Paclitaxel, Trastuzumab, and Pertuzumab before Surgery in Treating Patients with Inflammatory Breast Cancer
This phase II trial studies how well paclitaxel, trastuzumab, and pertuzumab before surgery work in treating patients with inflammatory breast cancer. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as trastuzumab and pertuzumab, may interfere with the ability of tumor cells to grow and spread. Pertuzumab may also stop the growth of breast cancer by blocking blood flow to the tumor. Giving paclitaxel, trastuzumab, and pertuzumab may work better in treating breast cancer.
Inclusion Criteria
- Participants must have histologically confirmed invasive breast cancer; all histologic subtypes are eligible
- HER2-positive breast cancer, defined by American Society of Clinical Oncology College of American Pathologists (ASCO CAP) 2013 guidelines * Immunohistochemistry (IHC) 3+ based on circumferential membrane staining that is complete, intense AND/OR * Fluorescence in situ hybridization (FISH) positive based on one of the following three criteria: ** Single-probe average HER2 copy number >= 6.0 signals/cell OR ** Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number >= 6.0signals/cell; OR ** Dual-probe HER2/CEP17 ratio >= 2.0
- Patients must have the clinical diagnosis of inflammatory breast cancer as evidenced by the onset of all signs and symptoms noted below within a 6 month time-period: * Erythema of the breast * Edema of the skin of the breast * Enlargement of the breast
- Patients must be without visceral or bone involvement with metastatic breast cancer on physical exam or any diagnostic study; patients with extensive nodal involvement classified as stage IV disease, are eligible
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- The effects of pertuzumab on the developing human fetus are unknown; for this reason and because these agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for at least 7 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
- Willingness to undergo a research biopsy of the affected breast * Biopsies may be done with local anesthesia or intravenous conscious sedation, according to standard institutional guidelines * If a biopsy requires general anesthesia, then it is not allowed on this protocol * Patients who undergo a research biopsy procedure for the purpose of this protocol, and in whom inadequate tissue is obtained, are still eligible and are not required to undergo a repeat biopsy in order to enter the study * Some patients may have had a clinically indicated biopsy upon recent disease progression and agreed to submit tissue to their institution’s frozen tumor bank; if the tissue was processed as specified in this protocol, no additional pre-treatment biopsy is required as that specimen can be used for the purposes of participation in this clinical trial
- Prior therapy for the treatment of breast cancer is not allowed
- Leukocytes > 3,000/mcL
- Absolute neutrophil count > 1,500/mcL
- Platelets > 100,000/mcL
- Total bilirubin within normal institutional limits
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 X institutional upper limit of normal
- Creatinine =< 1.5 x upper limit of normal (institutional ULN)
- Cardiac ejection fraction, as assessed by either multigated acquisition (MUGA) scan or echocardiogram, greater than or equal to 50%, within 28 days prior to registration
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria
- Participants may not be receiving any other investigational or commercial agents or therapies other than those described in this protocol to treat their malignancy
- Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
- Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs, resulting in dyspnea at rest
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to paclitaxel, trastuzumab, pertuzumab; patients with minor (grade 1 or 2) allergic reactions to these agents, controlled with standard supportive measures, are eligible
- 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
- Pregnant women are excluded from this study because paclitaxel, trastuzumab, and pertuzumab have the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is treated on study; these potential risks may also apply to other agents used in this study
- Individuals with a history of a different malignancy are ineligible except for the following circumstances; individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin
- Human immunodeficiency virus (HIV)-positive individuals on combination antiretroviral therapy are eligible so long as they meet all other criteria; HIV-positive individuals who are not on combination antiretroviral therapy are not eligible because these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated
- Patients with metastatic disease involving viscera or bones are ineligible; patients with extensive nodal involvement alone classified as stage IV disease, are eligible
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT01796197.
PRIMARY OBJECTIVES:
I. To determine pathologic complete response (pCR) rate after preoperative therapy with combination paclitaxel (T), trastuzumab (H) and pertuzumab (P) in human epidermal growth factor receptor (HER)2+ inflammatory breast cancer.
II. To assess the residual cancer burden (RCB) after preoperative therapy with combination paclitaxel (T), trastuzumab (H) and pertuzumab (P) in HER2+ inflammatory breast cancer.
SECONDARY OBJECTIVES:
I. To assess the toxicity of protocol therapy, including clinically-significant congestive heart failure (CHF).
II. To determine the efficacy of therapy defined as disease-free survival (DFS), time to treatment failure (TTF), and overall survival (OS).
III. To assess microarray analysis on pre-treatment breast cancer biopsy specimens using Prediction Analysis of Microarray (PAM)50 to correlate the intrinsic subtype with pCR.
IV. To assess microarray analysis on residual disease within the breast accessed at the time of mastectomy and by using PAM50 correlate the intrinsic subtype of the resistance clone with residual disease.
V. To identify early adaptive responses that are associated with resistance to HER2 directed therapies, i.e., trastuzumab and pertuzumab, but analyzing breast tissue specimens obtained 8 days after exposure to only HER2 directed treatment.
VI. To assess changes in circulating biomarkers, including circulating tumor-derived deoxyribonucleic acid (ctDNA), with pCR.
VII. To develop patient-derived xenograph (PDX) models of HER2 positive inflammatory breast cancer in order to facilitate extensive research on this disease.
OUTLINE:
PRE-OPERATIVE TREATMENT PHASE: Patients receive paclitaxel intravenously (IV) over 60 minutes once weekly (beginning week 2) and trastuzumab IV over 60-90 minutes once weekly for up to 16 weeks. Patients also receive pertuzumab IV once every 21 days until surgery.
SURGERY: Within 4-5 weeks of completion of pre-operative treatment, patients undergo total mastectomy and axillary lymph node dissection. Patients are then assigned to 1 of 2 post-operative treatment phases determined by the treating physician.
POST-OPERATIVE TREATMENT PHASE OPTION I: Within 4-5 weeks following surgery, patients receive doxorubicin hydrochloride IV over 3-5 minutes and cyclophosphamide IV over 30 minutes. Treatment repeats every 14-21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Within 3-4 weeks following completion of doxorubicin hydrochloride and cyclophosphamide, patients receive trastuzumab IV over 60-90 minutes and pertuzumab IV. Treatment repeats every 21 days for 12 months in the absence of disease progression or unacceptable toxicity.
POST-OPERATIVE TREATMENT PHASE OPTION II: Within 4-5 weeks following surgery, patients receive trastuzumab IV over 60-90 minutes and pertuzumab IV. Treatment repeats every 21 days for 12 months in the absence of disease progression or unacceptable toxicity.
RADIATION THERAPY: Within 3-6 weeks following the last dose of doxorubicin hydrochloride and cyclophosphamide (Post-Operative Treatment Phase Option I) or following surgery (Post-Operative Treatment Phase Option II), patients undergo radiation therapy.
ENDOCRINE THERAPY: At the start of or after completion of radiation therapy, patients receive tamoxifen citrate or an aromatase inhibitor.
Patients with stage IV disease with nodal involvement will continue trastuzumab and pertuzumab every 3 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 4 years, and then annually thereafter.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorFilipa Lynce
- Primary ID12-497
- Secondary IDsNCI-2013-01110, ML28193
- ClinicalTrials.gov IDNCT01796197