Atezolizumab, Paclitaxel, Trastuzumab, and Pertuzumab in Treating Patients with HER2 Positive Breast Cancer That Is Locally Recurrent, Metastatic, or Cannot Be Removed by Surgery
- Women diagnosed with pathologically confirmed HER2-overexpressing breast cancer, that is locally recurrent, unresectable or metastatic (negative or positive for ER/PR, and positive for HER2)
- HER2 status confirmed positive by means of immunohistochemistry (IHC) or in situ hybridization (ISH) according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2013 guidelines; it is considered positive if scored as 3+ by an IHC method defined as uniform membrane staining for HER2 in 10% or more of tumor cells or demonstrate HER2 gene amplification by an ISH method (single probe, average HER2 copy number >= 6.0 signals/cell; dual probe HER2/CEP17 ratio >= 2.0 with an average HER2 copy number >= 4.0 signals/cell; dual probe HER2/chromosome enumeration probe (CEP)17 ratio >= 2.0 with an average HER2 copy number < 4.0 signals/cell; HER2/CEP17 ratio < 2.0 with an average HER2 copy number >= 6.0 signals/cell)
- Have measurable clinical disease: measurable disease, defined as at least 1 measurable lesion on a computed tomography (CT) scan as defined by RECIST (version v1.1)
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
- Hemoglobin >= 8 g/dL
- Platelets >= 100 x 10^9/L
- Serum bilirubin =< 1.5 x upper normal limit (UNL), except patients with Gilbert's syndrome
- Serum alanine aminotransferase (ALT) =< 2 x UNL or =< 5.0 x UNL in case of liver metastases
- Serum aspartate aminotransferase (AST) =< 2 x UNL or =< 5.0 x UNL in case of liver metastases
- Serum creatinine < 140 umol/L (< 1.6 mg/dL) or 1.5 x the upper limit of normal, whichever is less
- Serum alkaline phosphatase (ALP) =< UNL or =< 2.5 x upper limit of normal (ULN) in case of liver and bone metastases
- Left ventricular ejection fraction of 50% or more at baseline (by echocardiography or multiple-gated acquisition scanning)
- Patients may have received one prior hormonal treatment for metastatic disease
- Patients may have received adjuvant or neoadjuvant chemotherapy with or without trastuzumab and pertuzumab with an interval greater than 12 months since completion of adjuvant/neoadjuvant treatment
- Patients may have received Kadcyla in adjuvant setting
- Ability to understand and willingness to sign a written informed consent and Health Insurance Portability and Accountability Act (HIPAA) consent document
- Female participants of childbearing age must be willing to use contraception methods, or abstain from sexual activity throughout the course of the study and for 7 months after the last dose of atezolizumab
- Have provided tissue from a newly obtained biopsy obtained from a focus of metastatic disease (an archival tissue sample may be substituted if new biopsy cannot be obtained and by discretion of sponsor investigator)
- Patients participating in another trial of an investigational agent within 4 weeks of the 1st dose of the study
- Patients with tumors that cannot be measured or clinically followed
- Patients who had received therapy for metastatic breast cancer (other than that described above)
- Patients with active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 4 weeks prior to trial treatment
- Patients with any baseline grade 2 neuropathy
- Patients with known prior hypersensitivity reaction to any of the study drugs
- Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal gland or pituitary insufficiency) or treatment with drugs (e.g., neomercazole, carbamazole, etc) that function to decrease the generation of thyroid by a hyperfunctiong thyroid gland (e.g., in Graves disease) is not considered a form of systemic treatment of an autoimmune disease
- Diagnosis of immunosuppression or receiving steroid therapy or other immunosuppressive therapy within 4 weeks of the study
- Have evidence of interstitial lung disease or active, non-infectious pneumonitis
- Patients with human immunodeficiency virus (HIV1/2); an HIV test must be performed to confirm status prior to enrollment
- Patients who are carriers of hepatitis virus B and C; hepatitis B and C testing must be performed to confirm status prior to enrollment
- Prior therapy with an anti-programmed cell death 1 (PD-1), anti-programmed cell death 1 ligand (PDL-1), anti-PD-L2, anti-CD137 antibody, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody
- Pregnant, breastfeeding, or expecting to conceive within the projected time of the trial, starting with the pre-screening or screening visit and through 7 months after the last dose of trial treatment
- Active infection requiring systemic therapy
- Active substance abuse or psychiatric disorders; in case, the patient falls under the lower spectrum of psychiatric disorders and is able to function well under medication, the patient could be accrued at the discretion of the physician
- The use of a RANKL inhibitor (denosumab) must be discontinued during the study; bisphosphonate therapy is permitted
- The following treatments must be discontinued: * Herbal medications * Immunomodulatory agents, including but not limited to interferons or IL-2 * Immunosuppressive medications, including but not limited to cyclophosphamide, azathioprine, methotrexate, and thalidomide * Systemic corticosteroids * Anti−TNF-alpha agents
- Any live, attenuated vaccine within 28 days prior to the first day of treatment or during study treatment, or unwillingness to avoid live, attenuated vaccines within 90 days following the last dose of atezolizumab
I. To assess the safety and tolerability of atezolizumab plus the standard regimen of paclitaxel, trastuzumab, and pertuzumab in patients with metastatic HER2-overexpressing breast cancer.
II. To assess antitumor activity using Response Evaluation Criteria in Solid Tumors (RECIST version [v]1.1) (every 9 weeks the first 6 months, then every 3 months thereafter) and the overall response rate of patients with metastatic HER2-overexpressing breast cancer treated with atezolizumab plus the standard regimen of paclitaxel, trastuzumab, and pertuzumab in patients with metastatic HER2-overexpressing breast cancer.
I. To assess the overall survival (OS), time to treatment failure (TTF), and time to tumor progression (TTP) of subjects enrolled in this trial.
II. To assess the progression free survival (PFS) as well as the clinical benefit rate (CBR) defined as the rate of complete response (CR), partial response (PR) and stable disease (SD), in patients with metastatic HER2-positive breast cancer treated with atezolizumab in combination with paclitaxel, pertuzumab and trastuzumab.
III. To assess duration of response (DOR) as per RECIST v1.1, assessed by three parameters: duration of overall response (measured from the time measurement criteria are met for CR or PR - whichever is first recorded- until the first date that recurrent or progressive disease is objectively documented), duration of CR/PR (measured from the time measurement criteria are first met for CR/PR until the first date that progressive disease is objectively documented), and duration of SD (measured from the start of the treatment until the criteria for progression are met).
IV. To correlate biomarkers related to PD-L1 blockade (such as soluble [s]TILs, PD-1, PD-L1, PD-L2, and CTLA-4, and peripheral blood T cell activation) with overall response rate (ORR), clinical benefit rate (CBR), progression free survival (PFS), overall survival (OS), and duration of response (DOR) and assessing efficacy according to tumor PD-L1 expression level and tumor infiltrating lymphocytes PD-L1 expression levels. Further, exploratory analyses on peripheral blood and on tumor tissue samples will be performed to characterize the molecular and biological profiles of tumors responding to the combination of atezolizumab, pertuzumab, trastuzumab, and paclitaxel.
V. To assess efficacy according to hormone receptor status (estrogen receptor/progesterone receptor [ER/PR]).
VI. To assess the feasibility of discontinuation of corticosteroids use after 2 weekly doses of paclitaxel (starting paclitaxel dose # 3 through end of study for patients whose premedication regimen was discontinued).
VII. To assess the rate of occurrence of a paclitaxel-related infusion hypersensitivity reaction
after discontinuation of corticosteroid use.
VIII. To evaluate cardiac safety based on quarterly multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO) results in order to assess the occurrence of left ventricular dysfunction.
Patients receive atezolizumab intravenously (IV) over 30-60 minutes, pertuzumab IV over 30-60 minutes, and trastuzumab IV over 30-90 minutes on day 1. Patients also receive paclitaxel IV over 1 hour on days 1, 8, and 15. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, every 3 months for year 1, every 6 months for years 2-3, and annually for years 4-5.
Trial Phase Phase II
Trial Type Treatment
Fox Chase Cancer Center
Lori J. Goldstein
- Primary ID BR-093
- Secondary IDs NCI-2017-00929, 17-1010
- Clinicaltrials.gov ID NCT03125928