Estrogen Receptor Negative, Estrogen Receptor Positive, HER2/Neu Negative, HER2/Neu Positive, Invasive Breast Carcinoma, Progesterone Receptor Negative, Progesterone Receptor Positive, Stage IA Breast Cancer, Stage IIA Breast Cancer, Stage IIB Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage III Breast Cancer, Stage IIIC Breast Cancer, Triple-Negative Breast Carcinoma
Conditions
Brief summary
This phase II trial studies the side effects and how well giving paclitaxel and cyclophosphamide with or without trastuzumab before surgery works in treating patients with previously untreated breast cancer. Drugs used in chemotherapy, such as paclitaxel and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as trastuzumab, may block tumor growth in different ways by targeting certain cells. Giving combination chemotherapy with or without trastuzumab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the toxicities and tolerability of a neoadjuvant dose-dense regimen cyclophosphamide and paclitaxel with or without trastuzumab/radiation therapy (as clinically indicated) in patients with newly diagnosed stage T1cN0 and II-III breast cancer; followed by maintenance trastuzumab in human epidermal growth factor receptor 2 (HER2) positive OR adriamycin (doxorubicin hydrochloride) followed by radiation therapy (RT) in stage II-III triple negative HER2 (-), estrogen receptor (ER) (-), progesterone receptor (PR) (-) stage T1cN0 and II-III breast cancer patients. II. To determine the pathological complete response rate (pCR) of this treatment regimen. III. To identify possible gene expression profile signatures from whole genome array analysis that correlate with clinical response/resistance to chemotherapy as measured by pathologic complete response rate (pCR). OUTLINE: NEOADJUVANT THERAPY: Patients receive paclitaxel intravenously (IV) over 3 hours and cyclophosphamide IV over 1 hour on day 1. Patients with HER2-positive cancer also receive trastuzumab IV over 30 minutes on day 1. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients without metastasis undergo mastectomy or breast conserving surgery 4-8 weeks later. POST-SURGERY/SYSTEMIC THERAPY: HER2-POSITIVE PATIENTS: Patients receive standard radiation therapy. Patients also receive trastuzumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. ER/PR POSITIVE PATIENTS: Patients receive standard adjuvant hormonal or endocrine therapy. STAGE T1cN0 TRIPLE NEGATIVE PATIENTS: Patients receive standard radiation therapy. STAGE II-III TRIPLE NEGATIVE PATIENTS: Patients receive doxorubicin hydrochloride IV over 15 minutes on day 1. Treatment repeats every 14 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients also receive standard radiation therapy. After completion of study treatment, patients are followed up every 3 months for 2 years, and then annually thereafter for 5 years.
Interventions
DRUGCyclophosphamide
Given IV
DRUGDoxorubicin Hydrochloride
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGPaclitaxel
Given IV
RADIATIONRadiation Therapy
Undergo RT
PROCEDURETherapeutic Conventional Surgery
Undergo mastectomy or breast conserving surgery
BIOLOGICALTrastuzumab
Given IV
Sponsors
University of Nebraska
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Women with histologically proven invasive breast cancer without distant metastases; a clinical tumor classification of tumor size must be at least 1 cm with or without clinical pathologic evidence of positive nodes * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * At least one lesion that can be accurately measured in two dimensions utilizing mammogram, ultrasound, or magnetic resonance imaging (MRI) images to define specific size and validate complete clinical and pathologic response * Patients who received radiation therapy \> 5 years ago for malignancies other than breast cancer and whose radiation therapy field is not overlapping with the 20% isodose line of current radiation field are eligible, provided that radiation therapy was completed \> 5 years ago and that there is no evidence of the second malignancy at the time of study entry * Absolute neutrophil count greater than or equal to 1,500/mcl * Platelet count equal to or greater than 150,000/mcl * Alkaline phosphatase equal or less than 1.5 times the upper limit of normal (ULN) * Total bilirubin equal to or less than 1.5 times the ULN * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) no greater than 1.5 times the ULN * Creatinine less than 1.5 times the ULN * All included patients must have normal cardiac function as defined by an ejection fraction of \>= 50% and no decrease in wall motion by echocardiogram * The patient must be aware of the neoplastic nature of his/her disease and willingly provide written, informed consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts * Women of reproductive potential must be non-pregnant and non-nursing and must agree to employ an effective barrier method of birth control throughout the study and for up to 6 months following treatment * Women of child-bearing potential must have a negative pregnancy test within 7 days of initiating study; (no childbearing potential is defined as age 55 years or older and no menses for two years or any age with surgical removal of the uterus and/or both ovaries)
Exclusion criteria
* Any patient with inflammatory breast cancer or stage IV or confirmed metastatic disease * Patients who have had any prior chemotherapy, or endocrine therapy for the treatment of breast cancer or any other cancer * Patients who cannot undergo surgery * Patients with a known or documented anaphylactic reaction or allergy to any of chemotherapy agents used in this protocol, or to antiemetics appropriate for administration in conjunction with protocol-directed therapy * Uncontrolled inter-current illness including, but not limited to ongoing or active infection requiring intravenous antibiotics, symptomatic congestive heart failure, unstable angina pectoris, or serious, uncontrolled cardiac arrhythmia, that might jeopardize the ability of the patient to receive the therapy program outlined in this protocol with reasonable safety * Patients with preexisting grade II peripheral neuropathy * Pregnant and nursing women are excluded from this study * Patients with prior malignancy will be excluded except for adequately treated basal cell or squamous cell skin cancer, adequately treated noninvasive carcinomas * Inability to cooperate with treatment protocol * Patients with known human immunodeficiency virus (HIV) infection, infectious hepatitis, type A, B or C, active hepatitis, or hepatic insufficiency * Patients may not be receiving or have received any other investigational agents during/or within 1 month prior * Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form * Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Incidence of Toxicities, Graded According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Up to 30 days after completion of study treatment, maximum of 114 days | Number of participants in each subset (Her2 positive and Her2 negative) who experience at least one adverse event \[overall incidence of toxicities, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0\]. |
| Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | Up to 30 days after completion of study treatment, maximum of 114 days | Results reported as total events per grade for human epidermal growth factor receptor 2 (HER2)negative and HER2 positive (Overall severity of toxicities, graded according to the NCI CTCAE version 4.0). |
| Number of Participants in the Subgroups Who Had a Pathologic Complete Response (pCR) | Up to 12 weeks (after the first 6 courses of treatment), maximum of 168 days | The number of participants in the subgroups who had a pathologic complete response (pCR) determined from the surgical specimen and defined as the absence of invasive carcinoma in both the breast and axilla at microscopic examination of the resection specimen, regardless of the presence of carcinoma in situ. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Complete Response | up to 2 years | The absence of all detectable cancer after treatment is complete |
| Failure- Free Survival (FFS) | The time from the date of administration of study drug to the date of first appearance of tumor lesions by imaging, or death, assessed up to 2 years | The analysis will be based on Kaplan- Meier estimates. FFS will be summarized overall and for human epidermal growth factor receptor 2 (HER2) + and HER- subsets |
| Identification of Gene Expression Profile Signatures That Correlate With Clinical Response as Measured by pCR | Up to 2 years | The number of the identified mutated genes, the frequency of each gene being validated by reverse transcriptase-polymerase chain reaction (RT-PCR)/Sanger sequencing method, and the functions of these identified genes will be descriptively summarized. |
| Overall Survival (OS) | The time from the date of the date of administration of study drug to the date of death from any cause, assessed up to 2 years | The analysis will be based on Kaplan-Meier estimates. OS will be summarized overall and for HER+ and HER- subsets. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAmulya C Yellala, MD
University of Nebraska
Participant flow
Pre-assignment details
99 subjects were enrolled but 7 were screen fails (after signing consent) so only 92 started.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Chemotherapy, Surgery, Post-operative Therapy) See Detailed Description
Cyclophosphamide: Given IV
Doxorubicin Hydrochloride: Given IV
Laboratory Biomarker Analysis: Correlative studies
Paclitaxel: Given IV
Radiation Therapy: Undergo RT
Therapeutic Conventional Surgery: Undergo mastectomy or breast conserving surgery
Trastuzumab: Given IV | 92 |
| Total | 92 |
Baseline characteristics
| Characteristic | Treatment (Chemotherapy, Surgery, Post-operative Therapy) |
|---|---|
| Age, Continuous | 57.65 Years STANDARD_DEVIATION 10.19 |
| ER Status Negative | 35 Participants |
| ER Status Positive | 57 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 89 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Her-2 NEU Status (human epidermal growth factor receptor) Negative | 73 Participants |
| Her-2 NEU Status (human epidermal growth factor receptor) Positive | 19 Participants |
| PR Status (progesterone receptors) Negative | 49 Participants |
| PR Status (progesterone receptors) Positive | 43 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 80 Participants |
| Sex: Female, Male Female | 92 Participants |
| Sex: Female, Male Male | 0 Participants |
| Stage of Cancer Stage I | 22 Participants |
| Stage of Cancer Stage II | 65 Participants |
| Stage of Cancer Stage IIIA | 5 Participants |
| Treatment paclitaxel & cyclophosphamide (PC) | 56 Participants |
| Treatment paclitaxel & cyclophosphamide (PC) + Adriamycin | 17 Participants |
| Treatment paclitaxel, cyclophosphamide & trastuzumab (PCH) | 19 Participants |
| Triple Negative No | 63 Participants |
| Triple Negative Yes | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 92 |
| other Total, other adverse events | 92 / 92 |
| serious Total, serious adverse events | 16 / 92 |
Outcome results
Primary
Number of Participants in the Subgroups Who Had a Pathologic Complete Response (pCR)
The number of participants in the subgroups who had a pathologic complete response (pCR) determined from the surgical specimen and defined as the absence of invasive carcinoma in both the breast and axilla at microscopic examination of the resection specimen, regardless of the presence of carcinoma in situ.
Time frame: Up to 12 weeks (after the first 6 courses of treatment), maximum of 168 days
Population: Participants who completed 6 courses of treatment (87). 16 subjects were not evaluated. Total of 71 participants were evaluated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Her-2 Negative | Number of Participants in the Subgroups Who Had a Pathologic Complete Response (pCR) | 13 participants |
| Her-2 Positive | Number of Participants in the Subgroups Who Had a Pathologic Complete Response (pCR) | 2 participants |
Primary
Overall Incidence of Toxicities, Graded According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
Number of participants in each subset (Her2 positive and Her2 negative) who experience at least one adverse event \[overall incidence of toxicities, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0\].
Time frame: Up to 30 days after completion of study treatment, maximum of 114 days
Population: All subjects who received at least one cycle of treatment and experienced an adverse event.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Her-2 Negative | Overall Incidence of Toxicities, Graded According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | 73 Participants |
| Her-2 Positive | Overall Incidence of Toxicities, Graded According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | 19 Participants |
Primary
Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0
Results reported as total events per grade for human epidermal growth factor receptor 2 (HER2)negative and HER2 positive (Overall severity of toxicities, graded according to the NCI CTCAE version 4.0).
Time frame: Up to 30 days after completion of study treatment, maximum of 114 days
Population: Participant events were analyzed for each group-Her-2 Negative and Her-2 Positive
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Her-2 Negative | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | Non-SAE grade 4 | 11 Events |
| Her-2 Negative | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | SAE grade 1 | 1 Events |
| Her-2 Negative | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | SAE grade 2 | 10 Events |
| Her-2 Negative | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | SAE grade 3 | 22 Events |
| Her-2 Negative | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | SAE grade 4 | 2 Events |
| Her-2 Negative | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | SAE grade 5 | 1 Events |
| Her-2 Negative | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | Non-SAE grade 1 | 1286 Events |
| Her-2 Negative | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | Non-SAE grade 3 | 93 Events |
| Her-2 Negative | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | Non-SAE grade 2 | 390 Events |
| Her-2 Positive | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | Non-SAE grade 4 | 4 Events |
| Her-2 Positive | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | SAE grade 5 | 1 Events |
| Her-2 Positive | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | SAE grade 1 | 9 Events |
| Her-2 Positive | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | Non-SAE grade 3 | 23 Events |
| Her-2 Positive | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | SAE grade 2 | 4 Events |
| Her-2 Positive | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | Non-SAE grade 1 | 302 Events |
| Her-2 Positive | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | SAE grade 3 | 8 Events |
| Her-2 Positive | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | Non-SAE grade 2 | 143 Events |
| Her-2 Positive | Overall Severity of Toxicities, Graded According to the NCI CTCAE Version 4.0 | SAE grade 4 | 2 Events |
Secondary
Clinical Complete Response
The absence of all detectable cancer after treatment is complete.
Time frame: Up to 2 years
Secondary
Failure-free Survival (FFS)
The analysis will be based on Kaplan-Meier estimates. FFS will be summarized overall and for human epidermal growth factor receptor 2 (HER2)+ and HER- subsets.
Time frame: The time from the date of administration of study drug to the date of first appearance of tumor lesions by imaging, or death, assessed up to 2 years
Secondary
Identification of Gene Expression Profile Signatures That Correlate With Clinical Response as Measured by pCR
The number of the identified mutated genes, the frequency of each gene being validated by reverse transcriptase-polymerase chain reaction (RT-PCR)/Sanger sequencing method, and the functions of these identified genes will be descriptively summarized.
Time frame: Up to 2 years
Secondary
Overall Survival (OAS)
The analysis will be based on Kaplan-Meier estimates. OAS will be summarized overall and for HER+ and HER- subsets.
Time frame: The time from the date of the date of administration of study drug to the date of death from any cause, assessed up to 2 years