A Two-Arm Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Subcutaneous Administration of the Fixed-Dose Combination of Pertuzumab and Trastuzumab in Combination With Chemotherapy in Chinese Participants With HER2-Positive Early Breast Cancer

Study Overview
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Brief Summary
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This study will evaluate the pharmacokinetics, efficacy, and safety of the pertuzumab and trastuzumab fixed-dose combination for subcutaneous administration (PH FDC SC) as compared with those of the pertuzumab intravenous (IV) and trastuzumab IV formulations in Chinese participants with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer.

Official Title
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A Phase III, Randomized, Multicenter, Open-Label, Two-Arm Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Subcutaneous Administration of the Fixed-Dose Combination of Pertuzumab and Trastuzumab in Combination With Chemotherapy in Chinese Patients With HER2-Positive Early Breast Cancer

Conditions
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HER2-positive Early Breast Cancer

Intervention / Treatment
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* Drug: Pertuzumab IV
* Drug: Trastuzumab IV
* Drug: Pertuzumab and Trastuzumab FDC SC
* Drug: Doxorubicin
* Drug: Cyclophosphamide
* Drug: Docetaxel
* Procedure: Surgery
* Radiation: Post-Operative Radiotherapy
* Drug: Hormone Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to comply with the study protocol, in the investigator's judgment Eastern Cooperative Oncology Group (ECOG) Performance Status greater or equal to (≤)1 Stage II-IIIC (T2-T4 plus any N, or any T plus N1-3, M0), locally advanced, inflammatory, or early-stage, unilateral, and histologically confirmed invasive breast cancer Primary tumor greater than (>)2 centimeters (cm) in diameter, or node-positive disease (clinically or on imaging, and node positivity confirmed with cytology and/or histopathology) Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer confirmed by a central laboratory prior to study enrollment. HER2-positive status will be determined based on pretreatment breast biopsy material and defined as 3+ by immunohistochemistry (IHC) and/or positive by HER2 amplification by in situ hybridization (ISH) with a ratio of ≥2 for the number of HER2 gene copies to the number of signals for chromosome 17 copies Hormone receptor status of the primary tumor, centrally confirmed Patient agreement to undergo mastectomy or breast conserving surgery after neoadjuvant therapy Availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue for central confirmation of HER2, hormone receptor status, and PIK3CA mutational analyses Baseline left ventricular ejection fraction (LVEF) ≥55% measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) For women of childbearing potential (WOCBP) who are sexually active: agreement to remain abstinent (refrain from heterosexual intercourse) or use one highly effective non-hormonal contraceptive method with a failure rate of less than (<)1% per year, or two effective non-hormonal contraceptive methods during the treatment period and for 7 months after the last dose of HER2-targeted therapy, and agreement to refrain from donating eggs during this same period For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom in combination with a spermicidal foam, gel, film, cream, or suppository, and agreement to refrain from donating sperm, as specified in the protocol A negative serum pregnancy test must be available prior to randomization for WOCBP (premenopausal women and women <12 months after the onset of menopause), unless they have undergone surgical sterilization (removal of ovaries and/or uterus) No major surgical procedure unrelated to breast cancer within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment Exclusion Criteria: Stage IV (metastatic) breast cancer History of invasive breast cancer History of concurrent or previously treated non-breast malignancies except for appropriately treated 1) non-melanoma skin cancer and/or 2) in situ carcinomas, including cervix, colon, and skin Have received any previous systemic therapy (including chemotherapy, immunotherapy, HER2-targeted agents, endocrine therapy [selective estrogen receptor modulators, aromatase inhibitors], and antitumor vaccines) for treatment or prevention of breast cancer, or radiation therapy for treatment of cancer Have a past history of ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS) if they have received any systemic therapy for its treatment or radiation therapy to the ipsilateral breast High-risk for breast cancer and have received chemopreventative drugs in the past Multicentric (multiple tumors involving more than one quadrant) breast cancer, unless all tumors are HER2-positive Bilateral breast cancer Have undergone an excisional biopsy of primary tumor and/or axillary lymph nodes Axillary lymph node dissection (ALND) prior to initiation of neoadjuvant therapy Sentinel lymph node biopsy (SLNB) prior to neoadjuvant therapy Treatment with any investigational drug within 28 days prior to randomization Serious cardiac illness or medical conditions Inadequate bone marrow function Impaired liver function Inadequate renal function with serum creatinine >1.5X upper limit of normal (ULN) Current severe, uncontrolled systemic disease that may interfere with planned treatment (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound-healing disorders) Pregnant or breastfeeding, or intending to become pregnant during the study or within 7 months after the last dose of HER2-targeted therapy Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study Known active liver disease, for example, active viral hepatitis infection (i.e., hepatitis B or hepatitis C), autoimmune hepatic disorders, or sclerosing cholangitis Concurrent, serious, uncontrolled infections, or known infection with HIV Known hypersensitivity to study drugs, excipients, and/or murine proteins Current chronic daily treatment with corticosteroids (dose >10 milligrams [mg] methylprednisolone or equivalent excluding inhaled steroids) History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, colon, skin, and/or non-melanoma skin carcinoma History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease (e.g., severe LVSD, left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: Pertuzumab IV + Trastuzumab IV + Chemotherapy<br>Participants will receive 8 cycles of neoadjuvant chemotherapy: 4 cycles of doxorubicin plus cyclophosphamide (AC) once every 3 weeks (Q3W) followed by docetaxel Q3W for 4 cycles. Pertuzumab and trastuzumab will be given intravenously (IV) for 4 cycles Q3W concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants will undergo surgery. Thereafter, participants will receive an additional 14 cycles of pertuzumab IV and trastuzumab IV for a total of 18 cycles. | Drug: Pertuzumab IV<br>* Pertuzumab will be administered as a fixed non-weight-based loading dose of 840-milligrams (mg) IV and then a 420-mg IV maintenance dose Q3W.<br>* Other names: RO4368451;Drug: Trastuzumab IV<br>* Trastuzumab will be administered as an 8-milligram per kilogram of body weight (mg/kg) IV loading dose and then 6 mg/kg IV maintenance dose Q3W.<br>* Other names: RO0452317;Drug: Doxorubicin<br>* Doxorubicin 60 milligrams per meter squared of body surface area (mg/m^2) will be administered IV on Day 1 of each cycle of treatment (as part of AC Q3W) for Cycles 1-4.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide 600 mg/m^2 will be administered IV on Day 1 of each cycle of treatment (as part of AC Q3W) for Cycles 1-4.<br>Drug: Docetaxel<br>* Docetaxel 75 mg/m^2 will be administered IV on Day 1 of Cycle 5. At the investigator's discretion the dose may be escalated to 100 mg/m^2 IV for Cycles 6-8 (Q3W) provided no dose-limiting toxicity occurs.<br>Procedure: Surgery<br>* Participants in both cohorts are scheduled to undergo surgery after 8 cycles of neoadjuvant therapy. Participants may undergo breast-conserving surgery or mastectomy according to routine clinical practice.<br>Radiation: Post-Operative Radiotherapy<br>* If indicated, radiotherapy is given after chemotherapy and surgery, during adjuvant HER2-targeted therapy and hormone therapy (for hormone-receptor positive disease).<br>Drug: Hormone Therapy<br>* For hormone receptor positive breast cancer, tamoxifen or aromatase inhibitors will be allowed as adjuvant hormone therapy for postmenopausal participants and with ovarian suppression or ablation for premenopausal participants in countries where it has been registered for this indication. Its use must be consistent with the registered label. Hormone therapy is given after chemotherapy and surgery during adjuvant HER2-targeted therapy.<br>|
| Experimental: Arm B: Pertuzumab and Trastuzumab FDC SC + Chemotherapy<br>Participants will receive 8 cycles of neoadjuvant chemotherapy: 4 cycles of AC Q3W followed by docetaxel Q3W for 4 cycles. The pertuzumab and trastuzumab fixed-dose combination for subcutaneous administration (PH FDC SC) will be given subcutaneously (SC) for 4 cycles (Q3W) concurrently with the taxane component of chemotherapy. After completing their neoadjuvant therapy, participants will undergo surgery. Thereafter, participants will receive an additional 14 cycles of the PH FDC SC for a total of 18 cycles. | Drug: Pertuzumab and Trastuzumab FDC SC<br>* The pertuzumab and trastuzumab fixed-dose combination for subcutaneous administration (PH FDC SC) will be administered SC at a fixed non-weight-based dose. A loading dose of 1200 mg SC pertuzumab and 600 mg SC trastuzumab is then followed by a maintenance dose of 600 mg SC pertuzumab and 600 mg SC trastuzumab Q3W.<br>* Other names: RO7198574;Drug: Doxorubicin<br>* Doxorubicin 60 milligrams per meter squared of body surface area (mg/m^2) will be administered IV on Day 1 of each cycle of treatment (as part of AC Q3W) for Cycles 1-4.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide 600 mg/m^2 will be administered IV on Day 1 of each cycle of treatment (as part of AC Q3W) for Cycles 1-4.<br>Drug: Docetaxel<br>* Docetaxel 75 mg/m^2 will be administered IV on Day 1 of Cycle 5. At the investigator's discretion the dose may be escalated to 100 mg/m^2 IV for Cycles 6-8 (Q3W) provided no dose-limiting toxicity occurs.<br>Procedure: Surgery<br>* Participants in both cohorts are scheduled to undergo surgery after 8 cycles of neoadjuvant therapy. Participants may undergo breast-conserving surgery or mastectomy according to routine clinical practice.<br>Radiation: Post-Operative Radiotherapy<br>* If indicated, radiotherapy is given after chemotherapy and surgery, during adjuvant HER2-targeted therapy and hormone therapy (for hormone-receptor positive disease).<br>Drug: Hormone Therapy<br>* For hormone receptor positive breast cancer, tamoxifen or aromatase inhibitors will be allowed as adjuvant hormone therapy for postmenopausal participants and with ovarian suppression or ablation for premenopausal participants in countries where it has been registered for this indication. Its use must be consistent with the registered label. Hormone therapy is given after chemotherapy and surgery during adjuvant HER2-targeted therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Trough Concentration (Ctrough) of Pertuzumab During Cycle 7 (Pre-Dose Cycle 8) | The observed pertuzumab trough serum concentration (Ctrough) at Cycle 7 was assessed following 3 cycles of pertuzumab IV and trastuzumab IV or the fixed-dose combination (FDC) of pertuzumab and trastuzumab SC. The Per Protocol Pharmacokinetics (PK) analysis population includes all enrolled participants who adhered to the protocol. Exclusions from the Per Protocol PK analysis population were made for the following reasons: participants were missing the Ctrough pre-dose Cycle 8 PK sample, participants with a Ctrough sample collected with at least 2 days deviation from the planned date on Day 21 (i.e., before Day 19 or after Day 23), participants given a dose amount that deviated from the planned dose by >20% within 3 cycles (from Cycle 5), participants with a dose delay of more than 7 days, a Cycle 7 subcutaneous injection site other than thigh was used, if the Cycle 8 IV pre-dose and post-dose PK samples were switched, and an assay error impacting Ctrough measurement. | Pre-dose at Cycle 8 (one cycle is 21 days) | 
| Serum Ctrough of Trastuzumab During Cycle 7 (Pre-Dose Cycle 8) | The observed trastuzumab trough serum concentration (Ctrough) at Cycle 7 was assessed following 3 cycles of pertuzumab IV and trastuzumab IV or the fixed-dose combination (FDC) of pertuzumab and trastuzumab SC. The Per Protocol Pharmacokinetics (PK) analysis population includes all enrolled participants who adhered to the protocol. Exclusions from the Per Protocol PK analysis population were made for the following reasons: participants were missing the Ctrough pre-dose Cycle 8 PK sample, participants with a Ctrough sample collected with at least 2 days deviation from the planned date on Day 21 (i.e., before Day 19 or after Day 23), participants given a dose amount that deviated from the planned dose by >20% within 3 cycles (from Cycle 5), participants with a dose delay of more than 7 days, a Cycle 7 subcutaneous injection site other than thigh was used, if the Cycle 8 IV pre-dose and post-dose PK samples were switched, and an assay error impacting Ctrough measurement. | Pre-dose at Cycle 8 (one cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Total Pathological Complete Response (tpCR), According to Local Pathologist Assessment | Total pathological complete response (tpCR) was defined as eradication of invasive disease in the breast and axilla; that is, ypT0/is ypN0, according to the local pathologists' assessment. Pathologic response to therapy was determined at the time of surgery. The tpCR rate is the percentage of participants in the ITT population who achieved a tpCR. Participants with missing data for tpCR (i.e., do not undergo surgery or have an invalid pCR assessment) were included in the analysis and classified as non-responders. Rates of tpCR were calculated in each treatment arm and were assessed using the difference between the Arm B: Pertuzumab and Trastuzumab FDC SC and the Arm A: Pertuzumab IV and Trastuzumab IV tpCR rates and corresponding 95% Clopper-Pearson confidence intervals (CIs). The difference between the tpCR rates along with corresponding 95% Hauck-Anderson CIs were calculated. | Following completion of surgery (up to 33 weeks) | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Invasive Disease-Free Survival (iDFS; Excluding Second Primary Non-Breast Cancer [SPNBC]) Criteria | iDFS (excluding SPNBC) is defined as the time from the first date of no disease (i.e., the date of primary surgery) to the first occurrence of one of the following events: ipsilateral invasive breast tumor recurrence; ipsilateral local-regional invasive breast cancer reccurrence; distant recurrence; contralateral invasive breast cancer; or death attributable to any cause. Ipsilateral or contralateral in situ disease and SPNBC (including in situ carcinomas and non-melanoma skin cancers) will not be counted as progressive disease or relapse. | From date of surgery to iDFS (excluding SPNBC) event (up to 5 years) | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to iDFS (Including SPNBC) Criteria | iDFS including SPNBC is defined in the same way as iDFS but including SPNBC as an event (with the exception of non-melanoma skin cancers and in situ carcinoma of any site). | From date of surgery to iDFS (including SPNBC) event (up to 5 years) | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Event-Free Survival (EFS; Excluding SPNBC) Criteria | EFS (excluding SPNBC) is defined as the time from enrollment to the first occurrence of one of the following events: breast cancer progression; breast cancer recurrence; or death from any cause. Ipsilateral or contralateral in situ disease and SPNBC (including in situ carcinomas and non-melanoma skin cancers) will not be counted as progressive disease or relapse. | From baseline to EFS (excluding SPNBC) event (up to 5.5 years) | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to EFS (Including SPNBC) Criteria | EFS including SPNBC is defined in the same way as EFS, but including SPNBC as an event (with the exception of non-melanoma skin cancers and in situ carcinoma of any site). | From baseline to EFS (including SPNBC) event (up to 5.5 years) | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Distant Recurrence-Free Interval (DRFI) Criteria | DRFI is defined as the time between randomization and the date of distant breast cancer recurrence. | From baseline to DFRI event (up to 5.5 years) | 
| Kaplan-Meier Estimate of the Percentage of Participants in Overall Survival |  | From baseline to death from any cause (up to 5.5 years) | 
| Number of Participants With at Least One Adverse Event by Severity, Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4 (NCI CTCAE v4) |  | From baseline until study completion (up to 5.5 years) | 
| Number of Participants With a Primary Cardiac Event | A primary cardiac event is defined as either a symptomatic ejection fraction decrease (heart failure) of New York Heart Association (NYHA) Class III/IV and a drop in left ventricular ejection fraction (LVEF) of at least 10-percentage points from baseline and to below 50%, or a definite or probable cardiac death. NYHA Class III is defined as: marked limitation of physical activity; comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. NYHA Class IV is defined as: Inability to carry on any physical activity without discomfort; symptoms of cardiac insufficiency at rest; if any physical activity is undertaken, discomfort is increased. Definite cardiac death is defined as death due to heart failure, myocardial infarction, or documented primary arrhythmia. Probable cardiac death is defined as sudden unexpected death within 24 hours of a definite or probable cardiac event (e.g., syncope, cardiac arrest, chest pain, etc.) without documented etiology. | From baseline until study completion (up to 5.5 years) | 
| Number of Participants With a Secondary Cardiac Event, Defined as an Asymptomatic or Mildly Symptomatic Left Ventricular Systolic Dysfunction (LVSD) of NYHA Class II | An LVSD (Ejection fraction decreased) of NYHA Class II is defined as a left ventricular ejection fraction (LVEF) decrease of ≥10-percentage points below the baseline measurement to an absolute LVEF value of <50%, confirmed by a second LVEF assessment within approximately 3 weeks also showing a documented drop. | From baseline until study completion (up to 5.5 years) |