Breast Neoplasms
Conditions
Brief summary
This phase II trial studies the efficacy of trastuzumab treatment in breast cancer patients with stage II-III human epidermal growth factor receptor 2 (HER2)-negative tumors and HER2-expressing bone marrow disseminated tumor cells (DTCs). Administering targeted trastuzumab therapy to these patients may result in the elimination of HER2 expressing disseminated tumor cells and improved disease free survival.
Interventions
DRUGDoxorubicin
BIOLOGICALTrastuzumab
DRUGCyclophosphamide
DRUGPaclitaxel
DRUGEpirubicin
DRUGDocetaxel
DRUGCarboplatin
DRUGFluorouracil
Sponsors
Genentech, Inc.
Washington University School of Medicine
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
Pre-Registration Inclusion Criteria: * Histologically confirmed HER2-negative primary invasive ductal or invasive lobular breast carcinoma. For patients enrolling for neoadjuvant treatment, diagnosis must be clinical stage II or III; for patients enrolling for adjuvant treatment, diagnosis must be pathologic stage IIA to IIIC. Standard HER2 testing will be performed in the surgical specimen at Washington University according to the standard of care in the Department of Pathology. A HER2-negative primary breast cancer sample from a patient eligible for randomization should have a HER2 IHC score of 0 or 1+ Those patients with IHC score of 2+ should be HER2 FISH-negative in standard testing. Patient will have undergone staging studies including a CT of the chest/abdomen/pelvis and bone scan and/or PET scan either prior to the initiation of treatment or prior to entry into the trial. In addition, patients with non-metastatic, HER2-negative, recurrent tumors who need chemotherapy are eligible. * Planning to receive best practice adjuvant or neoadjuvant chemotherapy according to institutional guidelines. Adjuvant tamoxifen or aromatase inhibitors treatment will be allowed for hormone receptor-positive patients. Patients who have failed neoadjuvant endocrine therapy will also be eligible. * At least 18 years old. * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. * Patient (or legally authorized representative) must be able to understand and willing to sign a written informed consent document. Pre-Registration
Exclusion criteria
* Prior chemotherapy for this cancer (excluding initiation of best practice chemotherapy to be given as standard of care as described in this protocol, which may be initiated after the pre-registration bone marrow collection but before final confirmation of eligibility and randomization). * Previous treatment with trastuzumab or any other Her2 targeted therapy. * Presence of an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Registration Inclusion Criteria * Presence of bone marrow ERBB2 overexpressing DTCs at the time of diagnosis; bone marrow aspiration will be performed in consented patients to evaluate DTCs following pre-registration provided patients meet all eligibility criteria as described in this section. * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. * Adequate cardiac function as demonstrated by LVEF of \>55% performed no more than 4 weeks prior to randomization. * Normal organ and marrow function as defined below: * leukocytes ≥3,000/mcL * absolute neutrophil count ≥1,500/mcL * platelets ≥100,000/mcL * hemoglobin ≥ 10 g/dL * total bilirubin within institutional upper limits of normal unless related to primary disease * AST(SGOT)/ALT(SGPT) ≤2.0 X institutional upper limit of normal * Creatinine ≤ 1.5 institutional upper limits of normal OR creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal * If a woman of childbearing potential, patient must use two forms of effective contraception for a minimum of 6 months following trastuzumab. Effective methods of birth control include use of established oral, injected, or implanted hormonal methods of birth control, IUD, IUS, and condoms. Registration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Disease Recurrence | Up to 3 years after completion of treatment (estimated to be 4 years) | -Disease recurrence is defined as the documented appearance of local (breast, chest wall, axillary, supraclavicular nodes) or distant disease. |
| Death Rate | Up to 3 years after completion of treatment (estimated to be 4 years) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Elimination of ERBB2 Overexpressing Bone Marrow DTCs | Before treatment and after treatment (estimated to be 6-18 months) | Bone marrow disseminated tumor cells (DTCs) are evaluated by RT-PCR performed on specimens collected 6-18 months apart (one before and one after therapy). The proportion of samples turned negative after therapy will be calculated. Samples will be considered negative for ERBB2-expression if expression from bone marrow collected from each iliac crest is less than 2 standard deviations above the ERBB2-level in pooled normal bone marrow specimens. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Definitive Therapy) Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are:
* doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel
* docetaxel plus cyclophosphamide
* single-agent paclitaxel
* docetaxel plus carboplatin
* fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel | 4 |
| Arm II (Definitive Therapy, Trastuzumab) Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are:
* doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel
* docetaxel plus cyclophosphamide
* single-agent paclitaxel
* docetaxel plus carboplatin
* fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel
Patients will also receive trastuzumab IV over 30-90 minutes for 52 weeks starting such that there is a minimum of 8 weeks of overlap with the standard of care chemotherapy. Trastuzumab may be given weekly, every 2 weeks, or every 3 weeks while overlapping with standard of care chemotherapy. Trastuzumab will be given every 3 weeks after all standard of care chemotherapy has concluded. Treatment continues in the absence of disease progression or unacceptable toxicity. | 3 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Arm I (Definitive Therapy) | Total | Arm II (Definitive Therapy, Trastuzumab) |
|---|---|---|---|
| Age, Continuous | 63.5 years | 63 years | 58 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 7 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 6 Participants | 2 Participants |
| Region of Enrollment United States | 4 participants | 7 participants | 3 participants |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 3 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 | 1 / 3 | 0 / 3 |
| other Total, other adverse events | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 |
Outcome results
Primary
Death Rate
Time frame: Up to 3 years after completion of treatment (estimated to be 4 years)
Population: One participant in Arm 1 was not evaluable as they withdrew before receiving any treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Definitive Therapy) | Death Rate | 1 Participants |
| Arm II (Definitive Therapy, Trastuzumab) | Death Rate | 0 Participants |
Primary
Number of Participants With Disease Recurrence
-Disease recurrence is defined as the documented appearance of local (breast, chest wall, axillary, supraclavicular nodes) or distant disease.
Time frame: Up to 3 years after completion of treatment (estimated to be 4 years)
Population: One participant in Arm 1 was not evaluable as they withdrew before receiving any treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Definitive Therapy) | Number of Participants With Disease Recurrence | 1 Participants |
| Arm II (Definitive Therapy, Trastuzumab) | Number of Participants With Disease Recurrence | 0 Participants |
Secondary
Elimination of ERBB2 Overexpressing Bone Marrow DTCs
Bone marrow disseminated tumor cells (DTCs) are evaluated by RT-PCR performed on specimens collected 6-18 months apart (one before and one after therapy). The proportion of samples turned negative after therapy will be calculated. Samples will be considered negative for ERBB2-expression if expression from bone marrow collected from each iliac crest is less than 2 standard deviations above the ERBB2-level in pooled normal bone marrow specimens.
Time frame: Before treatment and after treatment (estimated to be 6-18 months)
Population: Data was not collected.