Breast Cancer
Conditions
Keywords
Neoadjuvant Breast Cancer, HER2 positive Breast Cancer
Brief summary
This is a randomized, open label Phase II neoadjuvant study comparing the efficacy and safety of trastuzumab emtansine (T-DM1) plus lapatinib (L)followed by abraxane (A) versus trastuzumab plus pertuzumab followed by paclitaxel in patients with HER2-overexpressing breast cancer.
Detailed description
This is a randomized, open label Phase II neoadjuvant study comparing the efficacy and safety of trastuzumab emtansine (T-DM1) plus lapatinib (L) followed by abraxane (A) versus trastuzumab plus pertuzumab followed by paclitaxel in patients with HER2-overexpressing breast cancer. Patients will be randomized (1:1) to one of the two treatment arms: arm 1, trastuzumab emtansine plus lapatinib for 6 weeks, followed by trastuzumab emtansine plus lapatinib plus abraxane for 12 weeks; arm 2, trastuzumab plus pertuzumab for six weeks, followed by trastuzumab plus pertuzumab plus paclitaxel for 12 weeks. Patients will undergo surgery after neoadjuvant therapy. All patients will have a core needle biopsy at baseline, after week 6, and at the time of disease progression. Surgical specimens will be obtained after week 18.
Interventions
DRUGLapatinib
Dual tyrosine kinase inhibitor (HER2 and EGFR)
DRUGAbraxane
albumin-bound paclitaxel. chemotherapy - microtubule inhibitor.
DRUGPaclitaxel
chemotherapy - microtubule inhibitor
DRUGPertuzumab
anti-HER2 monoclonal antibody
DRUGT-DM1
antibody-drug conjugate of trastuzumab and emtansine
DRUGTrastuzumab
anti-Her2 monoclonal antibody
Sponsors
Celgene Corporation
Novartis
The Methodist Hospital Research Institute
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 gender; * Age ≥18 years; * Performance Status- Eastern Cooperative Oncology Group (ECOG) 0-1 * Histologically confirmed invasive breast cancer: * Primary tumor greater than 1 cm diameter, measured by clinical examination and mammography or ultrasound. * Any N, * No evidence of metastasis (M0) (isolated supra-clavicular node involvement allowed); * Over expression and/or amplification of HER2 in the invasive component of the primary tumor and confirmed by a certified laboratory prior to randomization. * Known hormone receptor status. * Hematopoietic status: * CBC not less than .75 of institutional lower limit. Absolute neutrophil count ≥ 1,5 x 10\^9/L, Platelet count ≥ 100 x 10\^9/L, Hemoglobin at least 9 g/dl, * Hepatic status: Serum total bilirubin ≤ 2 x upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher serum total bilirubin (\< 1.5 x ULN) is allowed, Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 3.5 times ULN, Alkaline phosphatase ≤ 2.5 times ULN, • Renal status: Creatinine ≤ 1.5mg/dL, • Cardiovascular: Baseline left ventricular ejection fraction (LVEF) ³ ≥50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan, * Negative serum or urine β-hCG pregnancy test at screening for patients of childbearing potential within 2-weeks (preferably 7 days) prior to randomization. * Fertile patients must use effective contraception (barrier method - condoms, diaphragm - also in conjunction with spermicidal jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not allowed) * Signed informed consent form (ICF) * Patient accepts to make available tumor samples for submission to central laboratory to conduct translational studies as part of this protocol.
Exclusion criteria
* Previous (less than 5 years) or current history of malignant neoplasms, except for curatively treated: Basal and squamous cell carcinoma of the skin; Carcinoma in situ of the cervix. * Patients with a prior malignancy diagnosed more than 5 years prior to randomization may enter the study. * Preexisting peripheral neuropathy ≥ grade 2 * Known history of uncontrolled or symptomatic angina, clinically significant arrhythmias, congestive heart failure, transmural myocardial infarction, uncontrolled hypertension (≥180/110), unstable diabetes mellitus, dyspnea at rest, or chronic therapy with oxygen; * Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject's safety; * Unresolved or unstable, serious adverse events from prior administration of another investigational drug; * Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of ICF; * Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded; * Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy other than the trial therapies); * Concurrent treatment with an investigational agent or participation in another therapeutic clinical trial; * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trastuzumab Emtansine, trastuzumab, lapatinib, paclitaxel, abraxane or their components; * Pregnant or lactating women; * Concomitant use of CYP3A4 inhibitors or inducers * Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol * Patients have an active infection and require IV or oral antibiotics. * Pregnant or breast-feeding women * Patients unwilling or unable to comply with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response (pCR) RCB-0 or RCB-1 | From date of randomization until the date of surgery, approximately 16 weeks | To evaluate the pathological complete response (pCR) in the breast after treatment with Trastuzumab Emtansine plus Lapatinib follow by Abraxane in women with HER2 Neu over-expressed breast cancer patients per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR., or similar definition that is accurate and appropriate. Residual cancer burden (RCB)-0 was synonymous with pCR, indicating no residual disease present. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Breast Imaging Response to Treatment: Number of Eventual Responders in Standard Arm | From date of randomization until 6 weeks post treatment | To determine the change in tumor size by MRI at 6 weeks post treatment using RECIST v1.0. Criteria. Since all patients in the experimental arm achieved RCB-0 or RCB-1 (pCR), changes in tumor size by MRI were only evaluated in patients on the standard arm. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Determine Predictive Markers | approximately 1 year | To determine predictive markers for sensitivity and resistance to Trastuzumab Emtansine when combined with Lapatinib follow by Abraxane |
Countries
United States
Participant flow
Recruitment details
16 patients were enrolled into each arm of the study, for a total of 32 patients. The trial was closed early due to superiority, with 14 patients completing the experimental arm and 16 patients completing the standard, control arm.
Participants by arm
| Arm | Count |
|---|---|
| T-DM1 + Lapatinib + Abraxane T-DM1 intravenously (IV) every three weeks plus Lapatinib orally once daily for 6 weeks followed by abraxane IV weekly for 12 weeks.
T-DM1: antibody-drug conjugate of trastuzumab and emtansine
Lapatinib: Dual tyrosine kinase inhibitor (HER2 and EGFR)
Abraxane: albumin-bound paclitaxel. chemotherapy - microtubule inhibitor. | 14 |
| Trastuzumab + Pertuzumab + Paclitaxel Trastuzumab IV weekly plus pertuzumab IV every 3 weeks for 6 weeks, followed by paclitaxel IV weekly for 12 weeks.
Trastuzumab: anti-Her2 monoclonal antibody
Paclitaxel: chemotherapy - microtubule inhibitor
Pertuzumab: anti-HER2 monoclonal antibody | 16 |
| Total | 30 |
Baseline characteristics
| Characteristic | Total | T-DM1 + Lapatinib + Abraxane | Trastuzumab + Pertuzumab + Paclitaxel |
|---|---|---|---|
| Age, Continuous | 55.1 years | 53.1 years | 57.2 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 5 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 9 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Invasive ductal carcinoma | 27 Participants | 13 Participants | 14 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 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 | 27 Participants | 12 Participants | 15 Participants |
| Region of Enrollment United States | 30 participants | 14 participants | 16 participants |
| Sex: Female, Male Female | 30 Participants | 14 Participants | 16 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Tumor grade: 2 | 15 Participants | 7 Participants | 8 Participants |
| Tumor grade: 3 | 15 Participants | 7 Participants | 8 Participants |
| Tumor stage: II | 15 Participants | 7 Participants | 8 Participants |
| Tumor stage: III | 15 Participants | 7 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 16 |
| other Total, other adverse events | 14 / 14 | 16 / 16 |
| serious Total, serious adverse events | 0 / 14 | 0 / 16 |
Outcome results
Primary
Pathological Complete Response (pCR) RCB-0 or RCB-1
To evaluate the pathological complete response (pCR) in the breast after treatment with Trastuzumab Emtansine plus Lapatinib follow by Abraxane in women with HER2 Neu over-expressed breast cancer patients per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR., or similar definition that is accurate and appropriate. Residual cancer burden (RCB)-0 was synonymous with pCR, indicating no residual disease present.
Time frame: From date of randomization until the date of surgery, approximately 16 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T-DM1 + Lapatinib + Abraxane | Pathological Complete Response (pCR) RCB-0 or RCB-1 | 14 Participants |
| Trastuzumab + Pertuzumab + Paclitaxel | Pathological Complete Response (pCR) RCB-0 or RCB-1 | 10 Participants |
p-value: <0.01Fisher Exact
Secondary
Breast Imaging Response to Treatment: Number of Eventual Responders in Standard Arm
To determine the change in tumor size by MRI at 6 weeks post treatment using RECIST v1.0. Criteria. Since all patients in the experimental arm achieved RCB-0 or RCB-1 (pCR), changes in tumor size by MRI were only evaluated in patients on the standard arm.
Time frame: From date of randomization until 6 weeks post treatment
Population: Since all patients in the experimental arm achieved RCB-0 or RCB-1 (pCR), changes in tumor size by MRI were only evaluated in patients on the standard arm. Of 16 patients enrolled in the standard arm, 5 had incomplete imaging data. Therefore, 11 patients were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T-DM1 + Lapatinib + Abraxane | Breast Imaging Response to Treatment: Number of Eventual Responders in Standard Arm | 5 Participants |
Other Pre-specified
Determine Predictive Markers
To determine predictive markers for sensitivity and resistance to Trastuzumab Emtansine when combined with Lapatinib follow by Abraxane
Time frame: approximately 1 year