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
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 346
- Locations
- 84
- Primary Endpoint
- Cross-over Period: Percentage of Participants Who Preferred the Administration of PH FDC SC in the Home Setting Compared With the Hospital Setting in Question 1 of the Patient Preference Questionnaire (PPQ)
Study Overview
Brief Summary
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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)
Arms & Interventions
Arm A: Pertuzumab IV and Trastuzumab IV Plus Investigator's Choice of Chemotherapy
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).
Intervention: Pertuzumab IV (Drug)
Arm A: Pertuzumab IV and Trastuzumab IV Plus Investigator's Choice of Chemotherapy
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).
Intervention: Trastuzumab IV (Drug)
Arm A: Pertuzumab IV and Trastuzumab IV Plus Investigator's Choice of Chemotherapy
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).
Intervention: Investigator's Choice of Chemotherapy (Drug)
Arm A: Pertuzumab IV and Trastuzumab IV Plus Investigator's Choice of Chemotherapy
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).
Intervention: Surgery (Procedure)
Arm A: Pertuzumab IV and Trastuzumab IV Plus Investigator's Choice of Chemotherapy
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).
Intervention: Radiotherapy (Radiation)
Arm B: PH FDC SC Plus Investigator's Choice of Chemotherapy
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).
Intervention: Fixed Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Use (PH FDC SC) (Drug)
Arm B: PH FDC SC Plus Investigator's Choice of Chemotherapy
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).
Intervention: Investigator's Choice of Chemotherapy (Drug)
Arm B: PH FDC SC Plus Investigator's Choice of Chemotherapy
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).
Intervention: Surgery (Procedure)
Arm B: PH FDC SC Plus Investigator's Choice of Chemotherapy
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).
Intervention: Radiotherapy (Radiation)
Arm C: Adjuvant PH FDC SC in Hospital, Then at Home
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.
Intervention: Fixed Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Use (PH FDC SC) (Drug)
Arm D: Adjuvant PH FDC SC at Home, Then in Hospital
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.
Intervention: Fixed Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Use (PH FDC SC) (Drug)
Arm E: Adjuvant Trastuzumab Emtansine
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.
Intervention: Trastuzumab Emtansine (Drug)
Outcomes
Primary Outcomes
Cross-over Period: Percentage of Participants Who Preferred the Administration of PH FDC SC in the Home Setting Compared With the Hospital Setting in Question 1 of the Patient Preference Questionnaire (PPQ)
Time Frame: Upon completion of adjuvant cross-over period (Day 1 of Cycle 8 or 9; Cycle length = 21 days)
The PPQ was used to evaluate the participant preference for PH FDC SC compared to P+H IV. Participants completed the PPQ, where Question (Q) 1 was: "All things considered, which setting for your treatment did you prefer?" Participants were required to select one of the following options: home, hospital or no preference. The reported results show the percentage of participants who preferred receiving PH FDC SC at home setting over the hospital setting. Percentages were rounded off.
Secondary Outcomes
- Neoadjuvant Phase: Percentage of HCPs by Their Responses to Question 1a of HCPQ - Drug Preparation Area(Day 1 of Cycles 1-8 (Cycle length = 21 days))
- Neoadjuvant Phase: Duration of Treatment Preparation, According to Healthcare Professionals' Responses to Question 1b of HCPQ - Drug Preparation Area(Day 1 of Cycles 1-8 (Cycle length = 21 days))
- Neoadjuvant Phase: Percentage of HCPs by Their Response to Question 2 of the HCPQ - Drug Preparation Area(Up to Day 1 of Cycle 8 (Cycle length = 21 days))
- Neoadjuvant Phase: Percentage of HCPs by Their Responses to Questions 1a-1e of the HCPQ - Administering Treatment(Day 1 of Cycles 1-8 (Cycle length = 21 days))
- Neoadjuvant Phase: Duration of Treatment Administration According to HCPs' Responses to Questions 1c (Sub-part), 1f, and 1g of the HCPQ - Administering Treatment(Day 1 of Cycles 1-8 (Cycle length = 21 days))
- Neoadjuvant Phase: Percentage of HCPs by Their Response to Question 2 (2a to 2e) of the HCPQ - Administering Treatment(Up to Cycle 8 (Cycle length = 21 days))
- Neoadjuvant Phase: Percentage of HCPs by Their Responses to Question 2 (2f to 2j) of the HCPQ - Administering Treatment(Up to Cycle 8 (Cycle length = 21 days))
- Neoadjuvant Phase: Percentage of HCPs by Their Responses to Question 3 to 11 of the HCPQ - Administering Treatment(Up to Cycle 8 (Cycle length = 21 days))
- Percentage of Participants Who Achieved pCR Post-surgery(Up to approximately 7.8 months)
- Neoadjuvant Phase: Change From Baseline in Health-related Quality of Life (HRQoL) Assessed by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ C30) Scores(Baseline, Day 1 of Cycles 6 and 8 (Cycle length = 21 days))
- Adjuvant Phase: Change From Baseline in HRQoL Assessed by EORTC QLQ C30 Scores(Baseline (Cycle 1) of Run-in Period; Day 1 of Cycles 1, 3, and 6 in the Cross-over Period (Cycle length = 21 days))
- Adjuvant Cross-over Period: Percentage of HCPs by Their Responses to Questions 1a and 1c of the HCPQ - Drug Preparation Area(Day 1 of Cycles 3 and 6 (Cycle length = 21 days))
- Adjuvant Cross-over Period: Duration of Treatment Preparation, According to HCPs' Responses to Question 1b of the HCPQ - Drug Preparation Area(Day 1 of Cycles 3 and 6 (Cycle length = 21 days))
- Adjuvant Cross-over Period: Percentage of HCPs by Their Responses to Questions 2, 3 and 4 of the HCPQ - Drug Preparation Area(Day 1 of Cycle 6 (Cycle length = 21 days))
- Adjuvant Cross-over Period: Duration of Administering Treatment, According to HCPs' Responses to Question 1a to 1f of the HCPQ - Administering Treatment(Day 1 of Cycles 3 and 6 (Cycle length = 21 days))
- Adjuvant Cross-over Period: Percentage of HCPs by Their Responses to Questions 1g, 1h, and 1i of the HCPQ - Administering Treatment(Day 1 of Cycles 3 and 6 (Cycle length = 21 days))
- Adjuvant Cross-over Period: Percentage of HCPs by Their Responses to Questions 1j, 1k, and 1l of the HCPQ - Administering Treatment(Day 1 of Cycle 6 (Cycle length = 21 days))
- Adjuvant Cross-over Period: Percentage of HCPs by Their Responses to Question 2 of the HCPQ - Administering Treatment(Day 1 of Cycle 6 (Cycle length = 21 days))
- Adjuvant Cross-over Period: Percentage of HCPs by Their Responses to Questions 3 to 7 of the HCPQ - Administering Treatment(Day 1 of Cycle 6 (Cycle length = 21 days))
- Adjuvant Phase: HRQoL Assessed by EORTC QLQ C30 Scores in Participants Treated With Trastuzumab Emtansine IV(Day 1 of Cycles 1 and 6 (1 Cycle = 21 days))
- Percentage of Participants Who Selected the Administration of PH FDC SC in the Home Setting Compared With the Hospital Setting in the Treatment Continuation Period(Upon completion of adjuvant cross-over period (Day 1 of Cycle 8 or 9; Cycle length = 21 days))
- Neoadjuvant Phase: Number of Participants With Adverse Events (AEs), Grade ≥ 3 AEs, Serious AEs (SAEs), and Cardiac AEs(From initiation of study treatment until 28 days after the last treatment cycle (up to approximately 7.4 months))
- Neoadjuvant Phase: Number of Participants With Premature Withdrawal From PH FDC SC and P+H IV Due to AEs(Up to Cycle 8 (1 Cycle = 21 days))
- Adjuvant Cross-over Period: Number of Participants With AEs, Grade ≥ 3 AEs, SAEs, and Cardiac AEs(From initiation of study treatment until 28 days after the last treatment cycle (up to approximately 5.8 months))
- Adjuvant Cross-over Period: Number of Participants With Premature Withdrawal From PH FDC SC Due to AEs(Up to Cycle 6 (Cycle length = 21 days))
- Treatment Continuation Period and Trastuzumab Emtansine IV Period: Number of Participants With AEs, Grade ≥ 3 AEs, SAEs, and Cardiac AEs(From initiation of study treatment until 28 days after the last treatment cycle (up to approximately 3.5 years))
- Treatment Continuation Period and Trastuzumab Emtansine IV Period: Number of Participants With Premature Withdrawal From PH FDC SC and Trastuzumab Emtansine IV Due to AEs(From initiation of study treatment in the adjuvant phase until 28 days after the last treatment cycle (up to approximately 3.5 years))