Breast Cancer
Conditions
Brief summary
In this open-label multicenter trial, participants with operable or locally advanced breast cancer will be randomized to pre-operative treatment with 8 cycles of chemotherapy (4 cycles of docetaxel followed by 4 cycles of 5-fluorouracil, epirubicin, and cyclophosphamide) concurrent with either SC Herceptin or IV Herceptin. After surgery, participants will receive a further 10 cycles of SC or IV Herceptin as per randomization to complete 1 year of treatment. All cycles will be 21 days in length. After the end of study treatment, participants will be followed for safety and efficacy for up to 5 years or until disease recurrence, whichever is earlier.
Interventions
DRUG5-Fluorouracil
Participants will receive 5-fluorouracil, 500 milligrams per meter-squared (mg/m\^2) via IV bolus or infusion, on Day 1 of every 21-day cycle during Cycles 5 to 8.
DRUGCyclophosphamide
Participants will receive cyclophosphamide, 500 mg/m\^2 via IV bolus, on Day 1 of every 21-day cycle during Cycles 5 to 8.
DRUGDocetaxel
Participants will receive docetaxel, 75 mg/m\^2 via IV infusion on Day 1 of every 21-day cycle during Cycles 1 to 4.
DRUGEpirubicin
Participants will receive epirubicin, 75 mg/m\^2 via IV bolus or infusion, on Day 1 of every 21-day cycle during Cycles 5 to 8.
DRUGHerceptin IV [trastuzumab]
Herceptin will be administered as 8 mg/kg (loading dose during Cycle 1) and 6 mg/kg (subsequent cycles) via IV infusion on Day 1 of each 21-day cycle for a total of 18 cycles.
DRUGHerceptin SC [trastuzumab]
Herceptin will be administered as fixed dose 600 mg SC on Day 1 of each 21-day cycle for a total of 18 cycles.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult women greater than or equal to (≥) 18 years of age * Non-metastatic primary invasive adenocarcinoma of the breast clinical stage I to IIIC, including inflammatory and multicentric/multifocal breast cancer, with tumor size ≥1 centimeter (cm) by ultrasound or ≥2 cm by palpation, centrally confirmed HER2-positive (immunohistochemical score \[IHC\] 3+ or in situ hybridization \[ISH\]-positive) * At least 1 measurable lesion in breast or lymph nodes (≥1 cm by ultrasound or ≥2 cm by palpation), except for inflammatory carcinoma (T4d) * Baseline left ventricular ejection fraction (LVEF) ≥55% * Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 * Adequate organ function at Baseline
Exclusion criteria
* History of any prior (ipsilateral and/or contralateral) invasive breast carcinoma * Past or current history of malignant neoplasms, except for curatively treated basal and squamous cell carcinoma of the skin and in situ carcinoma of the cervix * Metastatic disease * Any prior therapy with anthracyclines * Prior anti-HER2 therapy or biologic or immunotherapy * Serious cardiac illness * Pregnant or lactating women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Observed Serum Trough Concentration (Ctrough) of Trastuzumab Prior to Surgery | Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days) | Pre-dose samples were obtained prior to surgery (Cycle 8). The observed Ctrough was recorded, averaged among all participants, and expressed in micrograms per milliliter (μg/mL). |
| Percentage of Participants With Pathological Complete Response (pCR) | After surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months from Baseline) | Participants were evaluated following eight cycles of treatment and after surgery to assess for pCR, defined as absence of neoplastic invasive cells in the breast according to pathologist examination. The percentage of participants with pCR was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Predicted Ctrough of Trastuzumab After Surgery | Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days) | Predicted Ctrough at pre-dose after surgery (Cycle 13) was determined on the basis of a population PK model from Study BP22023 (NCT00800436). The mean predicted Ctrough was expressed in μg/mL. |
| Number of Participants With Ctrough of Trastuzumab >20 μg/mL Prior to Surgery | Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days) | Pre-dose samples were obtained prior to surgery (Cycle 8). The number of participants who had an observed Ctrough \>20 μg/mL was reported. |
| Number of Participants With Ctrough of Trastuzumab >20 μg/mL After Surgery | Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days) | Pre-dose samples were obtained after surgery (Cycle 13). The number of participants who had an observed Ctrough \>20 μg/mL was reported. |
| Maximum Serum Concentration (Cmax) of Trastuzumab Prior to Surgery | Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days) | PK samples were obtained prior to surgery (Cycle 7). The Cmax during Cycle 7 was recorded, averaged among all participants, and expressed in μg/mL. |
| Time of Maximum Serum Concentration (Tmax) of Trastuzumab Prior to Surgery | Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days) | PK samples were obtained prior to surgery (Cycle 7). The Tmax during Cycle 7 was recorded, averaged among all participants, and expressed in days. |
| Area Under the Concentration-Time Curve From 0 to 21 Days (AUC21d) of Trastuzumab Prior to Surgery | Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days) | PK samples were obtained prior to surgery (Cycle 7). Values were extrapolated beyond Day 15 to produce the area over the full 21-day cycle. The AUC21d value at Cycle 7 was calculated from trastuzumab concentration-time profiles using standard non-compartmental PK methods, averaged among all participants, and expressed in days multiplied by micrograms per milliliters (d\*μg/mL). |
| Cmax of Trastuzumab After Surgery | Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days) | PK samples were obtained after surgery (Cycle 12). The Cmax during Cycle 12 was recorded, averaged among all participants, and expressed in μg/mL. |
| Tmax of Trastuzumab After Surgery | Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days) | PK samples were obtained after surgery (Cycle 12). The Tmax during Cycle 12 was recorded, averaged among all participants, and expressed in days. |
| AUC21d of Trastuzumab After Surgery | Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days) | PK samples were obtained after surgery (Cycle 12). Values were extrapolated beyond Day 15 to produce the area over the full 21-day cycle. The AUC21d value at Cycle 12 was calculated from trastuzumab concentration-time profiles using standard non-compartmental PK methods, averaged among all participants, and expressed in d\*μg/mL. |
| Observed Ctrough of Trastuzumab After Surgery | Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days) | Pre-dose samples were obtained after surgery (Cycle 13). The observed Ctrough was recorded, averaged among all participants, and expressed in μg/mL. |
| Percentage of Participants With Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0, Among Those With Measurable Disease at Baseline | Tumor assessments at Baseline; on Day 1 of Cycles 3, 5, 7 (cycle length of 21 days); and at time of surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months overall) | Tumor response was assessed using RECIST version 1.0. CR was defined as disappearance of all target lesions and short-axis reduction of any pathological lymph nodes to less than (\<) 10 millimeters (mm) with no prior assessment of progressive disease (PD). PR was defined as greater than or equal to (≥) 30% decrease from Baseline in sum diameter (SD) of target lesions with no prior assessment of PD. PD was defined as ≥20% relative increase and ≥5 mm of absolute increase in the SD of target lesions, taking as reference the smallest SD recorded since treatment started; or appearance of 1 or more new lesions. The percentage of participants with overall response of CR or PR at the end of neoadjuvant treatment was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method. |
| Time to Response According to RECIST Version 1.0, Among Those With Measurable Disease at Baseline | Tumor assessments at Baseline; on Day 1 Cycles 3, 5, 7 (cycle length of 21 days); and at time of surgery following eight cycles of chemotherapy (approximately 6 months overall) | Tumor response was assessed using RECIST version 1.0. CR was defined as disappearance of all target lesions and short-axis reduction of any pathological lymph nodes to \<10 mm with no prior assessment of PD. PR was defined as ≥30% decrease from Baseline in SD of target lesions with no prior assessment of PD. PD was defined as ≥20% relative increase and ≥5 mm of absolute increase in the SD of target lesions, taking as reference the smallest SD recorded since treatment started; or appearance of 1 or more new lesions. Time to response was defined as the time from first dose of study medication to the first assessment of CR or PR, which was the date the response was first documented by objective evidence, among participants with an overall response of CR or PR. |
| Percentage of Participants Who Experienced a Protocol-Defined Event | Screening; Day 1 of Cycle 18 (cycle length of 21 days); and Months 6, 12, 24, 36, 48, 60 from last dose of Cycle 18; then every 6 months until withdrawal for any reason (up to approximately 87 months overall) | Protocol-defined events included disease recurrence/progression (local, regional, distant, contralateral) or death from any cause. Imaging was performed at specified visits for up to 5 years after last dose. Thereafter, participants were followed for survival only. The percentage of participants who experienced a protocol-defined event at any time during the study was reported. |
| Event-Free Survival (EFS) | Screening; Day 1 of Cycle 18 (cycle length of 21 days); and Months 6, 12, 24, 36, 48, 60 from last dose of Cycle 18; then every 6 months until withdrawal for any reason (up to approximately 87 months overall) | Protocol-defined events included disease recurrence or progression (local, regional, distant, contralateral) or death from any cause. Imaging was performed at specified visits for up to 5 years after last dose. Thereafter, participants were followed for survival only. EFS was estimated by Kaplan-Meier analysis and defined as the time from randomization to the first protocol-defined event. |
| Percentage of Participants Who Died | Continuously during treatment (up to 12 months); at Months 1, 3, 6 from last dose of Cycle 18 (cycle length of 21 days); then every 6 months until withdrawal for any reason (up to approximately 87 months overall) | The percentage of participants who died at any time during the study was reported. |
| Overall Survival (OS) | Continuously during treatment (up to 12 months); at Months 1, 3, 6 from last dose of Cycle 18 (cycle length of 21 days); then every 6 months until withdrawal for any reason (up to approximately 87 months overall) | OS was estimated by Kaplan-Meier analysis and defined as the time from randomization to death from any cause. |
| Number of Participants With Anti-Drug Antibodies (ADAs) Against Trastuzumab | Baseline; pre-dose (0 hours) on Day 1 of Cycles 2, 5, 13, 18 (cycle length of 21 days); and Months 3, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 from last dose of Cycle 18 | Participants provided PK samples for evaluation of anti-trastuzumab antibodies. The number of participants with Treatment-induced ADAs and Treatment-enhanced ADA against trastuzumab at any time during or after treatment was reported. Treatment-induced ADA = a participant with negative or missing Baseline ADA result(s) and at least one positive post-Baseline ADA result. Treatment-enhanced ADA = a participant with positive ADA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result (four-fold increase of titer). |
| Number of Participants With ADAs Against Recombinant Human Hyaluronidase (rHuPH20) | Baseline; pre-dose (0 hours) on Day 1 of Cycles 2, 5, 13, 18 (cycle length of 21 days); and Months 3, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 from last dose of Cycle 18 | Participants in the Herceptin SC arm provided PK samples for evaluation of anti-rHuPH20 antibodies. The number of participants with Treatment-induced ADAs and Treatment-enhanced ADA against rHuPH20 (an excipient unique to the SC formulation) at any time during or after treatment was reported. Treatment-induced ADA = a participant with negative or missing Baseline ADA result(s) and at least one positive post-Baseline ADA result. Treatment-enhanced ADA = a participant with positive ADA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result (four-fold increase of titer). |
| Percentage of Participants With Total Pathological Complete Response (tpCR) | After surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months from Baseline) | Participants were evaluated following eight cycles of treatment and after surgery to assess for tpCR, defined as absence of neoplastic invasive cells in the breast and axillary lymph nodes according to pathologist examination. The percentage of participants with tpCR was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method. |
| Predicted Ctrough of Trastuzumab Prior to Surgery | Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days) | Predicted Ctrough at pre-dose prior to surgery (Cycle 8) was determined on the basis of a population PK model from Study BP22023 (NCT00800436). The mean predicted Ctrough was expressed in μg/mL. |
Countries
Argentina, Brazil, Canada, Colombia, Czechia, Estonia, France, Germany, Guatemala, Hong Kong, Hungary, Israel, Italy, Mexico, Panama, Peru, Poland, Russia, Slovakia, South Africa, South Korea, Spain, Sweden, Taiwan, Thailand, Turkey (Türkiye)
Participant flow
Pre-assignment details
A total of 833 participants were screened, out of which, 596 participants were enrolled into the study.
Participants by arm
| Arm | Count |
|---|---|
| Herceptin IV + Chemotherapy Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period. | 297 |
| Herceptin SC + Chemotherapy Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period. | 294 |
| Total | 591 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Neoadjuvant/Adjuvant Treatment Periods | Adverse Event or Intercurrent Illness | 6 | 15 |
| Neoadjuvant/Adjuvant Treatment Periods | Death | 1 | 3 |
| Neoadjuvant/Adjuvant Treatment Periods | Insufficient Therapeutic Response | 3 | 0 |
| Neoadjuvant/Adjuvant Treatment Periods | Lost to Follow-up | 2 | 1 |
| Neoadjuvant/Adjuvant Treatment Periods | Other | 1 | 1 |
| Neoadjuvant/Adjuvant Treatment Periods | Participant Refusal/Withdrawal | 4 | 5 |
| Neoadjuvant/Adjuvant Treatment Periods | Progression of Disease | 12 | 11 |
| Neoadjuvant/Adjuvant Treatment Periods | Protocol Violation | 1 | 0 |
| Neoadjuvant/Adjuvant Treatment Periods | Recurrence of Disease | 10 | 5 |
| Neoadjuvant/Adjuvant Treatment Periods | Violation of Selection Criteria | 2 | 1 |
| SFU Period | Death | 44 | 42 |
| SFU Period | Lost to Follow-up | 30 | 28 |
| SFU Period | Withdrawal by Subject | 4 | 8 |
| TFFU Period | Adverse Event or Intercurrent Illness | 3 | 4 |
| TFFU Period | Death | 4 | 1 |
| TFFU Period | Failure to Return | 16 | 16 |
| TFFU Period | Other | 4 | 3 |
| TFFU Period | Recurrence of Disease | 63 | 72 |
| TFFU Period | Refused Treatment | 10 | 11 |
Baseline characteristics
| Characteristic | Herceptin IV + Chemotherapy | Herceptin SC + Chemotherapy | Total |
|---|---|---|---|
| Age, Continuous | 49.5 years STANDARD_DEVIATION 10.83 | 50.3 years STANDARD_DEVIATION 11.08 | 49.9 years STANDARD_DEVIATION 10.95 |
| Sex: Female, Male Female | 297 Participants | 294 Participants | 591 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 277 / 298 | 283 / 297 |
| serious Total, serious adverse events | 45 / 298 | 65 / 297 |
Outcome results
Primary
Observed Serum Trough Concentration (Ctrough) of Trastuzumab Prior to Surgery
Pre-dose samples were obtained prior to surgery (Cycle 8). The observed Ctrough was recorded, averaged among all participants, and expressed in micrograms per milliliter (μg/mL).
Time frame: Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
Population: Primary Pharmacokinetic (PK) Per Protocol (PP) Population: All participants with at least one measurable trastuzumab serum concentration and who did not have any major protocol violations related to PK sampling for the primary endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Herceptin IV + Chemotherapy | Observed Serum Trough Concentration (Ctrough) of Trastuzumab Prior to Surgery | 57.8 μg/mL | Standard Deviation 30.3 |
| Herceptin SC + Chemotherapy | Observed Serum Trough Concentration (Ctrough) of Trastuzumab Prior to Surgery | 78.7 μg/mL | Standard Deviation 43.9 |
Comparison: PK sample size calculations based on percentage of coefficient of variation (CV%) for Ctrough of trastuzumab from previous metastatic breast cancer (MBC) and early breast cancer (EBC) studies. Because pre-surgery situation was comparable to MBC setting, interpatient CV% of 60 percent (%) was assumed and 130 participants per arm (260 participants total) were needed to demonstrate Ctrough comparability with 80% power if the true means of the two formulations did not differ by greater than (\>) 5%.90% CI: [1.24, 1.44]
Primary
Percentage of Participants With Pathological Complete Response (pCR)
Participants were evaluated following eight cycles of treatment and after surgery to assess for pCR, defined as absence of neoplastic invasive cells in the breast according to pathologist examination. The percentage of participants with pCR was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method.
Time frame: After surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months from Baseline)
Population: Efficacy (E) PP Population: All participants with at least one on-treatment efficacy assessment who received a full eight cycles of study treatment according to randomization and who met additional protocol-specified criteria.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Herceptin IV + Chemotherapy | Percentage of Participants With Pathological Complete Response (pCR) | 40.7 percentage of participants |
| Herceptin SC + Chemotherapy | Percentage of Participants With Pathological Complete Response (pCR) | 45.4 percentage of participants |
Comparison: Assuming pCR rates of at least 40% in both arms, 552 participants were necessary to conclude non-inferiority in pCR rate with a power of 80% using a one-sided 97.5% CI for the difference of the response rates and a non-inferiority margin of 12.5%.
Secondary
Area Under the Concentration-Time Curve From 0 to 21 Days (AUC21d) of Trastuzumab Prior to Surgery
PK samples were obtained prior to surgery (Cycle 7). Values were extrapolated beyond Day 15 to produce the area over the full 21-day cycle. The AUC21d value at Cycle 7 was calculated from trastuzumab concentration-time profiles using standard non-compartmental PK methods, averaged among all participants, and expressed in days multiplied by micrograms per milliliters (d\*μg/mL).
Time frame: Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
Population: Primary PKPP Population; only those participants who provided evaluable data were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Herceptin IV + Chemotherapy | Area Under the Concentration-Time Curve From 0 to 21 Days (AUC21d) of Trastuzumab Prior to Surgery | 2056 d*μg/mL | Standard Deviation 598 |
| Herceptin SC + Chemotherapy | Area Under the Concentration-Time Curve From 0 to 21 Days (AUC21d) of Trastuzumab Prior to Surgery | 2268 d*μg/mL | Standard Deviation 875 |
Secondary
AUC21d of Trastuzumab After Surgery
PK samples were obtained after surgery (Cycle 12). Values were extrapolated beyond Day 15 to produce the area over the full 21-day cycle. The AUC21d value at Cycle 12 was calculated from trastuzumab concentration-time profiles using standard non-compartmental PK methods, averaged among all participants, and expressed in d\*μg/mL.
Time frame: Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
Population: Secondary PKPP Population; only those participants who provided evaluable data were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Herceptin IV + Chemotherapy | AUC21d of Trastuzumab After Surgery | 2179 d*μg/mL | Standard Deviation 725 |
| Herceptin SC + Chemotherapy | AUC21d of Trastuzumab After Surgery | 2610 d*μg/mL | Standard Deviation 945 |
Secondary
Cmax of Trastuzumab After Surgery
PK samples were obtained after surgery (Cycle 12). The Cmax during Cycle 12 was recorded, averaged among all participants, and expressed in μg/mL.
Time frame: Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
Population: Secondary PKPP Population; only those participants who provided evaluable data were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Herceptin IV + Chemotherapy | Cmax of Trastuzumab After Surgery | 230 μg/mL | Standard Deviation 118 |
| Herceptin SC + Chemotherapy | Cmax of Trastuzumab After Surgery | 166 μg/mL | Standard Deviation 58.8 |
Secondary
Event-Free Survival (EFS)
Protocol-defined events included disease recurrence or progression (local, regional, distant, contralateral) or death from any cause. Imaging was performed at specified visits for up to 5 years after last dose. Thereafter, participants were followed for survival only. EFS was estimated by Kaplan-Meier analysis and defined as the time from randomization to the first protocol-defined event.
Time frame: Screening; Day 1 of Cycle 18 (cycle length of 21 days); and Months 6, 12, 24, 36, 48, 60 from last dose of Cycle 18; then every 6 months until withdrawal for any reason (up to approximately 87 months overall)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Herceptin IV + Chemotherapy | Event-Free Survival (EFS) | NA months |
| Herceptin SC + Chemotherapy | Event-Free Survival (EFS) | NA months |
p-value: 0.865195% CI: [0.74, 1.29]Log Rank
Secondary
Maximum Serum Concentration (Cmax) of Trastuzumab Prior to Surgery
PK samples were obtained prior to surgery (Cycle 7). The Cmax during Cycle 7 was recorded, averaged among all participants, and expressed in μg/mL.
Time frame: Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
Population: Primary PKPP Population; only those participants who provided evaluable data were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Herceptin IV + Chemotherapy | Maximum Serum Concentration (Cmax) of Trastuzumab Prior to Surgery | 221 μg/mL | Standard Deviation 118 |
| Herceptin SC + Chemotherapy | Maximum Serum Concentration (Cmax) of Trastuzumab Prior to Surgery | 149 μg/mL | Standard Deviation 64.8 |
Secondary
Number of Participants With ADAs Against Recombinant Human Hyaluronidase (rHuPH20)
Participants in the Herceptin SC arm provided PK samples for evaluation of anti-rHuPH20 antibodies. The number of participants with Treatment-induced ADAs and Treatment-enhanced ADA against rHuPH20 (an excipient unique to the SC formulation) at any time during or after treatment was reported. Treatment-induced ADA = a participant with negative or missing Baseline ADA result(s) and at least one positive post-Baseline ADA result. Treatment-enhanced ADA = a participant with positive ADA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result (four-fold increase of titer).
Time frame: Baseline; pre-dose (0 hours) on Day 1 of Cycles 2, 5, 13, 18 (cycle length of 21 days); and Months 3, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 from last dose of Cycle 18
Population: Safety Population; as rHuPH20 is unique to SC formulation, this outcome measure was applicable for Herceptin SC + Chemotherapy arm only. Here, Overall Number of Participants Analyzed = participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Herceptin IV + Chemotherapy | Number of Participants With ADAs Against Recombinant Human Hyaluronidase (rHuPH20) | Treatment-induced ADA | 49 participants |
| Herceptin IV + Chemotherapy | Number of Participants With ADAs Against Recombinant Human Hyaluronidase (rHuPH20) | Treatment-enhanced ADA | 13 participants |
Secondary
Number of Participants With Anti-Drug Antibodies (ADAs) Against Trastuzumab
Participants provided PK samples for evaluation of anti-trastuzumab antibodies. The number of participants with Treatment-induced ADAs and Treatment-enhanced ADA against trastuzumab at any time during or after treatment was reported. Treatment-induced ADA = a participant with negative or missing Baseline ADA result(s) and at least one positive post-Baseline ADA result. Treatment-enhanced ADA = a participant with positive ADA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result (four-fold increase of titer).
Time frame: Baseline; pre-dose (0 hours) on Day 1 of Cycles 2, 5, 13, 18 (cycle length of 21 days); and Months 3, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 from last dose of Cycle 18
Population: Safety Population: All participants who received at least one dose of study medication. Here, Overall Number of Participants Analyzed = participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Herceptin IV + Chemotherapy | Number of Participants With Anti-Drug Antibodies (ADAs) Against Trastuzumab | Treatment-induced ADAs | 28 participants |
| Herceptin IV + Chemotherapy | Number of Participants With Anti-Drug Antibodies (ADAs) Against Trastuzumab | Treatment-enhanced ADA | 2 participants |
| Herceptin SC + Chemotherapy | Number of Participants With Anti-Drug Antibodies (ADAs) Against Trastuzumab | Treatment-induced ADAs | 46 participants |
| Herceptin SC + Chemotherapy | Number of Participants With Anti-Drug Antibodies (ADAs) Against Trastuzumab | Treatment-enhanced ADA | 1 participants |
Secondary
Number of Participants With Ctrough of Trastuzumab >20 μg/mL After Surgery
Pre-dose samples were obtained after surgery (Cycle 13). The number of participants who had an observed Ctrough \>20 μg/mL was reported.
Time frame: Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
Population: Secondary PKPP Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Herceptin IV + Chemotherapy | Number of Participants With Ctrough of Trastuzumab >20 μg/mL After Surgery | 216 participants |
| Herceptin SC + Chemotherapy | Number of Participants With Ctrough of Trastuzumab >20 μg/mL After Surgery | 227 participants |
Secondary
Number of Participants With Ctrough of Trastuzumab >20 μg/mL Prior to Surgery
Pre-dose samples were obtained prior to surgery (Cycle 8). The number of participants who had an observed Ctrough \>20 μg/mL was reported.
Time frame: Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
Population: Primary PKPP Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Herceptin IV + Chemotherapy | Number of Participants With Ctrough of Trastuzumab >20 μg/mL Prior to Surgery | 232 participants |
| Herceptin SC + Chemotherapy | Number of Participants With Ctrough of Trastuzumab >20 μg/mL Prior to Surgery | 227 participants |
Secondary
Observed Ctrough of Trastuzumab After Surgery
Pre-dose samples were obtained after surgery (Cycle 13). The observed Ctrough was recorded, averaged among all participants, and expressed in μg/mL.
Time frame: Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
Population: Secondary PKPP Population: All participants with at least one measurable trastuzumab serum concentration and who did not have any major protocol violations related to PK sampling for the secondary endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Herceptin IV + Chemotherapy | Observed Ctrough of Trastuzumab After Surgery | 62.1 μg/mL | Standard Deviation 37.1 |
| Herceptin SC + Chemotherapy | Observed Ctrough of Trastuzumab After Surgery | 90.4 μg/mL | Standard Deviation 41.9 |
Comparison: Additional supportive analysis.90% CI: [1.4, 1.63]
Secondary
Overall Survival (OS)
OS was estimated by Kaplan-Meier analysis and defined as the time from randomization to death from any cause.
Time frame: Continuously during treatment (up to 12 months); at Months 1, 3, 6 from last dose of Cycle 18 (cycle length of 21 days); then every 6 months until withdrawal for any reason (up to approximately 87 months overall)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Herceptin IV + Chemotherapy | Overall Survival (OS) | NA months |
| Herceptin SC + Chemotherapy | Overall Survival (OS) | NA months |
p-value: 0.776795% CI: [0.61, 1.45]Log Rank
Secondary
Percentage of Participants Who Died
The percentage of participants who died at any time during the study was reported.
Time frame: Continuously during treatment (up to 12 months); at Months 1, 3, 6 from last dose of Cycle 18 (cycle length of 21 days); then every 6 months until withdrawal for any reason (up to approximately 87 months overall)
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Herceptin IV + Chemotherapy | Percentage of Participants Who Died | 14.5 percentage of participants |
| Herceptin SC + Chemotherapy | Percentage of Participants Who Died | 13.6 percentage of participants |
Secondary
Percentage of Participants Who Experienced a Protocol-Defined Event
Protocol-defined events included disease recurrence/progression (local, regional, distant, contralateral) or death from any cause. Imaging was performed at specified visits for up to 5 years after last dose. Thereafter, participants were followed for survival only. The percentage of participants who experienced a protocol-defined event at any time during the study was reported.
Time frame: Screening; Day 1 of Cycle 18 (cycle length of 21 days); and Months 6, 12, 24, 36, 48, 60 from last dose of Cycle 18; then every 6 months until withdrawal for any reason (up to approximately 87 months overall)
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Herceptin IV + Chemotherapy | Percentage of Participants Who Experienced a Protocol-Defined Event | 33.3 percentage of participants |
| Herceptin SC + Chemotherapy | Percentage of Participants Who Experienced a Protocol-Defined Event | 32.7 percentage of participants |
Secondary
Percentage of Participants With Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0, Among Those With Measurable Disease at Baseline
Tumor response was assessed using RECIST version 1.0. CR was defined as disappearance of all target lesions and short-axis reduction of any pathological lymph nodes to less than (\<) 10 millimeters (mm) with no prior assessment of progressive disease (PD). PR was defined as greater than or equal to (≥) 30% decrease from Baseline in sum diameter (SD) of target lesions with no prior assessment of PD. PD was defined as ≥20% relative increase and ≥5 mm of absolute increase in the SD of target lesions, taking as reference the smallest SD recorded since treatment started; or appearance of 1 or more new lesions. The percentage of participants with overall response of CR or PR at the end of neoadjuvant treatment was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method.
Time frame: Tumor assessments at Baseline; on Day 1 of Cycles 3, 5, 7 (cycle length of 21 days); and at time of surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months overall)
Population: EPP Population; only participants with measurable disease at Baseline were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Herceptin IV + Chemotherapy | Percentage of Participants With Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0, Among Those With Measurable Disease at Baseline | 88.8 percentage of participants |
| Herceptin SC + Chemotherapy | Percentage of Participants With Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0, Among Those With Measurable Disease at Baseline | 87.2 percentage of participants |
95% CI: [-7.4, 4.2]
95% CI: [0.5, 1.46]
Secondary
Percentage of Participants With Total Pathological Complete Response (tpCR)
Participants were evaluated following eight cycles of treatment and after surgery to assess for tpCR, defined as absence of neoplastic invasive cells in the breast and axillary lymph nodes according to pathologist examination. The percentage of participants with tpCR was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method.
Time frame: After surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months from Baseline)
Population: EPP Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Herceptin IV + Chemotherapy | Percentage of Participants With Total Pathological Complete Response (tpCR) | 34.2 percentage of participants |
| Herceptin SC + Chemotherapy | Percentage of Participants With Total Pathological Complete Response (tpCR) | 39.2 percentage of participants |
95% CI: [-3.5, 13.5]
Secondary
Predicted Ctrough of Trastuzumab After Surgery
Predicted Ctrough at pre-dose after surgery (Cycle 13) was determined on the basis of a population PK model from Study BP22023 (NCT00800436). The mean predicted Ctrough was expressed in μg/mL.
Time frame: Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
Population: PKPP Population; only participants with a Cycle 13 pre-dose PK measurement were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Herceptin IV + Chemotherapy | Predicted Ctrough of Trastuzumab After Surgery | 51.7 μg/mL | Standard Deviation 20 |
| Herceptin SC + Chemotherapy | Predicted Ctrough of Trastuzumab After Surgery | 80.6 μg/mL | Standard Deviation 33.4 |
Comparison: Additional supportive analysis.90% CI: [1.45, 1.64]
Secondary
Predicted Ctrough of Trastuzumab Prior to Surgery
Predicted Ctrough at pre-dose prior to surgery (Cycle 8) was determined on the basis of a population PK model from Study BP22023 (NCT00800436). The mean predicted Ctrough was expressed in μg/mL.
Time frame: Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
Population: PKPP Population: All participants with at least one measurable trastuzumab serum concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Herceptin IV + Chemotherapy | Predicted Ctrough of Trastuzumab Prior to Surgery | 51.4 μg/mL | Standard Deviation 19.4 |
| Herceptin SC + Chemotherapy | Predicted Ctrough of Trastuzumab Prior to Surgery | 80.3 μg/mL | Standard Deviation 33.2 |
Comparison: Additional supportive analysis.90% CI: [1.46, 1.64]
Secondary
Time of Maximum Serum Concentration (Tmax) of Trastuzumab Prior to Surgery
PK samples were obtained prior to surgery (Cycle 7). The Tmax during Cycle 7 was recorded, averaged among all participants, and expressed in days.
Time frame: Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
Population: Primary PKPP Population; only those participants who provided evaluable data were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Herceptin IV + Chemotherapy | Time of Maximum Serum Concentration (Tmax) of Trastuzumab Prior to Surgery | 0.05 days | Standard Deviation 0.04 |
| Herceptin SC + Chemotherapy | Time of Maximum Serum Concentration (Tmax) of Trastuzumab Prior to Surgery | 4.12 days | Standard Deviation 2.91 |
Secondary
Time to Response According to RECIST Version 1.0, Among Those With Measurable Disease at Baseline
Tumor response was assessed using RECIST version 1.0. CR was defined as disappearance of all target lesions and short-axis reduction of any pathological lymph nodes to \<10 mm with no prior assessment of PD. PR was defined as ≥30% decrease from Baseline in SD of target lesions with no prior assessment of PD. PD was defined as ≥20% relative increase and ≥5 mm of absolute increase in the SD of target lesions, taking as reference the smallest SD recorded since treatment started; or appearance of 1 or more new lesions. Time to response was defined as the time from first dose of study medication to the first assessment of CR or PR, which was the date the response was first documented by objective evidence, among participants with an overall response of CR or PR.
Time frame: Tumor assessments at Baseline; on Day 1 Cycles 3, 5, 7 (cycle length of 21 days); and at time of surgery following eight cycles of chemotherapy (approximately 6 months overall)
Population: EPP Population; only participants with measurable disease at Baseline and a response of CR or PR were included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Herceptin IV + Chemotherapy | Time to Response According to RECIST Version 1.0, Among Those With Measurable Disease at Baseline | 6.14 weeks |
| Herceptin SC + Chemotherapy | Time to Response According to RECIST Version 1.0, Among Those With Measurable Disease at Baseline | 6.14 weeks |
Secondary
Tmax of Trastuzumab After Surgery
PK samples were obtained after surgery (Cycle 12). The Tmax during Cycle 12 was recorded, averaged among all participants, and expressed in days.
Time frame: Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
Population: Secondary PKPP Population; only those participants who provided evaluable data were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Herceptin IV + Chemotherapy | Tmax of Trastuzumab After Surgery | 0.06 days | Standard Deviation 0.13 |
| Herceptin SC + Chemotherapy | Tmax of Trastuzumab After Surgery | 4.08 days | Standard Deviation 2.87 |