Her2-Positive Breast Cancer
Conditions
Brief summary
The main goal of this clinical trial is to test if adding pertuzumab (Perjeta), improves the anticancer activity of the combination chemotherapy regimen of trastuzumab (Herceptin) concomitant with paclitaxel, 5-fluorouracil, epirubicin, and cyclophosphamide (T-FEC). The study will also test the safety of this therapy.
Detailed description
Subjects will receive 6 months of T-FEC chemotherapy concomitant with trastuzumab and pertuzumab before surgery. Subsequently, subjects will undergo surgery to remove any cancer from the breast and axillary lymph nodes that may have survived the chemotherapy. It is expected that the majority of women will have no viable cancer left in the breast or lymph nodes by the time all chemotherapy is completed.
Interventions
DRUGCyclophosphamide
Administered at 500mg/m2 for every 3 weeks during weeks 13-24 (4 doses total).
DRUGPertuzumab
First dose is 840mg, maintenance dose is 420mg. Pertuzumab will be administered once every 3 weeks for 24 weeks (8 doses total)
DRUGTrastuzumab
For weeks 1-12, first dose is 4 mg/kg, maintenance dose is 2 mg/kg administered every week (12 doses total). For weeks 13-24, dose is 6mg/kg administered every 3 weeks (4 doses total).
DRUGPaclitaxel
Administered at 80mg/m2 every week from week 1 to 12 (12 doses total).
DRUG5-fluorouracil
Administered at 500 mg/m2 for every 3 weeks during weeks 13-24 (4 doses total).
DRUGEpirubicin
Administered at 75mg/m2 every 3 weeks during weeks 13-24 (4 doses total).
Sponsors
Genentech, Inc.
Yale University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
\- Patients with histologically confirmed stage I-III, HER2-positive invasive breast cancer for which adjuvant/neoadjuvant chemotherapy is indicated based on physician judgment following NCCN practice guidelines. HER2 overexpression or amplification will be based on local test results and is defined as either: (i) IHC staining of 3+ (uniform, intense membrane staining) in greater than or equal to 10% of invasive tumor cells or, (ii) Fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus or, (iii) FISH ratio (HER2 gene signals to chromosome 17 signals) of greater than or equal to 2.0. * Patients with synchronous bilateral breast cancers are eligible if at least one of the tumors is HER2-positive. * Left Ventricular Ejection Fraction (LVEF) greater or equal to 50% at baseline as determined by either ECHO or MUGA, or within the institution's normal limits. * Women of childbearing potential must have a negative pregnancy test (serum or urine beta HCG) prior to initiation of chemotherapy. Both female and male breast cancer patients who are sexually active have to agree to practice contraception while participating in the trial and for 3 month after completion of therapy. * Adequate bone marrow function as indicated by the following: * ANC greater than or equal to 1500/uL * Platelets greater than or equal to 100,000/uL * Hemoglobin greater than or equal to 10 g/dL * Adequate renal function, as indicated by creatinine less than or equal to 1.5 times upper limit of normal (ULN) * Adequate liver function, as indicated by bilirubin less than or equal to 1.5 X ULN and AST or ALT less than or equal to 2x ULN. * Signed informed consent.
Exclusion criteria
Patients will be excluded from the study based on any of the following criteria: * Patients who underwent partial excisional biopsy, lumpectomy, segmental mastectomy, modified radical mastectomy or sentinel node biopsy and, therefore cannot be assessed for pathologic response accurately. * Patients who are high risk for developing the following anthracycline, paclitaxel, trastuzumab or pertuzumab related toxicities including: History of congestive heart failure, myocardial infarction or cardiomyopathy, uncontrolled hypertension despite adequate medications Pre-existing peripheral neuropathy \> grade 3 Prior anthracycline therapy Known hypersensitivity to any of the study medications Patients older than age 65 due to increased risk of cardiotoxicity * Active infection requiring systemic antibiotic therapy. * Pregnant or lactating women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With a Pathologic Complete Response Rate | 20 weeks | To estimate the pathologic complete response rate (pCR) when pertuzumab is added to weekly trastuzumab/paclitaxel followed by trastuzumab/5-fluorouracil, epirubicin and cyclophosphamide neoadjuvant chemotherapy in HER2-positive breast cancer. This study will assess pCR rates separately in ER+ and ER- cancers. Pathologic complete response is defined as no evidence of viable invasive tumor cells at the primary tumor site and axillary lymph nodes in the surgical specimen. Residual Disease (RD) is defined as: Any invasive cancer in the breast or axillary lymph nodes in the surgical specimen. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cardiac Safety | Up to 1 year post surgery | To assess the safety of the regimen, cardiac safety was measured by rates of clinically symptomatic congestive heart failure, asymptomatic decrease in LVEF \>10%, and decrease of LVEF below normal level. This was assessed up to 1 year following surgery. |
| Count of Patients With Clinical Response | Up to 28 weeks | To assess clinical response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, the number of patients are presented with a clinical response. |
| Residual Cancer Burden Score | Up to 28 weeks | To assess cancer burben, the Residual Cancer Burden (RCB) score was used. This score has a range of 0 - III, where III (3) is the worst level of burden. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Chemo Plus Pertuzumab,Trastuzumab During weeks 1-12, patients will receive pertuzumab, trastuzumab, and paclitaxel at the same time; during weeks 13-24 patients will receive pertuzumab and trastuzumab at the same time with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC).
Pertuzumab: First dose is 840mg, maintenance dose is 420mg. Pertuzumab will be administered once every 3 weeks for 24 weeks (8 doses total)
Trastuzumab: For weeks 1-12, first dose is 4 mg/kg, maintenance dose is 2 mg/kg administered every week (12 doses total).
For weeks 13-24, dose is 6mg/kg administered every 3 weeks (4 doses total).
Paclitaxel: Administered at 80mg/m2 every week from week 1 to 12 (12 doses total).
5-fluorouracil: Administered at 500 mg/m2 for every 3 weeks during weeks 13-24 (4 doses total).
Epirubicin: Administered at 75mg/m2 every 3 weeks during weeks 13-24 (4 doses total).
Cyclophosphamide: Administered at 500mg/m2 for every 3 weeks during weeks 13-24 (4 doses total). | 50 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Chemo Plus Pertuzumab,Trastuzumab |
|---|---|
| Age, Continuous | 51 years |
| Clinical Tumor Status T1: Tumor is 2 cm or smaller | 18 Participants |
| Clinical Tumor Status T2: Tumor is larger than 2 cm, but no larger than | 25 Participants |
| Clinical Tumor Status T3: Tumor is larger than 5 cm | 5 Participants |
| Clinical Tumor Status T4: Tumor is any size, but has spread | 2 Participants |
| HER2 status Fluorescence in situ hybridization (FISH) positive | 27 Participants |
| HER2 status Immunohistochemistry (IHC) 3+ | 23 Participants |
| Hormone receptor status Estrogen Receptor - / Progesterone Receptor - | 26 Participants |
| Hormone receptor status Estrogen Receptor + / Progesterone Receptor - | 4 Participants |
| Hormone receptor status Estrogen Receptor + / Progesterone Receptor + | 20 Participants |
| Race/Ethnicity, Customized Race/Ethnicity African American | 4 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Asian | 2 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Hispanic | 6 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Unknown | 2 Participants |
| Race/Ethnicity, Customized Race/Ethnicity White | 36 Participants |
| Region of Enrollment United States | 50 participants |
| Sex: Female, Male Female | 50 Participants |
| Sex: Female, Male Male | 0 Participants |
| Type of surgery Breast conserving surgery | 13 Participants |
| Type of surgery Mastectomy | 35 Participants |
| Type of surgery No surgery (dropped out of study) | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 50 |
| other Total, other adverse events | 50 / 50 |
| serious Total, serious adverse events | 6 / 50 |
Outcome results
Primary
Proportion of Participants With a Pathologic Complete Response Rate
To estimate the pathologic complete response rate (pCR) when pertuzumab is added to weekly trastuzumab/paclitaxel followed by trastuzumab/5-fluorouracil, epirubicin and cyclophosphamide neoadjuvant chemotherapy in HER2-positive breast cancer. This study will assess pCR rates separately in ER+ and ER- cancers. Pathologic complete response is defined as no evidence of viable invasive tumor cells at the primary tumor site and axillary lymph nodes in the surgical specimen. Residual Disease (RD) is defined as: Any invasive cancer in the breast or axillary lymph nodes in the surgical specimen.
Time frame: 20 weeks
Population: For ER-negative cancers, the maximum sample size was set to n = 25 and the regimen would be considered of interest if \> 20 patients achieve pCR. For ER-positive patients, the maximum sample size for the ER-positive cohort was set to 39 and the regimen would be considered of interest in this subgroup if \> 23 patients achieve pCR.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemo Plus Pertuzumab,Trastuzumab | Proportion of Participants With a Pathologic Complete Response Rate | HR Positive | .26 proportion of participants |
| Chemo Plus Pertuzumab,Trastuzumab | Proportion of Participants With a Pathologic Complete Response Rate | HR Negative | .80 proportion of participants |
Secondary
Cardiac Safety
To assess the safety of the regimen, cardiac safety was measured by rates of clinically symptomatic congestive heart failure, asymptomatic decrease in LVEF \>10%, and decrease of LVEF below normal level. This was assessed up to 1 year following surgery.
Time frame: Up to 1 year post surgery
Population: All patients are assessed in each arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Chemo Plus Pertuzumab,Trastuzumab | Cardiac Safety | 0 Participants |
| Chemo Plus Pertuzumab,Trastuzumab-asympomatic Decrease in LVEF | Cardiac Safety | 14 Participants |
| Chemo Plus Pertuzumab,Trastuzumab-LVEF Below Normal Level | Cardiac Safety | 1 Participants |
Secondary
Count of Patients With Clinical Response
To assess clinical response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, the number of patients are presented with a clinical response.
Time frame: Up to 28 weeks
Population: All patients are assessed by HR-positive or HR-negative status.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Chemo Plus Pertuzumab,Trastuzumab | Count of Patients With Clinical Response | 6 Participants |
| Chemo Plus Pertuzumab,Trastuzumab-asympomatic Decrease in LVEF | Count of Patients With Clinical Response | 20 Participants |
Secondary
Residual Cancer Burden Score
To assess cancer burben, the Residual Cancer Burden (RCB) score was used. This score has a range of 0 - III, where III (3) is the worst level of burden.
Time frame: Up to 28 weeks
Population: Total participants that were analyzed for this score (n=43).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Chemo Plus Pertuzumab,Trastuzumab | Residual Cancer Burden Score | RCB = 0 | 28 Participants |
| Chemo Plus Pertuzumab,Trastuzumab | Residual Cancer Burden Score | RCB = I (1) | 5 Participants |
| Chemo Plus Pertuzumab,Trastuzumab | Residual Cancer Burden Score | RCB = II (2) | 4 Participants |
| Chemo Plus Pertuzumab,Trastuzumab | Residual Cancer Burden Score | RCB = III (3) | 4 Participants |