 was not defined for these 2 parameters per CTCAE version 4.03.
Time frame: Screening, Cycle 1 Day 1, Cycle 2 Day 1 ±3 Days, Day 1 ±3 Days in Subsequent Cycles, EOT ±3 Days and Safety Follow-up Visit (30 Days [±7 Days] After the EOT Visit) (Up to 36 Months)
Population: Safety Analysis Set included all participants who received at least 1 dose of study intervention. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of categories.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Alanine aminotransferase increased - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypocalcemia - Grade 4 | 2 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Creatinine increased - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypercalcemia - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypocalcemia - Grade 3 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypercalcemia - Grade 3 | 1 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypophosphatemia - Grade 3 | 1 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypoalbuminemia - Grade 3 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hyperglycemia - Grade 3 | 5 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Alkaline phosphatase increased - Grade 3 | 2 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypernatremia - Grade 3 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hyperkalemia - Grade 3 | 2 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypernatremia - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypermagnesemia - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hyperkalemia - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hyponatremia - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypermagnesemia - Grade 3 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Alkaline phosphatase increased - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Lipase increased - Grade 4 | 2 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hyponatremia - Grade 3 | 7 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Aspartate aminotransferase increased - Grade 3 | 7 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypophosphatemia - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypomagnesemia - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Aspartate aminotransferase increased - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Serum amylase increased - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypomagnesemia - Grade 3 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Blood bilirubin increased - Grade 3 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Alanine aminotransferase increased - Grade 3 | 6 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypokalemia - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Blood bilirubin increased - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypokalemia - Grade 3 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Creatine kinase increased - Grade 3 | 2 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Serum amylase increased - Grade 3 | 1 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypoglycemia - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Creatine kinase increased - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Lipase increased - Grade 3 | 8 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypoglycemia - Grade 3 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Creatinine increased - Grade 3 | 3 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Blood bilirubin increased - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypercalcemia - Grade 3 | 1 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Alanine aminotransferase increased - Grade 3 | 2 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Alanine aminotransferase increased - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Alkaline phosphatase increased - Grade 3 | 1 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Alkaline phosphatase increased - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Aspartate aminotransferase increased - Grade 3 | 2 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Aspartate aminotransferase increased - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Blood bilirubin increased - Grade 3 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Creatine kinase increased - Grade 3 | 1 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Creatine kinase increased - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Creatinine increased - Grade 3 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Creatinine increased - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypercalcemia - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hyperglycemia - Grade 3 | 1 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hyperkalemia - Grade 3 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hyperkalemia - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypermagnesemia - Grade 3 | 1 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypermagnesemia - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypernatremia - Grade 3 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypernatremia - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypoalbuminemia - Grade 3 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypocalcemia - Grade 3 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypocalcemia - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypoglycemia - Grade 3 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypoglycemia - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypokalemia - Grade 3 | 1 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypokalemia - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypomagnesemia - Grade 3 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypomagnesemia - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hyponatremia - Grade 3 | 2 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hyponatremia - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypophosphatemia - Grade 3 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypophosphatemia - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Lipase increased - Grade 3 | 3 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Lipase increased - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Serum amylase increased - Grade 3 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Serum amylase increased - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypophosphatemia - Grade 3 | 1 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypoglycemia - Grade 3 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Creatine kinase increased - Grade 3 | 3 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypercalcemia - Grade 3 | 2 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypoglycemia - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Blood bilirubin increased - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypophosphatemia - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypokalemia - Grade 3 | 1 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Blood bilirubin increased - Grade 3 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Alanine aminotransferase increased - Grade 3 | 8 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypokalemia - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Aspartate aminotransferase increased - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Serum amylase increased - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Aspartate aminotransferase increased - Grade 3 | 9 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Lipase increased - Grade 3 | 11 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypomagnesemia - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Alkaline phosphatase increased - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hyperkalemia - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypomagnesemia - Grade 3 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypermagnesemia - Grade 3 | 1 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hyperkalemia - Grade 3 | 2 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hyponatremia - Grade 3 | 9 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypermagnesemia - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hyperglycemia - Grade 3 | 6 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Alkaline phosphatase increased - Grade 3 | 3 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypernatremia - Grade 3 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Serum amylase increased - Grade 3 | 1 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypernatremia - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypercalcemia - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hyponatremia - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypoalbuminemia - Grade 3 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Creatinine increased - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Alanine aminotransferase increased - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypocalcemia - Grade 3 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Creatinine increased - Grade 3 | 3 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Lipase increased - Grade 4 | 2 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Hypocalcemia - Grade 4 | 2 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Chemistry Laboratory Test Values Based on CTCAE Grade | Creatine kinase increased - Grade 4 | 0 Participants |
Secondary
Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade
Blood and urine samples for the laboratory tests. A central laboratory will perform all clinical laboratory assessments. Baseline was the last available assessment performed prior to the study intervention start date/time. Grade 4 was not applicable for the parameters of anemia, hemoglobin increased, leukocytosis and lymphocyte count increased as Grade 4 was not defined for these 4 parameters per CTCAE version 4.03.
Time frame: Screening, Cycle 1 Day 1, Cycle 2 Day 1 ±3 Days, Day 1 ±3 Days in Subsequent Cycles, End of Treatment (EOT) ±3 Days and Safety Follow-up Visit (30 Days [±7 Days] After the EOT Visit) (Up to 36 Months)
Population: Safety Analysis Set included all participants who received at least 1 dose of study intervention. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of categories.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Anemia - Grade 3 | 9 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Hemoglobin increased - Grade 3 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Leukocytosis - Grade 3 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Lymphocyte count decreased - Grade 3 | 2 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Lymphocyte count decreased - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Lymphocyte count increased - Grade 3 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Neutrophil count decreased - Grade 3 | 1 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Neutrophil count decreased - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Platelet count decreased - Grade 3 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Platelet count decreased - Grade 4 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | White blood cell decreased - Grade 3 | 0 Participants |
| Treatment-Naive | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | White blood cell decreased - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | White blood cell decreased - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Anemia - Grade 3 | 1 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Neutrophil count decreased - Grade 3 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Platelet count decreased - Grade 3 | 1 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Hemoglobin increased - Grade 3 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Lymphocyte count increased - Grade 3 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | White blood cell decreased - Grade 3 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Leukocytosis - Grade 3 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Neutrophil count decreased - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Lymphocyte count decreased - Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Lymphocyte count decreased - Grade 3 | 3 Participants |
| Previously Treated | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Platelet count decreased - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Lymphocyte count decreased - Grade 3 | 5 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Lymphocyte count decreased - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Platelet count decreased - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Lymphocyte count increased - Grade 3 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Neutrophil count decreased - Grade 3 | 1 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Neutrophil count decreased - Grade 4 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | White blood cell decreased - Grade 3 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Anemia - Grade 3 | 10 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Hemoglobin increased - Grade 3 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Platelet count decreased - Grade 3 | 1 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | Leukocytosis - Grade 3 | 0 Participants |
| Total | Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or 4 at Post-baseline in Hematology Laboratory Test Values Based on CTCAE Grade | White blood cell decreased - Grade 4 | 0 Participants |
Secondary
Number of Participants With the Worst Post-baseline Left Ventricular Ejection Fraction (LVEF) Values Based on CTCAE Grade
Cardiac ejection fraction was assessed by transthoracic echocardiogram (ECHO) or multigated acquisition (MUGA). Participants who developed signs/symptoms of congestive heart failure (CHF) at any point during the study were required to have an evaluation of LVEF measurements by ECHO or MUGA and were monitored per institutional guidelines. Participants were considered as having a LVEF abnormality if the worst post-value was CTCAE Grade 2, 3 or 4 according to the following classification: Grade 0: Non-missing value below Grade 2. Grade 2: LVEF between 40% and 50%, inclusive, or absolute change from baseline between -10% and \< -20%. Grade 3: LVEF between 20% and 39%, inclusive, or absolute change from baseline ≤ -20%. Grade 4: LVEF lower than 20%. Baseline was defined as the last available and valid assessment before or on the start date of study intervention.
Time frame: Screening, Cycle 2 Day 1 ±3 Days, Every 12 Weeks ±7 Days, and EOT ±3 Days (Up to 36 Months)
Population: Analysis Population included all participants who received at least 1 dose of study intervention and had both baseline and post-baseline LVEF values. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of categories.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment-Naive | Number of Participants With the Worst Post-baseline Left Ventricular Ejection Fraction (LVEF) Values Based on CTCAE Grade | Grade 0 | 45 Participants |
| Treatment-Naive | Number of Participants With the Worst Post-baseline Left Ventricular Ejection Fraction (LVEF) Values Based on CTCAE Grade | Grade 2 | 11 Participants |
| Treatment-Naive | Number of Participants With the Worst Post-baseline Left Ventricular Ejection Fraction (LVEF) Values Based on CTCAE Grade | Grade 3 | 0 Participants |
| Treatment-Naive | Number of Participants With the Worst Post-baseline Left Ventricular Ejection Fraction (LVEF) Values Based on CTCAE Grade | Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With the Worst Post-baseline Left Ventricular Ejection Fraction (LVEF) Values Based on CTCAE Grade | Grade 4 | 0 Participants |
| Previously Treated | Number of Participants With the Worst Post-baseline Left Ventricular Ejection Fraction (LVEF) Values Based on CTCAE Grade | Grade 0 | 24 Participants |
| Previously Treated | Number of Participants With the Worst Post-baseline Left Ventricular Ejection Fraction (LVEF) Values Based on CTCAE Grade | Grade 3 | 2 Participants |
| Previously Treated | Number of Participants With the Worst Post-baseline Left Ventricular Ejection Fraction (LVEF) Values Based on CTCAE Grade | Grade 2 | 7 Participants |
| Total | Number of Participants With the Worst Post-baseline Left Ventricular Ejection Fraction (LVEF) Values Based on CTCAE Grade | Grade 4 | 0 Participants |
| Total | Number of Participants With the Worst Post-baseline Left Ventricular Ejection Fraction (LVEF) Values Based on CTCAE Grade | Grade 2 | 18 Participants |
| Total | Number of Participants With the Worst Post-baseline Left Ventricular Ejection Fraction (LVEF) Values Based on CTCAE Grade | Grade 3 | 2 Participants |
| Total | Number of Participants With the Worst Post-baseline Left Ventricular Ejection Fraction (LVEF) Values Based on CTCAE Grade | Grade 0 | 69 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
TEAE was a treatment-emergent adverse event that occurred during the on-treatment period. The on-treatment period was defined as the time from the first dose date of study intervention to the last dose of study drug administration date (when both drugs were permanently discontinued) +30 days or the earliest date of subsequent anti-cancer drug therapy minus 1 day, whichever occurred first. Relatedness to study intervention was determined by the investigator. The investigator made an assessment of intensity for each AE reported during the study according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03: Grade 3 events = severe AEs; Grade 4 events = life-threatening consequences, urgent intervention indicated; Grade 5 events = death related to AEs.
Time frame: From the time the participant provided informed consent, through and including a minimum of 30 calendar days, after the last administration of the study intervention, and the safety follow-up visit (30 days [±7 days] after the EOT visit) (up to 36 months)
Population: Safety Analysis Set included all participants who received at least 1 dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment-Naive | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants With TEAEs | 59 Participants |
| Treatment-Naive | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants With Treatment-related TEAEs | 58 Participants |
| Treatment-Naive | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with Maximum Grade 3 or 4 TEAEs | 37 Participants |
| Treatment-Naive | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with Maximum Treatment-related Grade 3 or 4 TEAEs | 27 Participants |
| Treatment-Naive | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants With Grade 5 TEAEs | 5 Participants |
| Treatment-Naive | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants With Treatment-related Grade 5 TEAEs | 1 Participants |
| Previously Treated | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants With Treatment-related Grade 5 TEAEs | 0 Participants |
| Previously Treated | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants With TEAEs | 38 Participants |
| Previously Treated | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with Maximum Treatment-related Grade 3 or 4 TEAEs | 13 Participants |
| Previously Treated | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants With Grade 5 TEAEs | 7 Participants |
| Previously Treated | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants With Treatment-related TEAEs | 34 Participants |
| Previously Treated | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with Maximum Grade 3 or 4 TEAEs | 18 Participants |
| Total | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants With Treatment-related TEAEs | 92 Participants |
| Total | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with Maximum Grade 3 or 4 TEAEs | 55 Participants |
| Total | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants With Treatment-related Grade 5 TEAEs | 1 Participants |
| Total | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with Maximum Treatment-related Grade 3 or 4 TEAEs | 40 Participants |
| Total | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants With TEAEs | 97 Participants |
| Total | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants With Grade 5 TEAEs | 12 Participants |
Secondary
Percentage of Participants With Confirmed Objective Response (OR) by Investigator Assessment
ORR was defined as the percentage of participants who had achieved a confirmed best overall response (CR or PR) per RECIST version 1.1. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. CR was defined by the disappearance of all non-lymph node target lesions (where all target lesions were recorded with a length of 0 mm, and any pathological lymph nodes \[recorded as target lesion\] must have reduction in short axis to \<10 mm) and the complete disappearance of all non-target lesions (where all non-target lesions were marked Absent, and all lymph nodes must be non-pathological in size \[\<10 mm in short axis\]). PR was defined by a 30% or more decrease in SOD of target lesions, taking as reference the baseline SOD. ORR according to derived investigator assessment was calculated with the exact 2-sided Clopper-Pearson 95% CI.
Time frame: From date of the first dose of study intervention until documented PD or start of new anticancer therapy (up to 36 months)
Population: Analysis population included all participants who received at least 1 dose of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment-Naive | Percentage of Participants With Confirmed Objective Response (OR) by Investigator Assessment | 62.7 Percentage of Participants |
| Previously Treated | Percentage of Participants With Confirmed Objective Response (OR) by Investigator Assessment | 41.0 Percentage of Participants |
Secondary
Progression-free Survival (PFS) by IRR and Investigator Assessments
PFS was defined as the time from the date of first dose of study intervention to the earliest date of disease progression, as determined by IRR and Investigator review of radiographic disease assessments per RECIST version 1.1, or death due to any cause, whichever occurred first. PD was defined by a 20% or more increase in the SOD of target lesions relative to nadir (smallest SOD considering baseline and all assessments prior to the time point under evaluation), with a minimum absolute increase of 5 mm relative to nadir; PD was assigned if any non-target lesion was marked unequivocal progression. If a participant had not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment. PFS (months) = \[(date of event or censoring - date of first dose) +1\]/30.4375. The survival distribution function for PFS was estimated using the Kaplan-Meier method.
Time frame: From the date of first dose of study drug to the earliest date of disease progression, or death due to any cause (up to 36 months)
Secondary
Time to Response (TTR) by IRR and Investigator Assessments
TTR based on IRR and Investigator assessments was defined, for participants with an objective response, as the time, in months, from the date of first dose to the first documentation of objective response (CR or PR) which was subsequently confirmed (by IRR and by Investigator, respectively). TTR was calculated for the subgroup of participants with a confirmed objective tumor response.
Time frame: From the date of first dose to the first documentation of confirmed objective response (CR or PR) (up to 36 months)
Population: Analysis population included all participants who received at least 1 dose of study intervention and who had confirmed objective tumor response (CR or PR). Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of categories.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment-Naive | Time to Response (TTR) by IRR and Investigator Assessments | TTR by IRR | 1.86 Months |
| Treatment-Naive | Time to Response (TTR) by IRR and Investigator Assessments | TTR by Investigator Assessment | 1.84 Months |
| Previously Treated | Time to Response (TTR) by IRR and Investigator Assessments | TTR by IRR | 1.74 Months |
| Previously Treated | Time to Response (TTR) by IRR and Investigator Assessments | TTR by Investigator Assessment | 1.81 Months |