A Dose-Finding Study of Pertuzumab (Perjeta) in Combination With Trastuzumab (Herceptin) in Healthy Male Participants and Women With Early Breast Cancer (EBC)

Study Overview
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Brief Summary
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This study involves a two-part design. Part 1 is designed to determine the optimal dose of subcutaneous (SC) Perjeta, injected alone or mixed with Herceptin, that results in comparable exposure to intravenous (IV) Perjeta. Exposure between SC Perjeta and IV Perjeta will be compared using a compilation of pharmacokinetic (PK) parameters such as area under the concentration-time curve (AUC), maximum serum concentration (Cmax), time of maximum concentration (Tmax), and serum trough concentration (Ctrough). Part 2 is designed to confirm the dosing regimen in women with EBC on the basis of safety, tolerability, and PK assessments.

Official Title
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A Phase I, Open-Label, Two-Part, Multicenter Perjeta® Subcutaneous Dose-Finding Study in Combination With Herceptin® in Healthy Male Volunteers and Female Patients With Early Breast Cancer

Conditions
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Early Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab
* Drug: Pertuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part 1: Healthy male volunteers 18 to 45 years of age Part 1: Left ventricular ejection fraction (LVEF) at least 55 percent (%) Part 1: Body mass index (BMI) 18 to 32 kilograms per meter-squared (kg/m^2) Part 1: Normal, intact skin without tattoos or lesions in the injection area Part 2: Females at least 18 years of age Part 2: Eastern Cooperative Oncology Group (ECOG) performance status of 0 Part 2: Previously treated, non-metastatic carcinoma of the breast Part 2: Baseline LVEF at least 55% Part 2: Negative pregnancy test and use of adequate contraceptive measures among women of childbearing potential Exclusion Criteria: Part 1: Positive urine test for drugs of abuse Part 1: History of exposure or active viral infection of Hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) Part 1: Cardiac disease including hypertension or hypotension Part 1: Lower extremity edema Part 1: Any clinically relevant history of systemic disease Part 1: History of breast cancer Part 1: Chronic corticosteroid use Part 1: Receipt of IV antibiotics within 7 days prior to enrollment Part 2: Concurrent malignancy requiring therapy that may interfere with pharmacokinetic investigations, or history of other malignancy within 5 years prior to Screening Part 2: Significant cumulative exposure to anthracyclines Part 2: Serious cardiac disease including uncontrolled hypertension Part 2: Poor hematologic, renal, or hepatic function Part 2: Pregnant or lactating women Part 2: History of exposure or active viral infection of Hepatitis B, hepatitis C, or HIV Part 2: Chronic corticosteroid use Part 2: Receipt of IV antibiotics within 7 days prior to enrollment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Part 1-Cohort 1: Pertuzumab 420 Milligrams (mg) IV<br>Part 1 includes healthy male participants. Participants will receive a single injection of pertuzumab 420 mg IV. | Drug: Pertuzumab<br>* Participants will receive pertuzumab as a single agent injection, co-mixed or formulated as FDC with trastuzumab depending upon cohort. The dose will range from 400 to 1200 mg.<br>* Other names: Perjeta, RO4368451;|
| Experimental: Part 1-Cohort 2: Pertuzumab 400 mg SC<br>Part 1 includes healthy male participants. Participants will receive a single injection of pertuzumab 400 mg SC. | Drug: Pertuzumab<br>* Participants will receive pertuzumab as a single agent injection, co-mixed or formulated as FDC with trastuzumab depending upon cohort. The dose will range from 400 to 1200 mg.<br>* Other names: Perjeta, RO4368451;|
| Experimental: Part 1-Cohort 3: Pertuzumab 600 mg SC<br>Part 1 includes healthy male participants. Participants will receive a single injection of pertuzumab 600 mg SC. | Drug: Pertuzumab<br>* Participants will receive pertuzumab as a single agent injection, co-mixed or formulated as FDC with trastuzumab depending upon cohort. The dose will range from 400 to 1200 mg.<br>* Other names: Perjeta, RO4368451;|
| Experimental: Part 1-Cohort 4: Pertuzumab 1200 mg SC<br>Part 1 includes healthy male participants. Participants will receive a single injection of pertuzumab 1200 mg SC. | Drug: Pertuzumab<br>* Participants will receive pertuzumab as a single agent injection, co-mixed or formulated as FDC with trastuzumab depending upon cohort. The dose will range from 400 to 1200 mg.<br>* Other names: Perjeta, RO4368451;|
| Active Comparator: Part 1-Cohort 5: Trastuzumab 600 mg SC<br>Part 1 includes healthy male participants. Participants will receive a single injection of trastuzumab 600 mg SC. | Drug: Trastuzumab<br>* Participants will receive a single dose of trastuzumab 600 mg SC separately, co-mixed or co-formulated with pertuzumab.<br>* Other names: Herceptin, RO0452317;|
| Experimental: Part 1-Cohort 6: Pertuzumab 400 mg SC + Trastuzumab 600 mg SC<br>Part 1 includes healthy male participants. Participants will receive a single injection of co-mixed pertuzumab 400 mg and trastuzumab 600 mg SC. | Drug: Trastuzumab<br>* Participants will receive a single dose of trastuzumab 600 mg SC separately, co-mixed or co-formulated with pertuzumab.<br>* Other names: Herceptin, RO0452317;Drug: Pertuzumab<br>* Participants will receive pertuzumab as a single agent injection, co-mixed or formulated as FDC with trastuzumab depending upon cohort. The dose will range from 400 to 1200 mg.<br>* Other names: Perjeta, RO4368451;|
| Experimental: Part 1-Cohort 7: Pertuzumab 1200 mg SC + Trastuzumab 600 mg SC<br>Part 1 includes healthy male participants. Participants will receive a single injection of co-mixed pertuzumab 1200 mg and trastuzumab 600 mg SC. | Drug: Trastuzumab<br>* Participants will receive a single dose of trastuzumab 600 mg SC separately, co-mixed or co-formulated with pertuzumab.<br>* Other names: Herceptin, RO0452317;Drug: Pertuzumab<br>* Participants will receive pertuzumab as a single agent injection, co-mixed or formulated as FDC with trastuzumab depending upon cohort. The dose will range from 400 to 1200 mg.<br>* Other names: Perjeta, RO4368451;|
| Experimental: Part 1-Cohort 8: Pertuzumab 1200 mg SC + Trastuzumab 600 mg SC<br>Part 1 includes healthy male participants. Participants will receive a single injection of co-mixed pertuzumab 1200 mg and trastuzumab 600 mg SC without recombinant human hyaluronidase (rHuPH20) excipient. | Drug: Trastuzumab<br>* Participants will receive a single dose of trastuzumab 600 mg SC separately, co-mixed or co-formulated with pertuzumab.<br>* Other names: Herceptin, RO0452317;Drug: Pertuzumab<br>* Participants will receive pertuzumab as a single agent injection, co-mixed or formulated as FDC with trastuzumab depending upon cohort. The dose will range from 400 to 1200 mg.<br>* Other names: Perjeta, RO4368451;|
| Experimental: Part 2-Cohort A: Pertuzumab SC + Trastuzumab SC<br>Part 2 includes women with early breast cancer. Cohort A will be enrolled only if FDC of pertuzumab and trastuzumab is not feasible. Participants will receive pertuzumab and trastuzumab (600 mg) SC administered separately. The dose of pertuzumab will be identified during Part 1. | Drug: Trastuzumab<br>* Participants will receive a single dose of trastuzumab 600 mg SC separately, co-mixed or co-formulated with pertuzumab.<br>* Other names: Herceptin, RO0452317;Drug: Pertuzumab<br>* Participants will receive pertuzumab as a single agent injection, co-mixed or formulated as FDC with trastuzumab depending upon cohort. The dose will range from 400 to 1200 mg.<br>* Other names: Perjeta, RO4368451;|
| Experimental: Part 2-Cohort B: Pertuzumab SC + Trastuzumab SC<br>Part 2 includes women with early breast cancer. Cohorts B and C will be enrolled if FDC of pertuzumab and trastuzumab is feasible. Participants will receive pertuzumab and trastuzumab (600 mg) SC; both agents administered in one injection (co-mixed). The dose of pertuzumab will be identified during Part 1. | Drug: Trastuzumab<br>* Participants will receive a single dose of trastuzumab 600 mg SC separately, co-mixed or co-formulated with pertuzumab.<br>* Other names: Herceptin, RO0452317;Drug: Pertuzumab<br>* Participants will receive pertuzumab as a single agent injection, co-mixed or formulated as FDC with trastuzumab depending upon cohort. The dose will range from 400 to 1200 mg.<br>* Other names: Perjeta, RO4368451;|
| Experimental: Part 2-Cohort C: Pertuzumab SC + Trastuzumab SC<br>Part 2 includes women with early breast cancer. Cohorts B and C will be enrolled if FDC of pertuzumab and trastuzumab is feasible. Participants will receive pertuzumab and trastuzumab (600 mg) SC; both agents formulated together and administered in one injection (FDC). The dose of pertuzumab will be identified during Part 1. | Drug: Trastuzumab<br>* Participants will receive a single dose of trastuzumab 600 mg SC separately, co-mixed or co-formulated with pertuzumab.<br>* Other names: Herceptin, RO0452317;Drug: Pertuzumab<br>* Participants will receive pertuzumab as a single agent injection, co-mixed or formulated as FDC with trastuzumab depending upon cohort. The dose will range from 400 to 1200 mg.<br>* Other names: Perjeta, RO4368451;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration from Time Zero to Time Infinity (AUC0-inf) of Pertuzumab SC |  | Pre-dose (0 hours) and 6, 8, and 12 hours post-dose on Day 1; on Days 2, 3, 5, 8, 10, 15, 22, 43, 85; and at follow-up visit (up to approximately 24 months) | 
| Maximum Serum Concentration (Cmax) of Pertuzumab SC |  | Pre-dose (0 hours) and 6, 8, and 12 hours post-dose on Day 1; on Days 2, 3, 5, 8, 10, 15, 22, 43, 85; and at follow-up visit (up to approximately 24 months) | 
| Time to Reach Cmax (Tmax) of Pertuzumab SC |  | Pre-dose (0 hours) and 6, 8, and 12 hours post-dose on Day 1; on Days 2, 3, 5, 8, 10, 15, 22, 43, 85; and at follow-up visit (up to approximately 24 months) | 
| Minimum Serum Concentration (Cmin) of Pertuzumab SC |  | Pre-dose (0 hours) and 6, 8, and 12 hours post-dose on Day 1; on Days 2, 3, 5, 8, 10, 15, 22, 43, 85; and at follow-up visit (up to approximately 24 months) | 
| AUC0-inf of Pertuzumab IV |  | Pre-dose (0 hours) and 1.5 and 3 hours post-dose on Day 1; on Days 2, 3, 5, 8, 15, 22, 35, 43, 85; and at follow-up visit (up to approximately 24 months) | 
| Cmax of Pertuzumab IV |  | Pre-dose (0 hours) and 1.5 and 3 hours post-dose on Day 1; on Days 2, 3, 5, 8, 15, 22, 35, 43, 85; and at follow-up visit (up to approximately 24 months) | 
| Tmax of Pertuzumab IV |  | Pre-dose (0 hours) and 1.5 and 3 hours post-dose on Day 1; on Days 2, 3, 5, 8, 15, 22, 35, 43, 85; and at follow-up visit (up to approximately 24 months) | 
| Cmin of Pertuzumab IV |  | Pre-dose (0 hours) and 1.5 and 3 hours post-dose on Day 1; on Days 2, 3, 5, 8, 15, 22, 35, 43, 85; and at follow-up visit (up to approximately 24 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Adverse Events |  | Baseline up to approximately 24 months | 
| Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) to Pertuzumab |  | Baseline, Day 22, Day 85, and 7 months post-dose (up to approximately 24 months overall) | 
| Percentage of Participants with ATAs to Trastuzumab |  | Baseline, Day 22, Day 85, and 7 months post-dose (up to approximately 24 months overall) | 
| Percentage of Participants with ATAs to rHuPH20 |  | Baseline, Day 22, Day 85, and 7 months post-dose (up to approximately 24 months overall) |