Trastuzumab Emtansine and Pertuzumab before Surgery in Treating Patients with HER2-Positive Stage II-III Breast Cancer
This phase II trial studies how well trastuzumab emtansine and pertuzumab before surgery work in treating patients with human epidermal growth factor receptor 2 (HER2)-positive stage II-III breast cancer. HER2 is a protein found on the surface of cancer cells that helps them to grow and spread. Pertuzumab may kill cancer cells by binding to HER2-positive on the surface of the tumor cells and blocking their ability to grow and spread. Trastuzumab emtansine is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called DM1. Trastuzumab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors, and delivers DM1 to kill them. Giving pertuzumab and trastuzumab emtansine before surgery may make the tumor smaller.
Inclusion Criteria
- Patients must have HER2-positive stage II or III histologically confirmed invasive carcinoma of the breast; a minimum tumor size of 2 cm determined by physical exam or imaging (whichever is larger) is required
- HER-2 positive by American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) 2013 guidelines, confirmed by central testing confirmed by central testing (NeoGenomics Laboratories): * Immunohistochemistry (IHC) 3+ based on circumferential membrane staining that is complete, intense AND/OR * FISH positive based on one of the three following criteria: ** Single-probe average HER2 copy number >= 6.0 signals/cell OR ** Dual-probe HER2/chromosome 17 centromere (CEP17) ratio < 2.0 with an average HER2 copy number >= 6.0 signals/cell OR ** Dual-probe HER2/CEP17 ratio >= 2.0 * NOTE: HER-2 status must be confirmed to be positive by central review prior to patient starting protocol therapy; patients previously having had HER2 testing at NeoGenomics Laboratories, Inc. (formerly Clarient Laboratories) do not need to undergo retesting for central confirmation of HER2 status; ductal carcinoma in situ (DCIS) components should not be counted in the determination of HER2 status
- Estrogen receptor (ER)/progesterone receptor (PR) determination is required; ER- and PR-assays should be performed by immunohistochemical methods according to the local institution standard protocol
- Bilateral breast cancers are allowed as long as both cancers are HER2-positive; however, only the primary cancer’s status requires central review
- Patients with multifocal or multicentric disease are eligible as long as at least one area meets eligibility criteria
- Breast imaging should include imaging of the ipsilateral axilla; for subjects with a clinically negative axilla, a sentinel lymph node biopsy will be performed either before or after preoperative therapy at the discretion of the subject’s physicians; for subjects with a clinically positive axilla, a needle aspiration, core biopsy or sentinel lymph node (SLN) procedure will be performed to determine the presence of metastatic disease in the lymph nodes
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- Absolute neutrophil count (ANC) >= 1500/mm^3
- Hemoglobin >= 9 g/dl
- Platelets >= 100,000/mm^3
- Serum creatinine < 1.5 X upper limit of normal (ULN) (institutional)
- Total bilirubin =< 1.0 X ULN (institutional); for patients with Gilbert syndrome, the direct bilirubin should be within the institutional normal range
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x ULN (institutional)
- Alkaline phosphatase =< 1.5 x ULN (institutional)
- Only for patients who test positive for hepatitis B virus or hepatitis C virus: partial thromboplastin time (PTT)/international normalized ratio (INR) =< ULN (institutional)
- Documentation of hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies is required: this includes hepatitis B surface antigen (HBsAg) and/or total hepatitis B core antibody (HBcAb) in addition to HCV antibody testing; the most recent serologic testing must have occurred within 12 weeks prior to registration; if such testing has not been done, it must be performed during screening * Note: patients who have positive HBV (i.e., HBsAg or HBcAb) or HCV serologies without known active disease must meet the eligibility criteria for ALT, AST, total bilirubin (TBILI), INR, activated partial thromboplastin time (aPTT)/PTT, and alkaline phosphatase (ALP) on at least two consecutive occasions, separated by at least 1 week, within the 30-day screening period; the second of these evaluations must be performed within 3 days prior to the first treatment administration
- Left ventricular ejection fraction (LVEF) >= 55%
- Premenopausal women must have a negative serum pregnancy test, including women who have had a tubal ligation and for women less than 12 months after the onset of menopause
- Women of childbearing potential and men with partners of childbearing potential must be willing to use one highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception by the patient and/or partner and continue its use for the duration of the study treatment and for 7 months after the last dose of study treatment
- Potent cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors, such as ketoconazole and erythromycin, should be avoided during the study treatment period with T-DM1
- Excessive alcohol intake should be avoided (occasional use is permitted)
- Patients with a history of ipsilateral DCIS are eligible
- Patients undergoing breast conservation therapy (i.e. lumpectomy) must not have any contraindications to radiation therapy
- Willing and able to sign informed consent
- Willing to provide tissue for research purposes
Exclusion Criteria
- Pregnant or nursing women due to the teratogenic potential of the study drugs
- Active, unresolved infection
- Receipt of intravenous antibiotics for infection within 7 days prior to enrollment
- Patients with active liver disease, for example, due to hepatitis B virus, hepatitis C virus, autoimmune hepatic disorder, or sclerosing cholangitis
- Uncontrolled hypertension (systolic > 180 mm Hg and/or diastolic > 100 mm Hg) or clinically significant (i.e. active) cardiovascular disease: cerebrovascular accident/stroke or myocardial infarction within 6 months prior to first study medication, unstable angina, congestive heart failure (CHF) of New York Heart Association (NYHA) grade II or higher, or serious cardiac arrhythmia requiring medication
- Significant symptoms (grade >= 2) peripheral neuropathy
- Other concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions/illness, uncontrolled infections, uncontrolled diabetes
- Any prior treatment for the current breast cancer, including chemotherapy, hormonal therapy, radiation or experimental therapy
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02326974.
PRIMARY OBJECTIVE:
I. To evaluate the relationship between pathologic complete response (pCR) and intratumor heterogeneity of HER2 amplification.
SECONDARY OBJECTIVES:
I. To assess the rate of pCR after preoperative T-DM1 (trastuzumab emtansine) plus pertuzumab in HER2-positive breast cancer.
II. To determine the clinical response rate, defined as the number of partial and complete responses after preoperative T-DM1 plus pertuzumab in HER2-positive breast cancer.
III. To determine the relationship between hormone receptor (HR) status and intratumor heterogeneity of HER2 amplification.
IV. To characterize safety and tolerability of T-DM1 plus pertuzumab.
V. To evaluate the relationship between pCR and HER2 heterogeneity assessed as a continuous variable.
VI. To determine if T-DM1 plus pertuzumab preoperative therapy enriches for HER2-negativity or HER2 heterogeneity in residual tumors.
VII. To determine whether T-DM1 plus pertuzumab activity defined by pCR is affected by the degree of intratumor heterogeneity of HER2 expression determined by immuno-fluorescence in situ hybridization (FISH).
VIII. To describe disease-free and overall survival in patient groups defined by HER2 heterogeneity who are treated with T-DM1 plus pertuzumab.
OUTLINE:
Patients receive trastuzumab emtansine intravenously (IV) over 30-90 minutes and pertuzumab IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Within 42 days after the last dose of treatment, patients undergo definitive surgery. Within 6 months of surgery, patients may continue receiving pertuzumab for up to 4 courses at the discretion of the treating physician.
After completion of study treatment, patients are followed up every 6 months for 5 years and then yearly for 5 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorOtto Metzger
- Primary ID14-409
- Secondary IDsNCI-2015-00454
- ClinicalTrials.gov IDNCT02326974