Breast Cancer
Conditions
Brief summary
This study will evaluate the efficacy and safety of pertuzumab (rhuMAb 2C4) in participants with metastatic breast cancer which has progressed during or after standard chemotherapy and which is not amenable to curative therapy. Those who are maintaining a response to therapy or who have stable disease at the end of the formal study period will continue treatment until disease progression or unacceptable toxicity. Approximately 120 participants will be enrolled.
Interventions
DRUGPertuzumab
Participants will receive one of two IV treatment regimens with pertuzumab: either 420 mg every 3 weeks, with an initial 840-mg loading dose, or 1050 mg every 3 weeks with no loading dose administered.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Females at least 18 years of age * Histologically-confirmed metastatic breast cancer with low HER2 expression and at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) * Karnofsky performance status at least 80% * Disease progression on/after up to 2 different chemotherapy regimens, including an anthracycline-containing therapy * Left ventricular ejection fraction (LVEF) at least 50% * Adequate liver function
Exclusion criteria
* Pleural effusions, ascites, or bone lesions as the only manifestation(s) of cancer * Pulmonary or central nervous system (CNS) metastases * Chemotherapy, radiotherapy, or immunotherapy within 4 weeks; or hormone therapy within 2 weeks of Day 1 * Previous treatment with any drug that targets the HER2 receptor family * Previous treatment with corticosteroids as cancer therapy * History of significant cardiac disease * Major surgery or trauma within 4 weeks of Day 1 * Pregnant or lactating women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving a Best Overall Response of Confirmed Complete Response (CR) or Partial Response (PR) | Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response) | Objective tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed CR was defined as the disappearance of all target lesions, and confirmed PR was defined as at least at 30 percent (%) decrease in the sum of the longest diameters of target lesions. Response was to be confirmed at follow-up assessment completed within 4 weeks of the first documented response. The percentage of participants achieving a best overall response of CR or PR was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response Among Participants Achieving a Best Overall Response of Confirmed CR or PR | Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response) | Objective tumor response was assessed using RECIST. Confirmed CR was defined as the disappearance of all target lesions, and confirmed PR was defined as at least at 30% decrease in the sum of the longest diameters of target lesions. Response was to be confirmed at follow-up assessment completed within 4 weeks of the first documented response. Duration of response was defined as the time from first documented response (ie, CR or PR) to PD or death. Participants who did not experience PD or death were censored from the last tumor assessment. Duration of response was estimated using Kaplan-Meier and expressed in weeks. |
| Percentage of Participants Achieving a Best Overall Response of Confirmed CR | Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response) | Objective tumor response was assessed using RECIST. Confirmed CR was defined as the disappearance of all target lesions. Response was to be confirmed at follow-up assessment completed within 4 weeks of the first documented response. The percentage of participants achieving a best overall response of CR was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100. |
| Duration of Response Among Participants Achieving a Best Overall Response of Confirmed CR | Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response) | Objective tumor response was assessed using RECIST. Confirmed CR was defined as the disappearance of all target lesions. Response was to be confirmed at follow-up assessment completed within 4 weeks of the first documented response. Duration of response was defined as the time from first documented response (ie, CR) to PD or death. Participants who did not experience PD or death were to be censored from the last tumor assessment. Duration of response was to be estimated using Kaplan-Meier. |
| Number of Participants Who Experienced PD or Death | Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response) | Objective tumor response was assessed using RECIST. PD was defined as the appearance of new lesion(s) or at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum obtained at Screening or during treatment. Participants who withdrew from the study early for insufficient therapeutic response without tumor assessment for PD were also included within the definition of PD. |
| Time to Progression | Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response) | Objective tumor response was assessed using RECIST. PD was defined as the appearance of new lesion(s) or at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum obtained at Screening or during treatment. Participants who withdrew from the study early for insufficient therapeutic response without tumor assessment for PD were also included within the definition of PD. Time to progression was defined as the time from treatment start to PD or death. Participants who did not experience PD or death were censored from the last tumor assessment. Time to progression was estimated using Kaplan-Meier and expressed in weeks. |
| Number of Participants Who Experienced PD or Withdrew From the Study Early | Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response) | Objective tumor response was assessed using RECIST. PD was defined as the appearance of new lesion(s) or at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum obtained at Screening or during treatment. |
| Time to Treatment Failure | Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response) | Objective tumor response was assessed using RECIST. PD was defined as the appearance of new lesion(s) or at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum obtained at Screening or during treatment. Time to treatment failure was defined as the time from treatment start to PD or early withdrawal from the study for death, toxicity, refusal/noncompliance, insufficient therapeutic response, or failure to return. Participants who did not experience PD or who did not withdraw from the study early were censored from the last tumor assessment. Time to treatment failure was estimated using Kaplan-Meier and expressed in weeks. |
| Percentage of Participants Who Died | Up to approximately 2 years (from start of treatment until death) | The percentage of participants who died was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100. |
| Overall Survival | Up to approximately 2 years (from start of treatment until death) | Overall survival was defined as the time from treatment start to death. Participants who did not die during follow-up were to be censored from the last known alive date. Overall survival was to be estimated using Kaplan-Meier. |
| Time to Response Among Participants Achieving a Best Overall Response of Confirmed CR or PR | Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response) | Objective tumor response was assessed using RECIST. Confirmed CR was defined as the disappearance of all target lesions, and confirmed PR was defined as at least at 30% decrease in the sum of the longest diameters of target lesions. Response was to be confirmed at follow-up assessment completed within 4 weeks of the first documented response. Time to response was defined as the time from treatment start to first documented response (ie, CR or PR). Participants with stable disease (SD) were censored from the last tumor assessment, and those with progressive disease (PD) or death were assigned an artificial censoring time of 1000 days. Time to response was estimated using Kaplan-Meier and expressed in weeks. |
| Apparent Half-Life (t1/2) of Pertuzumab | Pre-dose and within 15 minutes of the end of infusion on Day 1 of each cycle, and on Days 8 and 15 of Cycles 1 and 2 | Serum samples were obtained for pharmacokinetic (PK) assessment using a receptor-binding, enzyme-linked immunosorbent assay (ELISA). Pertuzumab concentrations at each collection point were used to determine the apparent t1/2 by non-compartmental analysis, defined as the time elapsed for pertuzumab concentrations to decrease by 50%. The derived value was averaged among all participants and expressed in days. |
| Maximum Plasma Concentration (Cmax) of Pertuzumab | Pre-dose and within 15 minutes of the end of infusion on Day 1 of each cycle, and on Days 8 and 15 of Cycles 1 and 2 | Serum samples were obtained for PK assessment using a receptor-binding ELISA. The maximum observed pertuzumab concentration across all collection points was documented. Cmax was averaged among all participants and expressed in micrograms per milliliter (mcg/mL). |
| Time to Maximum Plasma Concentration (Tmax) of Pertuzumab | Pre-dose and within 15 minutes of the end of infusion on Day 1 of each cycle, and on Days 8 and 15 of Cycles 1 and 2 | Serum samples were obtained for PK assessment using a receptor-binding ELISA. The time of maximum observed pertuzumab concentration across all collection points was documented. Tmax was averaged among all participants and expressed in days. |
| Area Under the Concentration-Time Curve (AUC) of Pertuzumab | Pre-dose and within 15 minutes of the end of infusion on Day 1 of each cycle, and on Days 8 and 15 of Cycles 1 and 2 | Serum samples were obtained for PK assessment using a receptor-binding ELISA. Pertuzumab concentrations at each collection point were used to determine AUC to the last measurable observation (AUClast) and AUC extrapolated to infinity (AUCinf) by non-compartmental analysis. The derived values were averaged among all participants and expressed in days by micrograms per milliliter (days\*mcg/mL). |
| Systemic Clearance (CL) of Pertuzumab | Pre-dose and within 15 minutes of the end of infusion on Day 1 of each cycle, and on Days 8 and 15 of Cycles 1 and 2 | Serum samples were obtained for PK assessment using a receptor-binding ELISA. Pertuzumab concentrations at each collection point were used to determine CL by non-compartmental analysis, defined as the rate at which pertuzumab was removed from the body. The derived value was averaged among all participants and expressed in milliliters per day (mL/day). |
| Volume of Distribution at Steady State (Vss) of Pertuzumab | Pre-dose and within 15 minutes of the end of infusion on Day 1 of each cycle, and on Days 8 and 15 of Cycles 1 and 2 | Serum samples were obtained for PK assessment using a receptor-binding ELISA. Pertuzumab concentrations at each collection point were used to determine the Vss by non-compartmental analysis, defined as the theoretical volume at which the total amount of pertuzumab would be uniformly distributed to produce the desired concentration. The derived value was averaged among all participants and expressed in milliliters (mL). |
| Mean Residence Time (MRT) of Pertuzumab | Pre-dose and within 15 minutes of the end of infusion on Day 1 of each cycle, and on Days 8 and 15 of Cycles 1 and 2 | Serum samples were obtained for PK assessment using a receptor-binding ELISA. Pertuzumab concentrations at each collection point were used to determine the MRT by non-compartmental analysis. The derived value was averaged among all participants and expressed in days. |
| Number of Participants Experiencing a Drop in Left Ventricular Ejection Fraction (LVEF) to a Value of Less Than 50% | Up to approximately 1 year (at Baseline; at the end of Cycles 2, 4, 8, 12, and 16; and up to 7 weeks following the last infusion) | Echocardiography was performed to determine LVEF, defined as the volume of blood pumped from the left ventricle as a percentage of end-diastolic volume. Theoretically, LVEF may range from 0 to 100%. The number of participants experiencing a drop in LVEF greater than or equal to (≥) 10 or 15 percentage points to a final LVEF of less than (\<) 50% is reported here. |
| Percentage of Participants Achieving a Best Overall Response of SD | Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response) | Objective tumor response was assessed using RECIST. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for PD. The percentage of participants achieving a best overall response of SD was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100. |
Countries
Australia, Belgium, Finland, Germany, Italy, Netherlands, Spain, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pertuzumab 420 mg Participants received a loading dose of 840 mg via IV infusion at the first infusion of pertuzumab, followed by a maintenance dose of 420 mg every 3 weeks until unacceptable toxicity or disease progression. | 41 |
| Pertuzumab 1050 mg Participants did not receive a loading dose, but received pertuzumab 1050 mg via IV infusion every 3 weeks until unacceptable toxicity or disease progression. | 37 |
| Total | 78 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Lack of Efficacy | 37 | 36 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Refused Treatment | 1 | 0 |
Baseline characteristics
| Characteristic | Pertuzumab 420 mg | Pertuzumab 1050 mg | Total |
|---|---|---|---|
| Age, Continuous | 55.3 years STANDARD_DEVIATION 10.04 | 53.5 years STANDARD_DEVIATION 8.72 | 54.4 years STANDARD_DEVIATION 9.42 |
| Sex: Female, Male Female | 41 Participants | 37 Participants | 78 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 36 / 41 | 37 / 37 |
| serious Total, serious adverse events | 10 / 41 | 8 / 37 |
Outcome results
Primary
Percentage of Participants Achieving a Best Overall Response of Confirmed Complete Response (CR) or Partial Response (PR)
Objective tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed CR was defined as the disappearance of all target lesions, and confirmed PR was defined as at least at 30 percent (%) decrease in the sum of the longest diameters of target lesions. Response was to be confirmed at follow-up assessment completed within 4 weeks of the first documented response. The percentage of participants achieving a best overall response of CR or PR was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100.
Time frame: Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response)
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pertuzumab 420 mg | Percentage of Participants Achieving a Best Overall Response of Confirmed Complete Response (CR) or Partial Response (PR) | 4.9 percentage of participants |
| Pertuzumab 1050 mg | Percentage of Participants Achieving a Best Overall Response of Confirmed Complete Response (CR) or Partial Response (PR) | 0 percentage of participants |
Secondary
Apparent Half-Life (t1/2) of Pertuzumab
Serum samples were obtained for pharmacokinetic (PK) assessment using a receptor-binding, enzyme-linked immunosorbent assay (ELISA). Pertuzumab concentrations at each collection point were used to determine the apparent t1/2 by non-compartmental analysis, defined as the time elapsed for pertuzumab concentrations to decrease by 50%. The derived value was averaged among all participants and expressed in days.
Time frame: Pre-dose and within 15 minutes of the end of infusion on Day 1 of each cycle, and on Days 8 and 15 of Cycles 1 and 2
Population: ITT Population. Participants with missing PK data were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pertuzumab 420 mg | Apparent Half-Life (t1/2) of Pertuzumab | 12.2 days | Standard Deviation 3.9 |
| Pertuzumab 1050 mg | Apparent Half-Life (t1/2) of Pertuzumab | 11.4 days | Standard Deviation 4.1 |
Secondary
Area Under the Concentration-Time Curve (AUC) of Pertuzumab
Serum samples were obtained for PK assessment using a receptor-binding ELISA. Pertuzumab concentrations at each collection point were used to determine AUC to the last measurable observation (AUClast) and AUC extrapolated to infinity (AUCinf) by non-compartmental analysis. The derived values were averaged among all participants and expressed in days by micrograms per milliliter (days\*mcg/mL).
Time frame: Pre-dose and within 15 minutes of the end of infusion on Day 1 of each cycle, and on Days 8 and 15 of Cycles 1 and 2
Population: ITT Population. Participants with missing PK data were excluded from the analysis, and the number of participants analyzed (n) is presented here.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pertuzumab 420 mg | Area Under the Concentration-Time Curve (AUC) of Pertuzumab | AUClast (n=40,37) | 2517 days*mcg/mL | Standard Deviation 896 |
| Pertuzumab 420 mg | Area Under the Concentration-Time Curve (AUC) of Pertuzumab | AUCinf (n=38,36) | 3598 days*mcg/mL | Standard Deviation 1402 |
| Pertuzumab 1050 mg | Area Under the Concentration-Time Curve (AUC) of Pertuzumab | AUClast (n=40,37) | 3465 days*mcg/mL | Standard Deviation 1051 |
| Pertuzumab 1050 mg | Area Under the Concentration-Time Curve (AUC) of Pertuzumab | AUCinf (n=38,36) | 4750 days*mcg/mL | Standard Deviation 1527 |
Secondary
Duration of Response Among Participants Achieving a Best Overall Response of Confirmed CR
Objective tumor response was assessed using RECIST. Confirmed CR was defined as the disappearance of all target lesions. Response was to be confirmed at follow-up assessment completed within 4 weeks of the first documented response. Duration of response was defined as the time from first documented response (ie, CR) to PD or death. Participants who did not experience PD or death were to be censored from the last tumor assessment. Duration of response was to be estimated using Kaplan-Meier.
Time frame: Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response)
Population: ITT Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pertuzumab 420 mg | Duration of Response Among Participants Achieving a Best Overall Response of Confirmed CR | NA weeks |
| Pertuzumab 1050 mg | Duration of Response Among Participants Achieving a Best Overall Response of Confirmed CR | NA weeks |
Secondary
Duration of Response Among Participants Achieving a Best Overall Response of Confirmed CR or PR
Objective tumor response was assessed using RECIST. Confirmed CR was defined as the disappearance of all target lesions, and confirmed PR was defined as at least at 30% decrease in the sum of the longest diameters of target lesions. Response was to be confirmed at follow-up assessment completed within 4 weeks of the first documented response. Duration of response was defined as the time from first documented response (ie, CR or PR) to PD or death. Participants who did not experience PD or death were censored from the last tumor assessment. Duration of response was estimated using Kaplan-Meier and expressed in weeks.
Time frame: Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response)
Population: ITT Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pertuzumab 420 mg | Duration of Response Among Participants Achieving a Best Overall Response of Confirmed CR or PR | 24.6 weeks |
| Pertuzumab 1050 mg | Duration of Response Among Participants Achieving a Best Overall Response of Confirmed CR or PR | NA weeks |
Secondary
Maximum Plasma Concentration (Cmax) of Pertuzumab
Serum samples were obtained for PK assessment using a receptor-binding ELISA. The maximum observed pertuzumab concentration across all collection points was documented. Cmax was averaged among all participants and expressed in micrograms per milliliter (mcg/mL).
Time frame: Pre-dose and within 15 minutes of the end of infusion on Day 1 of each cycle, and on Days 8 and 15 of Cycles 1 and 2
Population: ITT Population. Participants with missing PK data were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pertuzumab 420 mg | Maximum Plasma Concentration (Cmax) of Pertuzumab | 289 mcg/mL | Standard Deviation 107 |
| Pertuzumab 1050 mg | Maximum Plasma Concentration (Cmax) of Pertuzumab | 409 mcg/mL | Standard Deviation 159 |
Secondary
Mean Residence Time (MRT) of Pertuzumab
Serum samples were obtained for PK assessment using a receptor-binding ELISA. Pertuzumab concentrations at each collection point were used to determine the MRT by non-compartmental analysis. The derived value was averaged among all participants and expressed in days.
Time frame: Pre-dose and within 15 minutes of the end of infusion on Day 1 of each cycle, and on Days 8 and 15 of Cycles 1 and 2
Population: ITT Population. Participants with missing PK data were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pertuzumab 420 mg | Mean Residence Time (MRT) of Pertuzumab | 16 days | Standard Deviation 5 |
| Pertuzumab 1050 mg | Mean Residence Time (MRT) of Pertuzumab | 15 days | Standard Deviation 6 |
Secondary
Number of Participants Experiencing a Drop in Left Ventricular Ejection Fraction (LVEF) to a Value of Less Than 50%
Echocardiography was performed to determine LVEF, defined as the volume of blood pumped from the left ventricle as a percentage of end-diastolic volume. Theoretically, LVEF may range from 0 to 100%. The number of participants experiencing a drop in LVEF greater than or equal to (≥) 10 or 15 percentage points to a final LVEF of less than (\<) 50% is reported here.
Time frame: Up to approximately 1 year (at Baseline; at the end of Cycles 2, 4, 8, 12, and 16; and up to 7 weeks following the last infusion)
Population: Safety Population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pertuzumab 420 mg | Number of Participants Experiencing a Drop in Left Ventricular Ejection Fraction (LVEF) to a Value of Less Than 50% | Drop ≥10 percentage points | 3 participants |
| Pertuzumab 420 mg | Number of Participants Experiencing a Drop in Left Ventricular Ejection Fraction (LVEF) to a Value of Less Than 50% | Drop ≥15 percentage points | 3 participants |
| Pertuzumab 1050 mg | Number of Participants Experiencing a Drop in Left Ventricular Ejection Fraction (LVEF) to a Value of Less Than 50% | Drop ≥10 percentage points | 5 participants |
| Pertuzumab 1050 mg | Number of Participants Experiencing a Drop in Left Ventricular Ejection Fraction (LVEF) to a Value of Less Than 50% | Drop ≥15 percentage points | 3 participants |
Secondary
Number of Participants Who Experienced PD or Death
Objective tumor response was assessed using RECIST. PD was defined as the appearance of new lesion(s) or at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum obtained at Screening or during treatment. Participants who withdrew from the study early for insufficient therapeutic response without tumor assessment for PD were also included within the definition of PD.
Time frame: Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response)
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pertuzumab 420 mg | Number of Participants Who Experienced PD or Death | 38 participants |
| Pertuzumab 1050 mg | Number of Participants Who Experienced PD or Death | 36 participants |
Secondary
Number of Participants Who Experienced PD or Withdrew From the Study Early
Objective tumor response was assessed using RECIST. PD was defined as the appearance of new lesion(s) or at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum obtained at Screening or during treatment.
Time frame: Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response)
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pertuzumab 420 mg | Number of Participants Who Experienced PD or Withdrew From the Study Early | 41 participants |
| Pertuzumab 1050 mg | Number of Participants Who Experienced PD or Withdrew From the Study Early | 37 participants |
Secondary
Overall Survival
Overall survival was defined as the time from treatment start to death. Participants who did not die during follow-up were to be censored from the last known alive date. Overall survival was to be estimated using Kaplan-Meier.
Time frame: Up to approximately 2 years (from start of treatment until death)
Population: Median survival was not reached because the study program was terminated early. Analysis of the incomplete data set was not performed because it could potentially produce skewed or statistically irrelevant data.
Secondary
Percentage of Participants Achieving a Best Overall Response of Confirmed CR
Objective tumor response was assessed using RECIST. Confirmed CR was defined as the disappearance of all target lesions. Response was to be confirmed at follow-up assessment completed within 4 weeks of the first documented response. The percentage of participants achieving a best overall response of CR was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100.
Time frame: Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response)
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pertuzumab 420 mg | Percentage of Participants Achieving a Best Overall Response of Confirmed CR | 0 percentage of participants |
| Pertuzumab 1050 mg | Percentage of Participants Achieving a Best Overall Response of Confirmed CR | 0 percentage of participants |
Secondary
Percentage of Participants Achieving a Best Overall Response of SD
Objective tumor response was assessed using RECIST. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for PD. The percentage of participants achieving a best overall response of SD was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100.
Time frame: Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response)
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pertuzumab 420 mg | Percentage of Participants Achieving a Best Overall Response of SD | 43.9 percentage of participants |
| Pertuzumab 1050 mg | Percentage of Participants Achieving a Best Overall Response of SD | 37.8 percentage of participants |
Secondary
Percentage of Participants Who Died
The percentage of participants who died was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.
Time frame: Up to approximately 2 years (from start of treatment until death)
Population: Safety Population: All randomized participants who received at least one dose of pertuzumab and had at least one post-baseline safety assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pertuzumab 420 mg | Percentage of Participants Who Died | 46 percentage of participants |
| Pertuzumab 1050 mg | Percentage of Participants Who Died | 32 percentage of participants |
Secondary
Systemic Clearance (CL) of Pertuzumab
Serum samples were obtained for PK assessment using a receptor-binding ELISA. Pertuzumab concentrations at each collection point were used to determine CL by non-compartmental analysis, defined as the rate at which pertuzumab was removed from the body. The derived value was averaged among all participants and expressed in milliliters per day (mL/day).
Time frame: Pre-dose and within 15 minutes of the end of infusion on Day 1 of each cycle, and on Days 8 and 15 of Cycles 1 and 2
Population: ITT Population. Participants with missing PK data were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pertuzumab 420 mg | Systemic Clearance (CL) of Pertuzumab | 270 mL/day | Standard Deviation 113 |
| Pertuzumab 1050 mg | Systemic Clearance (CL) of Pertuzumab | 247 mL/day | Standard Deviation 90 |
Secondary
Time to Maximum Plasma Concentration (Tmax) of Pertuzumab
Serum samples were obtained for PK assessment using a receptor-binding ELISA. The time of maximum observed pertuzumab concentration across all collection points was documented. Tmax was averaged among all participants and expressed in days.
Time frame: Pre-dose and within 15 minutes of the end of infusion on Day 1 of each cycle, and on Days 8 and 15 of Cycles 1 and 2
Population: ITT Population. Participants with missing PK data were excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pertuzumab 420 mg | Time to Maximum Plasma Concentration (Tmax) of Pertuzumab | 0.073 days |
| Pertuzumab 1050 mg | Time to Maximum Plasma Concentration (Tmax) of Pertuzumab | 0.073 days |
Secondary
Time to Progression
Objective tumor response was assessed using RECIST. PD was defined as the appearance of new lesion(s) or at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum obtained at Screening or during treatment. Participants who withdrew from the study early for insufficient therapeutic response without tumor assessment for PD were also included within the definition of PD. Time to progression was defined as the time from treatment start to PD or death. Participants who did not experience PD or death were censored from the last tumor assessment. Time to progression was estimated using Kaplan-Meier and expressed in weeks.
Time frame: Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response)
Population: ITT Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pertuzumab 420 mg | Time to Progression | 6.1 weeks |
| Pertuzumab 1050 mg | Time to Progression | 6.1 weeks |
Secondary
Time to Response Among Participants Achieving a Best Overall Response of Confirmed CR or PR
Objective tumor response was assessed using RECIST. Confirmed CR was defined as the disappearance of all target lesions, and confirmed PR was defined as at least at 30% decrease in the sum of the longest diameters of target lesions. Response was to be confirmed at follow-up assessment completed within 4 weeks of the first documented response. Time to response was defined as the time from treatment start to first documented response (ie, CR or PR). Participants with stable disease (SD) were censored from the last tumor assessment, and those with progressive disease (PD) or death were assigned an artificial censoring time of 1000 days. Time to response was estimated using Kaplan-Meier and expressed in weeks.
Time frame: Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response)
Population: ITT Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pertuzumab 420 mg | Time to Response Among Participants Achieving a Best Overall Response of Confirmed CR or PR | 12.1 weeks |
| Pertuzumab 1050 mg | Time to Response Among Participants Achieving a Best Overall Response of Confirmed CR or PR | NA weeks |
Secondary
Time to Treatment Failure
Objective tumor response was assessed using RECIST. PD was defined as the appearance of new lesion(s) or at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum obtained at Screening or during treatment. Time to treatment failure was defined as the time from treatment start to PD or early withdrawal from the study for death, toxicity, refusal/noncompliance, insufficient therapeutic response, or failure to return. Participants who did not experience PD or who did not withdraw from the study early were censored from the last tumor assessment. Time to treatment failure was estimated using Kaplan-Meier and expressed in weeks.
Time frame: Up to approximately 1 year (at Baseline; every 6 weeks for the first 8 cycles, then every 12 weeks until progression or death; and up to 4 weeks after initial response)
Population: ITT Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pertuzumab 420 mg | Time to Treatment Failure | 6.3 weeks |
| Pertuzumab 1050 mg | Time to Treatment Failure | 6.0 weeks |
Secondary
Volume of Distribution at Steady State (Vss) of Pertuzumab
Serum samples were obtained for PK assessment using a receptor-binding ELISA. Pertuzumab concentrations at each collection point were used to determine the Vss by non-compartmental analysis, defined as the theoretical volume at which the total amount of pertuzumab would be uniformly distributed to produce the desired concentration. The derived value was averaged among all participants and expressed in milliliters (mL).
Time frame: Pre-dose and within 15 minutes of the end of infusion on Day 1 of each cycle, and on Days 8 and 15 of Cycles 1 and 2
Population: ITT Population. Participants with missing PK data were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pertuzumab 420 mg | Volume of Distribution at Steady State (Vss) of Pertuzumab | 4122 mL | Standard Deviation 1666 |
| Pertuzumab 1050 mg | Volume of Distribution at Steady State (Vss) of Pertuzumab | 3527 mL | Standard Deviation 1369 |