Safety Study of Pertuzumab (in Combination With Trastuzumab and Docetaxel) in Indian Participants With Breast Cancer

Study Overview
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Brief Summary
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This is a Phase 4, single-arm, open-label, multicenter study to assess the safety and efficacy of pertuzumab in combination with trastuzumab and docetaxel for the treatment of participants with human epidermal growth factor receptor 2 (HER2)-positive advanced (locally recurrent, unresectable, or metastatic) breast cancer.

Official Title
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A Phase IV, Multicenter, Open-Label, Single-Arm Study of Pertuzumab (in Combination With Trastuzumab and Docetaxel) in First Line Treatment of Indian Patients With HER2-Positive Advanced (Metastatic or Locally Recurrent) Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Pertuzumab
* Drug: Trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For women of childbearing potential and men with partners of childbearing potential, agreement to use a highly-effective non-hormonal form of contraception or two effective forms of non-hormonal contraception by the participant and/or partner Histologically or cytologically confirmed and documented adenocarcinoma of the breast with metastatic or locally recurrent disease not amenable to curative resection; participants with measurable and/or non-measurable disease are eligible Known and documented HER2-positive Known and documented LVEF of at least 50 percent (%) Adequate organ function A negative serum beta-human chorionic gonadotropin (beta-HCG) test for women of childbearing potential (premenopausal, or less than [<] 12 months of amenorrhea post-menopause, and women who have not undergone surgical sterilization [absence of ovaries and/or uterus]) within 7 days prior to the first dose of study treatment with the result available prior to first dosing Exclusion Criteria: Previous systemic non-hormonal anti-cancer therapy for the metastatic or locally recurrent disease Pregnant or lactating women Current clinical or radiographic evidence of central nervous system (CNS) metastases Disease progression while receiving or within 12 months of completion of trastuzumab and/or lapatinib treatment in the adjuvant or neo-adjuvant setting History of LVEF decline to below 50% during or after prior trastuzumab adjuvant or neo-adjuvant therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pertuzumab in Combination with Trastuzumab and Docetaxel<br>Participants will receive pertuzumab in combination with trastuzumab and docetaxel every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever occurs first. | Drug: Docetaxel<br>* Participants will receive docetaxel in line with locally approved Prescribing Information. After Cycle 6 (cycle length = 21 days), continuation of docetaxel treatment will be at the discretion of the investigator. Docetaxel will be administered after pertuzumab and trastuzumab.<br>Drug: Pertuzumab<br>* Participants will receive pertuzumab at an initial dose of 840 milligrams (mg) as a 60-minute intravenous infusion on Cycle 1 Day 1 (cycle length = 21 days), followed by every 3 weeks at a dose of 420 mg as a 30 to 60-minute intravenous infusion until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever occurs first.<br>* Other names: Perjeta®;Drug: Trastuzumab<br>* Participants will receive trastuzumab at an initial dose of 8 milligrams per kilogram (mg/kg) as a 90-minute intravenous infusion on Cycle 1 Day 1 (cycle length = 21 days), followed by every 3 weeks at a dose of 6 mg/kg as a 30 to 90-minute intravenous infusion until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever occurs first.<br>* Other names: Herclon®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Number of Participants by the Number of Serious Adverse Events Reported Per Participant | The number of participants with serious adverse events was counted in the four following categories for number of events reported per participant: greater than or equal to (≥) 1, 1, greater than (>) 1, or 0 serious adverse events. Participants with multiple occurrences of events (the ≥1 and >1 serious adverse event categories) were only counted once per category. | From Baseline until end of study (up to approximately 3 years) | 
| Overall Number of Participants With Serious Adverse Events by Severity (Initial and Most Extreme), According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03) | The number of participants with serious adverse events was counted by the initial and most extreme levels of severity of the adverse event, assessed as Grades 1-5 according to NCI CTCAE v4.03. Any adverse event not specifically listed in NCI CTCAE v4.03 was assessed according to the following grades of severity: Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe or medically significant; Grade 4 is life-threatening or urgent intervention indicated; and Grade 5 is death related to adverse event. The terms severe and serious are not synonymous. Severity refers to the intensity of an adverse event. The seriousness of an adverse event is based on whether it meets any of the criteria set out in the protocol's definition of a serious adverse event. Severity and seriousness were independently assessed for each adverse event. Participants with multiple occurrences of serious adverse events of the same severity were only counted once per severity category. | From Baseline until end of study (up to approximately 3 years) | 
| Number of Participants With Serious Adverse Events Related to Docetaxel | The number of participants with serious adverse events was counted for any serious adverse event that was related to study treatment with docetaxel, in the investigator's judgment. Adverse events (AEs) were encoded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. More than one serious adverse event may have been reported per participant. Participants with multiple occurrences of the same serious adverse event were only counted once per preferred term. | From Baseline until end of study (up to approximately 3 years) | 
| Number of Participants With Serious Adverse Events Related to Pertuzumab | The number of participants with serious adverse events was counted for any serious adverse event that was related to study treatment with pertuzumab, in the investigator's judgment. Adverse events (AEs) were encoded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. More than one serious adverse event may have been reported per participant. Participants with multiple occurrences of the same serious adverse event were only counted once per preferred term. | From Baseline until end of study (up to approximately 3 years) | 
| Number of Participants With Serious Adverse Events Related to Trastuzumab | The number of participants with serious adverse events was counted for any serious adverse event that was related to study treatment with trastuzumab, in the investigator's judgment. Adverse events (AEs) were encoded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. More than one serious adverse event may have been reported per participant. Participants with multiple occurrences of the same serious adverse event were only counted once per preferred term. | From Baseline until end of study (up to approximately 3 years) | 
| Overall Number of Participants With Serious Adverse Events by Action Taken With Study Drug | The number of participants with serious adverse events was counted by the type of action taken with the study drug (docetaxel, pertuzumab, and trastuzumab) in response to the adverse event in the three following categories: infusion reduced, temporarily interrupted, or permanently discontinued. More than one serious adverse event may have been reported per participant. Participants with multiple occurrences of serious adverse events that required the same action to be taken with the study drug were only counted once per category. | From Baseline until end of study (up to approximately 3 years) | 
| Overall Number of Participants With Serious Adverse Events by Event Outcome | The number of participants with serious adverse events was counted by the event outcome in the six following categories: fatal, recovered/resolved, recovered/resolved with sequelae, recovering/resolving, not recovered/not resolved, or unknown. More than one serious adverse event may have been reported per participant. Participants with multiple occurrences of serious adverse events with the same outcome were only counted once per category. | From Baseline until end of study (up to approximately 3 years) | 
| Number of Participants With Hematological Abnormalities Reported as Serious Adverse Events | The number of participants with hematological laboratory abnormalities reported as serious adverse events was counted. Adverse events (AEs) were encoded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. More than one serious adverse event may have been reported per participant. Participants with multiple occurrences of the same serious adverse event were only counted once per preferred term. | From Baseline until end of study (up to approximately 3 years) | 
| Number of Participants With Serum Chemistry Abnormalities Reported as Serious Adverse Events | The number of participants with serum chemistry laboratory abnormalities reported as serious adverse events was counted. Adverse events (AEs) were encoded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. More than one serious adverse event may have been reported per participant. Participants with multiple occurrences of the same serious adverse event were only counted once per preferred term. | From Baseline until end of study (up to approximately 3 years) | 
| Number of Participants With Coagulation Abnormalities Reported as Serious Adverse Events | The number of participants with coagulation laboratory abnormalities reported as serious adverse events was counted. Adverse events (AEs) were encoded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. More than one serious adverse event may have been reported per participant. Participants with multiple occurrences of the same serious adverse event were only counted once per preferred term. | From Baseline until end of study (up to approximately 3 years) | 
| Number of Participants Who Died Due to a Serious Adverse Event by Cause of Death | The number of participants who died due to a serious adverse event was counted by the cause of death. | From Baseline until end of study (up to approximately 3 years) | 
| Overall Number of Participants by the Number of Non-Serious Adverse Events Reported Per Participant | The number of participants with non-serious adverse events was counted in the four following categories for number of events reported per participant: greater than or equal to (≥) 1, 1, greater than (>) 1, or 0 non-serious adverse events. Participants with multiple occurrences of events (the ≥1 and >1 non-serious adverse event categories) were only counted once per category. | From Baseline until end of study (up to approximately 3 years) | 
| Overall Number of Participants With Non-Serious Adverse Events by Severity, According to NCI-CTCAE v4.03 | The number of participants with non-serious adverse events was counted by the severity level of the adverse event, assessed as Grades 1-5 according to NCI CTCAE v4.03. Any adverse event not specifically listed in NCI CTCAE v4.03 was assessed according to the following grades of severity: Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe or medically significant; Grade 4 is life-threatening or urgent intervention indicated; and Grade 5 is death related to adverse event. The terms severe and serious are not synonymous. Severity refers to the intensity of an adverse event. The seriousness of an adverse event is based on whether it meets any of the criteria set out in the protocol's definition of a serious adverse event. Severity and seriousness were independently assessed for each adverse event. Participants with multiple occurrences of non-serious adverse events of the same severity were only counted once per severity category. | From Baseline until end of study (up to approximately 3 years) | 
| Number of Participants With Non-Serious Adverse Events Related to Docetaxel | The number of participants with non-serious adverse events was counted for any non-serious adverse event that was related to study treatment with docetaxel, in the investigator's judgment. Adverse events (AEs) were encoded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. More than one non-serious adverse event may have been reported per participant. Participants with multiple occurrences of the same non-serious adverse event were only counted once per preferred term. | From Baseline until end of study (up to approximately 3 years) | 
| Number of Participants With Non-Serious Adverse Events Related to Pertuzumab | The number of participants with non-serious adverse events was counted for any non-serious adverse event that was related to study treatment with pertuzumab, in the investigator's judgment. Adverse events (AEs) were encoded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. More than one non-serious adverse event may have been reported per participant. Participants with multiple occurrences of the same non-serious adverse event were only counted once per preferred term. | From Baseline until end of study (up to approximately 3 years) | 
| Number of Participants With Non-Serious Adverse Events Related to Trastuzumab | The number of participants with non-serious adverse events was counted for any non-serious adverse event that was related to study treatment with trastuzumab, in the investigator's judgment. Adverse events (AEs) were encoded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. More than one non-serious adverse event may have been reported per participant. Participants with multiple occurrences of the same non-serious adverse event were only counted once per preferred term. | From Baseline until end of study (up to approximately 3 years) | 
| Overall Number of Participants With Non-Serious Adverse Events by Chemotherapy Adjustment With Docetaxel and/or Trastuzumab | The number of participants with non-serious adverse events was counted by the type of action taken with docetaxel and/or trastuzumab in response to the adverse event in the three following categories: no adjustment, dosage modified/interrupted, and discontinued. More than one non-serious adverse event may have been reported per participant. Participants with multiple occurrences of non-serious adverse events that required the same action to be taken with the study drug were only counted once per category. | From Baseline until end of study (up to approximately 3 years) | 
| Overall Number of Participants With Non-Serious Adverse Events by Action Taken With Pertuzumab | The number of participants with non-serious adverse events was counted by the type of action taken with pertuzumab in response to the adverse event in the three following categories: no action taken, infusion slow down, infusion interrupted, and appropriate medical therapies administered. More than one non-serious adverse event may have been reported per participant. Participants with multiple occurrences of non-serious adverse events that required the same action to be taken with the study drug were only counted once per category. | From Baseline until end of study (up to approximately 3 years) | 
| Overall Number of Participants With Non-Serious Adverse Events by Event Outcome | The number of participants with non-serious adverse events was counted by the event outcome in the four following categories: resolved with no sequelae, resolved with sequelae, unresolved, or death. More than one non-serious adverse event may have been reported per participant. Participants with multiple occurrences of non-serious adverse events with the same outcome were only counted once per category. | From Baseline until end of study (up to approximately 3 years) | 
| Overall Number of Participants With Non-Serious Adverse Events by Treatment Emergence (TEAE Versus Non-TEAE) | The number of participants with non-serious adverse events was counted according to whether the event was considered a treatment emergent adverse event (TEAE), which is defined as an adverse event that emerges during treatment, having been absent pretreatment, or worsens relative to the pretreatment state. Participants with multiple occurrences of non-serious adverse events were only counted once per category. | From Baseline until end of study (up to approximately 3 years) | 
| Number of Participants With Hematological Abnormalities Reported as Non-Serious Adverse Events | The number of participants with hematological laboratory abnormalities reported as non-serious adverse events was counted. Adverse events (AEs) were encoded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. More than one non-serious adverse event may have been reported per participant. Participants with multiple occurrences of the same non-serious adverse event were only counted once per preferred term. | From Baseline until end of study (up to approximately 3 years) | 
| Number of Participants With Serum Chemistry Abnormalities Reported as Non-Serious Adverse Events | The number of participants with serum chemistry laboratory abnormalities reported as non-serious adverse events was counted. Adverse events (AEs) were encoded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. More than one non-serious adverse event may have been reported per participant. Participants with multiple occurrences of the same non-serious adverse event were only counted once per preferred term. | From Baseline until end of study (up to approximately 3 years) | 
| Number of Participants With Coagulation Abnormalities Reported as Non-Serious Adverse Events | The number of participants with coagulation laboratory abnormalities reported as non-serious adverse events was counted. Adverse events (AEs) were encoded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. More than one non-serious adverse event may have been reported per participant. Participants with multiple occurrences of the same non-serious adverse event were only counted once per preferred term. | From Baseline until end of study (up to approximately 3 years) | 
| Number of Participants With Congestive Heart Failure |  | From Baseline until end of study (up to approximately 3 years) | 
| Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Left ventricular ejection fraction (LVEF) assessments were performed within 42 days of enrollment and every three treatment cycles by either echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan; ECHO was the preferred method. In order to be eligible for this study, an LVEF of ≥50% was required at screening. The same method of LVEF assessment for each participant must have been used throughout the study, and to the extent possible, have been obtained at the same institution. | Baseline, every 3 cycles (1 cycle is 21 days) until treatment discontinuation, at Safety Follow-Up (28 days after last dose of study drug) and every 3 months thereafter until end of study (up to approximately 3 years) | 
| Number of Participants by Left Ventricular Ejection Fraction (LVEF) Findings Over Time | Left ventricular ejection fraction (LVEF) assessments were performed within 42 days of enrollment and every three treatment cycles by either echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan; ECHO was the preferred method. In order to be eligible for this study, an LVEF greater than or equal to (≥)50% was required at screening. The same method of LVEF assessment for each participant must have been used throughout the study, and to the extent possible, have been obtained at the same institution. The following are definitions for the three categories of LVEF findings: 'Normal' was defined as LVEF ≥45%; 'Abnormal but not clinically significant' was defined as LVEF <45% but not clinically significant in the investigator's judgment; 'Abnormal and clinically significant' was defined as LVEF <45% and clinically significant in the investigator's judgment. | Baseline, every 3 cycles (1 cycle is 21 days) until treatment discontinuation, at Safety Follow-Up (28 days after last dose of study drug) and every 3 months thereafter until end of study (up to approximately 3 years) | 
| Number of Participants With Adverse Events Leading to Treatment Discontinuation | The number of participants with any adverse event (serious or non-serious) that led to treatment discontinuation during the study was counted. Adverse events (AEs) were encoded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. More than one adverse event that led to treatment discontinuation may have been reported per participant. | From Baseline until end of study (up to approximately 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | The overall response rate (ORR) was defined as the percentage of participants with best overall response of Complete Response (CR) or Partial Response (PR), confirmed by repeat assessment no less than 4 weeks after the response criteria were first met, using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Participants who either had not achieved CR or PR or were without a post-baseline tumor assessment were to be considered non-responders. All measurable and non-measurable lesions were documented at screening and re-assessed at each subsequent tumor evaluation. Response was assessed by the investigator on the basis of physical examinations, computed tomography (CT) scans, and magnetic resonance imaging (MRI). The same radiographic procedure was used throughout the study, and assessments were preferably performed by the same evaluator. The 95% confidence intervals were calculated using Clopper-Pearson methodology. | From Baseline up to disease progression or death (assessed at every 9 weeks, up to approximately 3 years) | 
| Number of Participants by Best Overall Response | The best overall response was defined as the best response, out of all the documented responses over the course of the entire study period, using RECIST v1.1. All measurable and non-measurable lesions were documented at screening and re-assessed at each subsequent tumor evaluation. Response was assessed by the investigator on the basis of physical examinations, computed tomography (CT) scans, and magnetic resonance imaging (MRI). The same radiographic procedure was used throughout the study, and assessments were preferably performed by the same evaluator. | From Baseline up to disease progression or death (assessed at every 9 weeks, up to approximately 3 years) | 
| Number of Participants With Disease Progression or Death or Who Were Censored for Progression-Free Survival Analysis | Progression-free survival (PFS) was defined as the time from enrollment to the first occurrence of disease progression as determined by the investigator using RECIST v1.1, or death from any cause, whichever occurred first. Participants who had not progressed or died or were lost to follow up at the time of the analysis were censored on the last visit at which assessment for progression was done (2 years after the last participant was enrolled). PFS was analyzed by the Kaplan-Meier method. | From Baseline up to disease progression or death (assessed at every 9 weeks, up to approximately 3 years) | 
| Median Duration of Progression-Free Survival | Progression-free survival (PFS) was defined as the time from enrollment to the first occurrence of disease progression as determined by the investigator using RECIST v1.1, or death from any cause, whichever occurred first. Participants who had not progressed or died, or were lost to follow up at the time of the analysis, were censored on the last visit at which assessment for progression was done (2 years after the last participant was enrolled). PFS was analyzed by the Kaplan-Meier method. | From Baseline up to disease progression or death (assessed at every 9 weeks, up to approximately 3 years) | 
| Probability of Participants Remaining Event-Free in Progression-Free Survival From 2 to 32 Months | Progression-free survival (PFS) was defined as the time from enrollment to the first occurrence of disease progression as determined by the investigator using RECIST v1.1, or death from any cause, whichever occurred first. Participants who had not progressed, died or were lost to follow up at the time of the analysis were censored on the last visit at which assessment for progression was done (2 years after the last participant was enrolled). PFS was analyzed by the Kaplan-Meier method. | Months 2, 3, 5, 6, 7, 8, 9, 11, 13, 15, 16, 17, 18, 19, 23, 24, 25, 27, 29, and 32 | 
| Number of Participants Who Died or Were Censored for Overall Survival Analysis | Overall survival was defined as the time from enrollment to the the date of death from any cause. Participants who were alive at the time of the analysis, dropped out of the study, or lost to follow-up were censored at the date of the last follow-up assessment. Participants without follow-up assessment were censored at the day of last study medication, and participants with no post-baseline information were censored at baseline. Overall survival was analyzed by the Kaplan-Meier method. | From Baseline up to death from any cause (up to approximately 3 years) | 
| Median Duration of Overall Survival | Overall survival was defined as the time from enrollment to the the date of death from any cause. Participants who were alive at the time of the analysis, dropped out of the study, or lost to follow-up were censored at the date of the last follow-up assessment. Participants without follow-up assessment were censored at the day of last study medication, and participants with no post-baseline information were censored at baseline. Overall survival was analyzed by the Kaplan-Meier method. | From Baseline up to death from any cause (up to approximately 3 years) | 
| Probability of Participants Remaining Alive in Overall Survival From 3 to 34 Months | Overall survival was defined as the time from enrollment to the the date of death from any cause. Participants who were alive at the time of the analysis, dropped out of the study, or lost to follow-up were censored at the date of the last follow-up assessment. Participants without follow-up assessment were censored at the day of last study medication, and participants with no post-baseline information were censored at baseline. Overall survival was analyzed by the Kaplan-Meier method. | Months 3, 9, 13, 14, 15, 18, 19, 20, 24, 25, 27, 32, 33, and 34 |