Breast Cancer
Conditions
Brief summary
This study will assess the efficacy and safety of adding Herceptin to a paclitaxel-containing regimen followed by cyclophosphamide/methotrexate/fluorouracil (CMF) chemotherapy in women with locally advanced breast cancer and HER2/c-erbB-2 gene amplification. In a parallel observational study patients with HER2-negative disease will receive the same chemotherapy without Herceptin.
Interventions
DRUGTrastuzumab
8mg/kg IV on Day 1 of Cycle 1, followed by 6 mg/kg on Day 1 of Cycle 2 up a maximum of Cycle 17
DRUGDoxorubicin
60 mg/m2 IV on Day 1 of Cycles 1 through 3
DRUGPaclitaxel
150 mg/m2 IV on Day 1 of Cycles 1 through 3, followed by 175 mg/m2 IV on Day 1 of Cycles 4 through 7
DRUGCMF
CMF: Cyclophosphamide (600 mg/m2 IV bolus), methotrexate (40 mg/m2 IV bolus), 5-fluorouracil (600 mg/m2 IV bolus) on Day 1 of Cycles 8 through 10
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
* female patients, \>=18 years of age, with locally advanced breast cancer.
Exclusion criteria
* previous therapy for any invasive malignancy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival (EFS) - Percentage of Participants With an Event | Baseline (BL), Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | EFS was defined as the time between randomization and date of documented occurrence of disease recurrence or progression (local, regional, distant or contralateral) or death due to any cause. |
| Event-Free Survival | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | The median time, in months, between randomization and date of documented occurrence of an EFS event. |
| Percentage of Participants Event Free at 1 Year | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | — |
| Percentage of Participants Event Free at 2 Years | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | — |
| Percentage of Participants Event Free at 3 Years | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Surviving at 3 Years | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | — |
| Percentage of Participants Achieving Either Complete Response (CR) or Partial Response (PR) According to Modified Response Evaluation Criteria in Solid Tumors (RECIST) Criteria | BL, Presurgery: Day 1 of Cycles 1-10 | Assessments were made based on objective tumor measurements of the lesions as recorded in the case report form. In inflammatory cancer, progressive disease (PD) was defined as progression of any of the 2 signs of breast edema and erythema. In non-inflammatory cancer, PD was concluded if either the investigator judged the participant as having progressed at any time prior to surgery, or there was at least a 20% increase in the sum of target lesions (TLs), any new lesion, or clear progression of any nontarget lesion (NTLs). Clear progression of any NTL was defined as at least a 20% increase in the sum of NTLs compared to BL. PR was defined as at least a 30% decrease from BL in the sum of the longest diameter of TLs. CR was defined as no PD as assessed by the investigator and complete disappearance of all lesions. |
| Percentage of Participants With Total Pathological Complete Response (tpCR) | BL, Day 1 of Cycles 1-10 (pre-surgery) | tpCR was defined as a determination of bpCR and an absence of positive axillary nodes on pathology. |
| Percentage of Participants With Breast Pathological Complete Response (bpCR) | BL, Day 1 of Cycles 1-10 (pre-surgery) | bpCR was defined as an absence of any invasive cancer cell of the primary tumor at the time of major surgery after neoadjuvant chemotherapy with and without trastuzumab. |
| Overall Survival (OS) - Percentage of Participants With an Event | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | OS was defined as the time from the date of randomization to the date of the death due to any cause. |
| Overall Survival | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | OS was defined as the time from the date of randomization to the date of the death due to any cause. |
| Percentage of Participants Surviving at 1 Year | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | — |
| Percentage of Participants Surviving at 2 Years | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | — |
Countries
Austria, Germany, Italy, Portugal, Russia, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| HER2+ TC Participants with HER2+ breast cancer received treatment as follows:
Cycles 1-3 (3-week cycles): trastuzumab 8 mg/kg, IV on Day 1 (Cycle 1 only; 6 mg/kg in Cycles 2 and 3), doxorubicin 60 mg/m\^2, IV, and paclitaxel 150 mg/m\^2, IV, on Day 1 followed by 2 weeks off.
Cycles 4-7 (3-week cycles): trastuzumab 6 mg/kg, IV, paclitaxel 175 mg/m\^2, IV, on Day 1, followed by 2 weeks off.
Cycles 8-10 (3-week cycles): trastuzumab 6 mg/kg, IV, on Day 1 and cyclophosphamide 600 mg/m\^2, IV, methotrexate 40 mg/m\^2, IV, and 5-fluorouracil 600 mg/m\^2, IV, (collectively CMF) on Days 1 and 8, followed by 2 weeks off.
Cycles 11-17 (3-week cycles): postoperatively, participants received trastuzumab 6 mg/kg IV on Day 1, followed by 2 weeks off for maximum of 17 overall cycles with trastuzumab. Adjuvant tamoxifen, 20 mg/day was administered for up to 5 years. | 115 |
| HER2+ C Participants with HER2+ breast cancer received treatment as follows:
Cycles 1-3 (3-week cycles): doxorubicin 60 mg/m\^2, IV and paclitaxel 150 mg/m\^2, IV, on Day 1 followed by 2 weeks off.
Cycles 4-7 (3-week cycles): paclitaxel 175 mg/m\^2, IV, on Day 1, followed by 2 weeks off.
Cycles 8-10 (3-week cycles): cyclophosphamide 600 mg/m\^2, IV, methotrexate 40 mg/m\^2, IV, and 5-fluorouracil 600 mg/m\^2, IV, on Days 1 and 8, followed by 1 week off. | 112 |
| HER2- C Participants with HER2- breast cancer received treatment as follows:
Cycles 1-3 (3-week cycles): doxorubicin 60 mg/m\^2, IV, and paclitaxel 150 mg/m\^2, IV, on Day 1, followed by 2 weeks off.
Cycles 4-7 (3-week cycles): paclitaxel 175 mg/m\^2, IV, on Day 1, followed by 2 weeks off.
Cycles 8-10 (3-week cycles): cyclophosphamide 600 mg/m\^2, IV, methotrexate 40 mg/m\^2, IV, and 5-fluorouracil 600 mg/m\^2, IV, on Days 1 and 8, followed by 1 week off. | 99 |
| Total | 326 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Administrative/Other | 2 | 1 | 3 |
| Overall Study | Death | 21 | 30 | 17 |
| Overall Study | Failure to return | 0 | 2 | 4 |
| Overall Study | Lack of Efficacy | 10 | 9 | 8 |
| Overall Study | Other | 3 | 8 | 4 |
| Overall Study | Participants ongoing in follow-up | 77 | 60 | 58 |
| Overall Study | Violation of Selection Criteria | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 4 | 3 |
Baseline characteristics
| Characteristic | HER2+ TC | HER2+ C | HER2- C | Total |
|---|---|---|---|---|
| Age, Continuous | 50.2 years STANDARD_DEVIATION 9.78 | 52.3 years STANDARD_DEVIATION 10.97 | 50.6 years STANDARD_DEVIATION 10.46 | 51.0 years STANDARD_DEVIATION 10.42 |
| Sex: Female, Male Female | 115 Participants | 112 Participants | 99 Participants | 326 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 113 / 115 | 112 / 112 | 98 / 99 |
| serious Total, serious adverse events | 18 / 115 | 8 / 112 | 9 / 99 |
Outcome results
Primary
Event-Free Survival
The median time, in months, between randomization and date of documented occurrence of an EFS event.
Time frame: BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HER2+ TC | Event-Free Survival | NA months |
| HER2+ C | Event-Free Survival | 43.6 months |
| HER2- C | Event-Free Survival | 64.5 months |
p-value: 0.027595% CI: [0.44, 0.96]Log Rank
Primary
Event-Free Survival (EFS) - Percentage of Participants With an Event
EFS was defined as the time between randomization and date of documented occurrence of disease recurrence or progression (local, regional, distant or contralateral) or death due to any cause.
Time frame: Baseline (BL), Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Population: The full analysis set (FAS) included all participants who were randomized in the main study or registered in the parallel observational arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HER2+ TC | Event-Free Survival (EFS) - Percentage of Participants With an Event | 40.0 percentage of participants |
| HER2+ C | Event-Free Survival (EFS) - Percentage of Participants With an Event | 50.9 percentage of participants |
| HER2- C | Event-Free Survival (EFS) - Percentage of Participants With an Event | 42.4 percentage of participants |
Primary
Percentage of Participants Event Free at 1 Year
Time frame: BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HER2+ TC | Percentage of Participants Event Free at 1 Year | 89 percentage of participants |
| HER2+ C | Percentage of Participants Event Free at 1 Year | 82 percentage of participants |
| HER2- C | Percentage of Participants Event Free at 1 Year | 80 percentage of participants |
Primary
Percentage of Participants Event Free at 2 Years
Time frame: BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HER2+ TC | Percentage of Participants Event Free at 2 Years | 73 percentage of participants |
| HER2+ C | Percentage of Participants Event Free at 2 Years | 61 percentage of participants |
| HER2- C | Percentage of Participants Event Free at 2 Years | 69 percentage of participants |
Primary
Percentage of Participants Event Free at 3 Years
Time frame: BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HER2+ TC | Percentage of Participants Event Free at 3 Years | 65 percentage of participants |
| HER2+ C | Percentage of Participants Event Free at 3 Years | 52 percentage of participants |
| HER2- C | Percentage of Participants Event Free at 3 Years | 63 percentage of participants |
Secondary
Overall Survival
OS was defined as the time from the date of randomization to the date of the death due to any cause.
Time frame: BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HER2+ TC | Overall Survival | NA months |
| HER2+ C | Overall Survival | NA months |
| HER2- C | Overall Survival | NA months |
p-value: 0.055595% CI: [0.35, 1.02]Log Rank
Secondary
Overall Survival (OS) - Percentage of Participants With an Event
OS was defined as the time from the date of randomization to the date of the death due to any cause.
Time frame: BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HER2+ TC | Overall Survival (OS) - Percentage of Participants With an Event | 19.1 percentage of participants |
| HER2+ C | Overall Survival (OS) - Percentage of Participants With an Event | 28.4 percentage of participants |
| HER2- C | Overall Survival (OS) - Percentage of Participants With an Event | 21.2 percentage of participants |
Secondary
Percentage of Participants Achieving Either Complete Response (CR) or Partial Response (PR) According to Modified Response Evaluation Criteria in Solid Tumors (RECIST) Criteria
Assessments were made based on objective tumor measurements of the lesions as recorded in the case report form. In inflammatory cancer, progressive disease (PD) was defined as progression of any of the 2 signs of breast edema and erythema. In non-inflammatory cancer, PD was concluded if either the investigator judged the participant as having progressed at any time prior to surgery, or there was at least a 20% increase in the sum of target lesions (TLs), any new lesion, or clear progression of any nontarget lesion (NTLs). Clear progression of any NTL was defined as at least a 20% increase in the sum of NTLs compared to BL. PR was defined as at least a 30% decrease from BL in the sum of the longest diameter of TLs. CR was defined as no PD as assessed by the investigator and complete disappearance of all lesions.
Time frame: BL, Presurgery: Day 1 of Cycles 1-10
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HER2+ TC | Percentage of Participants Achieving Either Complete Response (CR) or Partial Response (PR) According to Modified Response Evaluation Criteria in Solid Tumors (RECIST) Criteria | 72.7 percentage of participants |
| HER2+ C | Percentage of Participants Achieving Either Complete Response (CR) or Partial Response (PR) According to Modified Response Evaluation Criteria in Solid Tumors (RECIST) Criteria | 66.4 percentage of participants |
| HER2- C | Percentage of Participants Achieving Either Complete Response (CR) or Partial Response (PR) According to Modified Response Evaluation Criteria in Solid Tumors (RECIST) Criteria | 65.6 percentage of participants |
p-value: 0.307795% CI: [-6.4, 19.1]Chi-squared
Secondary
Percentage of Participants Surviving at 1 Year
Time frame: BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HER2+ TC | Percentage of Participants Surviving at 1 Year | 100 percentage of participants |
| HER2+ C | Percentage of Participants Surviving at 1 Year | 99 percentage of participants |
| HER2- C | Percentage of Participants Surviving at 1 Year | 97 percentage of participants |
Secondary
Percentage of Participants Surviving at 2 Years
Time frame: BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HER2+ TC | Percentage of Participants Surviving at 2 Years | 95 percentage of participants |
| HER2+ C | Percentage of Participants Surviving at 2 Years | 88 percentage of participants |
| HER2- C | Percentage of Participants Surviving at 2 Years | 90 percentage of participants |
Secondary
Percentage of Participants Surviving at 3 Years
Time frame: BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HER2+ TC | Percentage of Participants Surviving at 3 Years | 85 percentage of participants |
| HER2+ C | Percentage of Participants Surviving at 3 Years | 78 percentage of participants |
| HER2- C | Percentage of Participants Surviving at 3 Years | 85 percentage of participants |
Secondary
Percentage of Participants With Breast Pathological Complete Response (bpCR)
bpCR was defined as an absence of any invasive cancer cell of the primary tumor at the time of major surgery after neoadjuvant chemotherapy with and without trastuzumab.
Time frame: BL, Day 1 of Cycles 1-10 (pre-surgery)
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HER2+ TC | Percentage of Participants With Breast Pathological Complete Response (bpCR) | 44.3 percentage of participants |
| HER2+ C | Percentage of Participants With Breast Pathological Complete Response (bpCR) | 26.7 percentage of participants |
| HER2- C | Percentage of Participants With Breast Pathological Complete Response (bpCR) | 19.2 percentage of participants |
p-value: 0.005195% CI: [5, 30.2]Chi-squared
Secondary
Percentage of Participants With Total Pathological Complete Response (tpCR)
tpCR was defined as a determination of bpCR and an absence of positive axillary nodes on pathology.
Time frame: BL, Day 1 of Cycles 1-10 (pre-surgery)
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HER2+ TC | Percentage of Participants With Total Pathological Complete Response (tpCR) | 40.0 percentage of participants |
| HER2+ C | Percentage of Participants With Total Pathological Complete Response (tpCR) | 20.7 percentage of participants |
| HER2- C | Percentage of Participants With Total Pathological Complete Response (tpCR) | 18.2 percentage of participants |
p-value: 0.001495% CI: [7.2, 31.4]Chi-squared