A Study to Evaluate Patient Preference for Home Administration of Fixed-Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Administration in Participants With Early or Locally Advanced/Inflammatory HER2-Positive Breast Cancer

Study Overview
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Brief Summary
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This is a Phase IIIb, multinational, multicenter, randomized, open-label study to evaluate patient preference of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous use (PH FDC SC) administration in the home setting compared with the hospital setting during the cross-over period of adjuvant treatment in participants with early or locally advanced/inflammatory human epidermal growth factor receptor 2-positive (HER2+) breast cancer.

Official Title
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A Phase IIIB, Multinational, Multicenter, Randomized, Open-Label Study to Evaluate Patient Preference for Home Administration of Fixed-Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Administration in Participants With Early or Locally Advanced/Inflammatory HER2-Positive Breast Cancer

Conditions
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Early Breast Cancer, Locally Advanced Breast Cancer, Inflammatory Breast Cancer

Intervention / Treatment
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* Drug: Fixed Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Use (PH FDC SC)
* Drug: Pertuzumab IV
* Drug: Trastuzumab IV
* Drug: Trastuzumab Emtansine
* Drug: Investigator's Choice of Chemotherapy
* Procedure: Surgery
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Intact skin at planned site of subcutaneous (SC) injections Left ventricular ejection fraction (LVEF) greater than or equal to (≥)55% by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) Negative human immunodeficiency virus (HIV) test at screening Negative hepatitis B surface antigen (HBsAg) test at screening Positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAb at screening accompanied by either of the following: Negative total hepatitis B core antibody (HBcAb); Positive total HBcAb test followed by a negative (per local laboratory definition) hepatitis B virus (HBV) DNA test Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening For female participants of childbearing potential: agreement to remain abstinent or use contraception and agree to refrain from donating eggs during the treatment period and for 7 months after the final dose of the study treatment For male participants: agreement to remain abstinent or use a condom, and agree to refrain from donating sperm during the treatment period and for 7 months after the final dose of study treatment Disease-specific Inclusion Criteria: Female and male participants with stage II-IIIC early or locally advanced/inflammatory human epidermal growth factor receptor 2-positive (HER2+) breast cancer Primary tumor >2 centimetres (cm) in diameter, or node-positive disease HER2+ breast cancer confirmed by a local laboratory prior to study enrollment. HER2+ 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) following American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines 2018 and updates (Wolff et al. Arch Pathol Lab Med 2018) Hormone receptor status of the primary tumor determined by local assessment following American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines and updates (Allison et al. J Clin Oncol 2020) Agreement to undergo mastectomy or breast conserving surgery after neoadjuvant therapy, including the axillary nodes Availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue block for local confirmation of HER2 and hormone receptor status following current ASCO/CAP guidelines Inclusion Criteria for Treatment with Adjuvant PH FDC SC: Completed the neoadjuvant phase of this study and underwent surgery, and achieved pathologic complete response (pCR), defined as eradication of invasive disease in the breast and axilla according to the current American Joint Committee on Cancer (AJCC) staging system classification, and using the resected specimen by the local pathologist on the basis of guidelines to be provided in a pathology manual Adequate wound healing after breast cancer surgery per investigator's assessment to allow initiation of study treatment within less than or equal to (≤)9 weeks of last systemic neoadjuvant therapy Exclusion Criteria: Stage IV (metastatic) 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. A participant with previous invasive non-breast cancer is eligible provided he/she has been disease free for more than 5 years Participants who are pregnant or breastfeeding or intending to become pregnant during the study or within 7 months after the final dose of study treatments Treatment with investigational therapy within 28 days prior to initiation of study treatment Active, unresolved infections at screening requiring treatment Participants who may have had a recent episode of thromboembolism and are still trying to optimize the anticoagulation dose and/or have not normalized their International Normalized Ratio (INR) Serious cardiac illness or medical conditions History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias Inadequate bone marrow function Impaired liver function Renal function with creatinine clearance <50 mL/min using the Cockroft-Gault formula and serum creatinine >1.5x upper limit of normal (ULN) Major surgical procedure unrelated to breast cancer within 28 days prior to study entry or anticipation of the need for major surgery during the course of study treatment Current severe, uncontrolled systemic disease that may interfere with planned treatment Any serious medical condition or abnormality in clinical laboratory tests that precludes an individual's safe participation in and completion of the study Treatment with a live vaccine (e.g., FluMist) in the 30 days prior to initiation of study treatment, or anticipation of need for such a vaccine during treatment or within 90 days after the final dose of study treatment Known active liver disease, for example, active viral hepatitis infection, autoimmune hepatic disorders, or sclerosing cholangitis Known hypersensitivity to any of the study drugs, excipients, and/or murine proteins or a history of severe allergic or immunological reactions, e.g., difficult to control asthma Current chronic daily treatment with corticosteroids Assessment by the investigator as being unable or unwilling to comply with the requirements of the protocol Cancer-specific Exclusion Criteria for Neoadjuvant Phase: Participants who have received any previous systemic therapy for treatment or prevention of breast cancer, or previous chest irradiation for the treatment of cancer Participants who 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 ipsi- or contralateral breast cancer Participants with high-risk for breast cancer who have received chemopreventive drugs in the past Participants with multicentric breast cancer, unless all tumors are HER2+ Participants with bilateral breast cancer Participants who 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 Exclusion Criterion for Treatment with Adjuvant Trastuzumab Emtansine (Arm E): Current Grade ≥3 peripheral neuropathy (according to the NCI CTCAE v5.0)

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 |
| --- | --- |
| Other: Arm A: Pertuzumab IV and Trastuzumab IV Plus Investigator's Choice of Chemotherapy<br>During the neoadjuvant phase, the enrolled participants randomized to this arm will receive treatment with pertuzumab and trastuzumab intravenously (PH IV) plus investigator's choice of chemotherapy (Option 1, 2, or 3). With chemotherapy Option 1, PH IV will be administered at each cycle from Cycles 1 to 6 (1 cycle is 3 weeks); with chemotherapy Options 2 and 3, PH IV will be administered once per cycle from Cycles 5 to 8 (1 cycle is 3 weeks). | Drug: Pertuzumab IV<br>* Pertuzumab is given as a fixed dose of 840 mg intravenous (IV) loading dose and then 420 mg IV for subsequent maintenance doses once every 3 weeks.<br>* Other names: RO4368451;Drug: Trastuzumab IV<br>* Trastuzumab is given as an 8 milligram per kilogram (mg/kg) intravenous (IV) loading dose and then 6 mg/kg IV for subsequent maintenance doses once every 3 weeks.<br>* Other names: RO0452317;Drug: Investigator's Choice of Chemotherapy<br>* Option 1: Docetaxel and carboplatin once every 3 weeks for 6 cycles; Option 2: Doxorubicin plus cyclophosphamide once every 3 weeks for 4 cycles, followed by a taxane (docetaxel once every 3 weeks for 4 cycles or paclitaxel once every week for 12 cycles); Option 3: Dose-dense doxorubicin plus cyclophosphamide (ddAC) once every 2 weeks for 4 cycles, followed by a taxane (docetaxel once every 3 weeks for 4 cycles or paclitaxel once every week for 12 cycles).<br>Procedure: Surgery<br>* After completing their neoadjuvant therapy, participants will undergo surgical resection for early or locally advanced HER2+ breast cancer (if eligible for surgery). Participants may undergo breast-conserving surgery or mastectomy according to routine clinical practice. The surgery cannot be performed ≤2 weeks from the last systemic neoadjuvant therapy and must be performed ≤6 weeks after the last systemic neoadjuvant therapy.<br>Radiation: Radiotherapy<br>* After surgery, radiotherapy is to be given as clinically indicated and as per local practice or institutional standards. The selected radiotherapy regimen should be initiated within 4 weeks after surgery.<br>|
| Other: Arm B: PH FDC SC Plus Investigator's Choice of Chemotherapy<br>During the neoadjuvant phase, the enrolled participants randomized to this arm will receive treatment with the fixed dose combination of pertuzumab and trastuzumab for subcutaneous use (PH FDC SC) plus investigator's choice of chemotherapy (Option 1, 2, or 3). With chemotherapy Option 1, PH FDC SC will be administered at each cycle from Cycles 1 to 6 (1 cycle is 3 weeks); with chemotherapy Options 2 and 3, PH FDC SC will be administered once per cycle from Cycles 5 to 8 (1 cycle is 3 weeks). | Drug: Fixed Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Use (PH FDC SC)<br>* PH FDC SC is administered subcutaneously (SC) as a fixed non-weight-based dose. A loading dose of 1200 milligram (mg) pertuzumab, 600 mg trastuzumab, and 30,000 units of recombinant human PH20 hyaluronidase (rHuPH20) is given in the first cycle (1 cycle is 21 days). In subsequent cycles, maintenance doses of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units rHuPH20 are administered once every 3 weeks (Q3W).<br>* Other names: RG6264;Drug: Investigator's Choice of Chemotherapy<br>* Option 1: Docetaxel and carboplatin once every 3 weeks for 6 cycles; Option 2: Doxorubicin plus cyclophosphamide once every 3 weeks for 4 cycles, followed by a taxane (docetaxel once every 3 weeks for 4 cycles or paclitaxel once every week for 12 cycles); Option 3: Dose-dense doxorubicin plus cyclophosphamide (ddAC) once every 2 weeks for 4 cycles, followed by a taxane (docetaxel once every 3 weeks for 4 cycles or paclitaxel once every week for 12 cycles).<br>Procedure: Surgery<br>* After completing their neoadjuvant therapy, participants will undergo surgical resection for early or locally advanced HER2+ breast cancer (if eligible for surgery). Participants may undergo breast-conserving surgery or mastectomy according to routine clinical practice. The surgery cannot be performed ≤2 weeks from the last systemic neoadjuvant therapy and must be performed ≤6 weeks after the last systemic neoadjuvant therapy.<br>Radiation: Radiotherapy<br>* After surgery, radiotherapy is to be given as clinically indicated and as per local practice or institutional standards. The selected radiotherapy regimen should be initiated within 4 weeks after surgery.<br>|
| Experimental: Arm C: Adjuvant PH FDC SC in Hospital, Then at Home<br>During the adjuvant phase, participants who have achieved pCR after surgery will be treated with 2 cycles of PH FDC SC in the hospital (run-in period). After completion of the last cycle of radiotherapy and the last cycle of PH FDC SC (run-in period), participants will then be randomized with a ratio of 1:1 into one of two treatment arms (Arm C or D) in a cross-over treatment period to receive the next 6 cycles of PH FDC SC treatment. Participants in Arm C will receive 3 cycles of PH FDC SC in the hospital and then 3 cycles of PH FDC SC in the home setting. After the cross-over treatment period, participants will receive the remaining PH FDC SC treatment cycles required to complete the planned 18 cycles of HER2-directed therapy, unless of disease recurrence, unacceptable toxicity, or withdrawal. Study treatment during this treatment continuation period will be administered either in the hospital or in the home setting as selected by the participant at the end of the crossover period. | Drug: Fixed Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Use (PH FDC SC)<br>* PH FDC SC is administered subcutaneously (SC) as a fixed non-weight-based dose. A loading dose of 1200 milligram (mg) pertuzumab, 600 mg trastuzumab, and 30,000 units of recombinant human PH20 hyaluronidase (rHuPH20) is given in the first cycle (1 cycle is 21 days). In subsequent cycles, maintenance doses of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units rHuPH20 are administered once every 3 weeks (Q3W).<br>* Other names: RG6264;|
| Experimental: Arm D: Adjuvant PH FDC SC at Home, Then in Hospital<br>During the adjuvant phase, participants who have achieved pCR after surgery will be treated with 2 cycles of PH FDC SC in the hospital (run-in period). After completion of the last cycle of radiotherapy and the last cycle of PH FDC SC (run-in period), participants will then be randomized with a ratio of 1:1 into one of two treatment arms (Arm C or D) in a cross-over treatment period to receive the next 6 cycles of PH FDC SC treatment. Participants in Arm D will receive 3 cycles of PH FDC SC in the home setting and then 3 cycles of PH FDC SC in the hospital. After the cross-over treatment period, participants will receive the remaining PH FDC SC treatment cycles required to complete the planned 18 cycles of HER2-directed therapy, unless of disease recurrence, unacceptable toxicity, or withdrawal. Study treatment during this treatment continuation period will be administered either in the hospital or in the home setting as selected by the participant at the end of the crossover period. | Drug: Fixed Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Use (PH FDC SC)<br>* PH FDC SC is administered subcutaneously (SC) as a fixed non-weight-based dose. A loading dose of 1200 milligram (mg) pertuzumab, 600 mg trastuzumab, and 30,000 units of recombinant human PH20 hyaluronidase (rHuPH20) is given in the first cycle (1 cycle is 21 days). In subsequent cycles, maintenance doses of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units rHuPH20 are administered once every 3 weeks (Q3W).<br>* Other names: RG6264;|
| Other: Arm E: Adjuvant Trastuzumab Emtansine<br>Participants with pathological evidence of residual invasive carcinoma in the breast or axillary lymph nodes following completion of preoperative therapy and surgery will enter Arm E to receive trastuzumab emtansine for 14 cycles. Trastuzumab emtansine will be administered IV in the hospital as per prescribing information. | Drug: Trastuzumab Emtansine<br>* Trastuzumab emtansine will be given at a dose of 3.6 mg/kg by intravenous (IV) infusion, once every 3 weeks.<br>* Other names: RO5304020;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Preferred the Administration of PH FDC SC in the Home Setting Compared With the Hospital Setting, Question 1 of the Patient Preference Questionnaire |  | Day 1 of Cycle 8 of adjuvant treatment (1 cycle is 3 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Treatment Preparation, According to Healthcare Professionals' Responses to Question 1 of the Healthcare Professional Questionnaire (HCPQ) - Neoadjuvant Phase Drug Preparation Area |  | Day 1 of each cycle from first cycle (Cycle 1 or 5) to last cycle (Cycle 6 or 8) of PH IV or PH FDC SC neoadjuvant treatment (1 cycle is 3 weeks) | 
| Percentage of Healthcare Professionals by Their Responses on Perception of Impact of PH FDC SC on Clinical Management and Clinical Efficiency, Question 2 of the HCPQ - Neoadjuvant Phase Drug Preparation Area |  | Day 1 of last cycle (Cycle 6 or 8) of neoadjuvant treatment (1 cycle is 3 weeks) | 
| Percentage of Healthcare Professionals by Their Responses on Perception of Time/Resource Use of Each Study Regimen, Questions 3 and 4 of the HCPQ - Neoadjuvant Phase Drug Preparation Area |  | Day 1 of last cycle (Cycle 6 or 8) of neoadjuvant treatment (1 cycle is 3 weeks) | 
| Duration of Treatment Administration Activities, According to Healthcare Professionals' Responses to Question 1 of the HCPQ - Neoadjuvant Phase Administering Treatment |  | Day 1 of each cycle from first cycle (Cycle 1 or 5) to last cycle (Cycle 6 or 8) of PH IV or PH FDC SC neoadjuvant treatment (1 cycle is 3 weeks) | 
| Percentage of Healthcare Professionals by Their Responses on Perception of Impact of PH FDC SC on Clinical Management and Clinical Efficiency, Question 2 of the HCPQ - Neoadjuvant Phase Administering Treatment |  | Day 1 of last cycle (Cycle 6 or 8) of neoadjuvant treatment (1 cycle is 3 weeks) | 
| Percentage of Healthcare Professionals by Their Responses on Perception of Time/Resource Use and Convenience of Each Study Regimen, Questions 3 to 10 of the HCPQ - Neoadjuvant Phase Administering Treatment |  | Day 1 of last cycle (Cycle 6 or 8) of neoadjuvant treatment (1 cycle is 3 weeks) | 
| Percentage of Healthcare Professionals by Their Responses to Question 11 of the HCPQ - Neoadjuvant Phase Administering Treatment |  | Day 1 of last cycle (Cycle 6 or 8) of neoadjuvant treatment (1 cycle is 3 weeks) | 
| Percentage of Participants Achieving Pathologic Complete Response (pCR) | pCR is defined as eradication of invasive disease in the breast and axilla (i.e., ypT0/Tis ypN0), according to local pathologist assessment following the American Joint Committee on Cancer (AJCC) criteria. | Post-surgery (up to 27 weeks) | 
| Health-Related Quality of Life Assessed by the European Organization for Research and Treatment of Cancer Core Quality of Life (EORTC QLQ)-C30 Questionnaire Scores in the Neoadjuvant Phase |  | Day 1 of Cycle 1 and Day 1 of last cycle of neoadjuvant treatment (Cycle 6 or 8; 1 cycle is 3 weeks) | 
| Health-Related Quality of Life Assessed by the EORTC QLQ-C30 Questionnaire Scores in Participants Treated with PH FDC SC During the Adjuvant Phase |  | Day 1 of Cycles 1, 3, 5, 8, and last cycle of adjuvant treatment (1 cycle is 3 weeks) | 
| Health-Related Quality of Life Assessed by the EORTC QLQ-C30 Questionnaire Scores in Participants Treated with Trastuzumab Emtansine During the Adjuvant Phase |  | Day 1 of Cycles 1, 7, and 14 of adjuvant treatment (1 cycle is 3 weeks) | 
| Duration of Treatment Preparation, According to Healthcare Professionals' Responses to Question 1 of the HCPQ - Adjuvant Phase Drug Preparation Area |  | Day 1 of Cycles 5 and 8 of adjuvant treatment (1 cycle is 3 weeks) | 
| Percentage of Healthcare Professionals by Their Responses on Perception of the Treatment Setting's Impact on Clinical Management and Clinical Efficiency, Question 2 of the HCPQ - Adjuvant Phase Drug Preparation Area |  | Day 1 of Cycle 8 of adjuvant treatment (1 cycle is 3 weeks) | 
| Percentage of Healthcare Professionals by Their Responses on Perception of Time/Resource Use in the Home and Hospital Settings, Questions 3 and 4 of the HCPQ - Adjuvant Phase Drug Preparation Area |  | Day 1 of Cycle 8 of adjuvant treatment (1 cycle is 3 weeks) | 
| Duration of Treatment Administration Activities, According to Healthcare Professionals' Responses to Question 1 of the HCPQ - Adjuvant Phase Administering Treatment |  | Day 1 of Cycles 5 and 8 of adjuvant treatment (1 cycle is 3 weeks) | 
| Percentage of Healthcare Professionals by Their Responses on Perception of the Treatment Setting's Impact on Clinical Management and Clinical Efficiency, Question 2 of the HCPQ - Adjuvant Phase Administering Treatment |  | Day 1 of Cycle 8 of adjuvant treatment (1 cycle is 3 weeks) | 
| Percentage of Healthcare Professionals by Their Responses on Perception of Time/Resource Use in the Home and Hospital Settings, Questions 3 to 6 of the HCPQ - Adjuvant Phase Administering Treatment |  | Day 1 of Cycle 8 of adjuvant treatment (1 cycle is 3 weeks) | 
| Percentage of Healthcare Professionals by Their Responses to Question 7 of the HCPQ - Adjuvant Phase Administering Treatment |  | Day 1 of Cycle 8 of adjuvant treatment (1 cycle is 3 weeks) | 
| Number of Participants with at Least One Adverse Event During the Neoadjuvant Treatment Phase, with Severity Determined According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0) |  | From Baseline until surgery (up to 27 weeks) | 
| Incidence of Premature Withdrawal from Neoadjuvant Treatment with PH FDC SC or Pertuzumab IV and Trastuzumab IV |  | From Cycle 1 to last cycle (Cycle 6 or 8) of neoadjuvant treatment (1 cycle is 3 weeks) | 
| Number of Participants with Clinical Laboratory Test Abnormalities During the Neoadjuvant Treatment Phase |  | From Baseline until surgery (up to 27 weeks) | 
| Number of Participants with Vital Sign Abnormalities During the Neoadjuvant Treatment Phase |  | From Baseline until surgery (up to 27 weeks) | 
| Number of Participants with at Least One Adverse Event During the Adjuvant Treatment Phase, with Severity Determined According to the NCI CTCAE v5.0 |  | From first dose post-surgery up to 9 months after the last dose of adjuvant treatment (up to 2 years) | 
| Incidence of Premature Withdrawal from Adjuvant Treatment with PH FDC SC |  | From Cycle 1 to last cycle (Cycle 12 or 14) of adjuvant treatment (1 cycle is 3 weeks) | 
| Incidence of Premature Withdrawal from Adjuvant Treatment with Trastuzumab Emtansine |  | From Cycle 1 to Cycle 14 (last cycle; 1 cycle is 3 weeks) | 
| Number of Participants with Clinical Laboratory Test Abnormalities During the Adjuvant Treatment Phase |  | From first dose post-surgery until the last dose of adjuvant treatment (up to 1.5 years) | 
| Number of Participants with Vital Sign Abnormalities During the Adjuvant Treatment Phase |  | From first dose post-surgery until the last dose of adjuvant treatment (up to 1.5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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patient preference, home administration, fixed-dose combination of pertuzumab and trastuzumab, subcutaneous administration