A Study of Pertuzumab in Participants With Metastatic Breast Cancer

Study Overview
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Brief Summary
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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.

Official Title
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Open-Label, Phase II, Multicenter, Randomized Study of Efficacy and Safety for Two Different Doses of a Recombinant Humanized Antibody to HER2 (rhuMAb 2C4) Administered Every 3 Weeks to Patients With Metastatic Breast Cancer With Low Expression of HER2

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Pertuzumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pertuzumab 1050 mg<br>Participants will not receive a loading dose, but will receive pertuzumab 1050 milligrams (mg) via intravenous (IV) infusion every 3 weeks until unacceptable toxicity or disease progression. | Drug: Pertuzumab<br>* 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.<br>* Other names: rhuMAb 2C4;|
| Experimental: Pertuzumab 420 mg<br>Participants will receive 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. | Drug: Pertuzumab<br>* 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.<br>* Other names: rhuMAb 2C4;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | Up to approximately 2 years (from start of treatment until death) | 
| 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. | Up to approximately 2 years (from start of treatment until death) | 
| 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. | 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) | 
| 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. | 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 | 
| 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). | 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 | 
| 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. | 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 | 
| 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). | 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 | 
| 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). | 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 | 
| 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). | 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 | 
| 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. | 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 | 
| 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. | 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) |