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NRG-BR004: A randomized, double-blind, phase III trial of paclitaxel/trastuzumab/pertuzumab with atezolizumab or placebo in first-line HER2-positive metastatic breast cancer

Description

This randomized, phase III trial studies how well paclitaxel, trastuzumab, and pertuzumab with or without atezolizumab works in treating patients with breast cancer that has spread to other parts of the body. 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. Immunotherapy with trastuzumab, pertuzumab, and atezolizumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving paclitaxel, trastuzumab, and pertuzumab with or without atezolizumab may kill more tumor cells.

Status

Accepting new patients

Primary Study Objective(s)

The primary objective of this study is to determine progression-free survival.

Core eligibility

Note: This is only a partial list of eligibility criteria.

Including patients who:

  • Have signed and dated an Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines
  • Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Have Histologically confirmed adenocarcinoma of the breast with locally recurrent, unresectable disease or metastatic disease confirmed as described below; eligible patients include those with either:
    • De novo metastatic disease presenting without prior history of HER2-positive breast cancer:
      • Diagnosis should have been made from a biopsy of a metastatic disease site, but biopsy from the breast primary or involved regional lymph nodes is acceptable if biopsy of the metastatic sites was thought to carry excessive risk for the patient
    • Locally recurrent or metastatic disease following prior therapy for early breast cancer:
      • Diagnosis must have been made from the biopsy of the locally recurrent or metastatic disease
      • There must be an interval of six  months or more between completion of neoadjuvant/adjuvant HER2-targeted therapy and documentation of locally recurrent or metastatic HER2-positive disease by biopsy
  • Have measurable disease based on RECIST 1.1, as determined by the site, to be eligible
  • Have a tumor specimen obtained at the time of diagnosis of locally recurrent or metastatic disease determined to be HER2-positive based on central testing according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines (Wolff 2018) (Note: HER2 status will initially be assessed using a Food and Drug Administration (FDA)-cleared IHC assay; positive is defined as IHC 3+ staining intensity; if HER2 IHC results are equivocal (2+), then HER2 status will be determined using a FDA-cleared HER2 in situ hybridization (ISH) test according to ASCO/CAP guidelines; sites can send biopsy specimens for central testing which have been determined to be HER2-positive or initially equivocal by either IHC or ISH on local testing.)
  • Have a tumor specimen obtained at the time of diagnosis used for HER2 testing that must also have central testing for PD-L1 status; patients will be eligible irrespective of PD-L1 testing result including PD-L1 indeterminant
  • Have a tumor specimen obtained at the time of diagnosis used for HER2 and PD-L1 testing that should also have central testing for estrogen receptor (ER) and progesterone receptor (PgR) according to current ASCO/CAP guideline recommendations for hormone receptor testing (Note: Patients with 1 percent ER and PgR staining by IHC will be classified as negative; if sufficient material for central confirmation of ER and PgR is unavailable, local testing results for ER and PgR may be used for eligibility.)
  • Have Localized palliative radiation therapy for symptom management if completed 14 days or more prior to randomization
  • Have imaging of the chest/abdomen/pelvis, preferably with a computed tomography (CT) scan, and a bone scan within four weeks prior to randomization (Note:  If a patient is unable to receive CT contrast, a magnetic resonance imaging [MRI] of the abdomen/pelvis and non-contrast chest CT should be performed; positron emission tomography/computed tomography [PET/CT] is not an acceptable alternative.)
  • Have an MRI of the brain (or contrast CT scan of the brain if patients are unable to undergo MRI) in patients with symptoms suggesting possible central nervous system (CNS) metastatic disease (Note: Neuroimaging is recommended but not required in asymptomatic patients.)
  • Have the following:
    • Absolute neutrophil count (ANC) must be >= 1200/mm^3 (within 14 days prior to randomization)
    • Platelet count must be >= 100,000/mm^3 (within 14 days prior to randomization)
    • Hemoglobin must be >= 8 g/dL (within 14 days prior to randomization)
    • Total bilirubin must be =< 1.5 x upper limit of normal (ULN) for the lab or direct bilirubin =< ULN for patients with bilirubin levels > 1.5 x ULN (within 14 days prior to randomization)
    • Aspartate aminotransferase (AST) and alanine aminotransaminase (ALT) must be =< 2.5 x ULN for the lab or =< 5 x ULN for patients with liver metastases (within 14 days prior to randomization)
    • Serum creatinine =< 1.5 x ULN or measured or calculated creatinine clearance >= 50 mL/min using the Cockroft-Gault formula for patients with creatinine levels > 1.5 x ULN for the lab (within 14 days prior to randomization)
    • If not receiving anti-coagulant therapy, have prothrombin time (PT) and international normalized ratio (INR) =< 1.5 x ULN within 14 days prior to randomization (For laboratories that do not report an ULN for the INR assay, use =< 1.5 as the value for the ULN; patients receiving anti-coagulants should have a baseline INR assessed, but the value does not affect eligibility)
    • Serum thyroid-stimulating hormone (TSH), free T4, and AM (morning) cortisol obtained within 14 days prior to randomization to obtain a baseline value and be within normal limits for the local laboratory
    • Left ventricular ejection fraction (LVEF) assessment performed within six weeks prior to randomization (Note: LVEF assessment performed by echocardiogram is preferred; however, multigated acquisition scan (MUGA) scan may be substituted based on institutional preferences; the LVEF must be >= 55% regardless of the cardiac imaging facility's lower limit of normal.)
  • If of reproductive or childbearing potential, agree to use adequate contraception, such as non-hormonal, barrier method or  abstinence,  prior to study entry, for the duration of study participation, and for five months (150 days) after the last dose of atezolizumab/placebo and seven months after the last dose of trastuzumab and pertuzumab (Note:  Administration of atezolizumab may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.)

Excluding patients who:

  • Have known primary central nervous system (CNS) malignancy or symptomatic CNS metastases, with the following exceptions:
    • Patients with asymptomatic untreated CNS disease may be enrolled, provided all of the following criteria are met:
      • Evaluable or measurable disease outside the CNS
      • No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm)
      • No history of intracranial hemorrhage or spinal cord hemorrhage
      • No ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of anticonvulsants are permitted
      • No neurosurgical resection or brain biopsy within 28 days prior to randomization
    • Patients with asymptomatic treated CNS metastases may be enrolled, provided all the criteria listed above are met as well as the following:
      • Radiographic demonstration of improvement upon the completion of CNS directed therapy and no evidence of interim progression between the completion of CNS directed therapy and the screening radiographic study
      • No stereotactic radiation or whole-brain radiation within 4 weeks prior to randomization
      • Screening CNS radiographic study 4 weeks from completion of radiotherapy and 2 weeks from discontinuation of corticosteroids
  • Have known leptomeningeal carcinomatosis
  • Have metastatic disease limited to the CNS
  • Have a history of systemic anti-cancer therapy (e.g., chemotherapy, targeted therapy) for metastatic breast cancer (MBC) with the exception of administration of trastuzumab or lapatinib concurrently with radiation therapy for brain metastases (Note: Toxicities related to lapatinib should be =< grade 1, per the CTCAE version (v)5.0 and must have been completed at least two weeks prior to randomization.)
  • Have a history of exposure to cumulative doses of doxorubicin greater than 360 mg per square meter of body-surface area or its equivalent
  • Had prior treatment with mTOR inhibitors or CDK 4/6 inhibitors in combination with endocrine therapy for treatment of metastatic disease
  • Had prior treatment with CD137 agonists or immune checkpoint-blockade therapies, including anti-CD40, anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
  • Have a history of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within five years prior to randomization
  • Have uncontrolled hypertension defined as sustained systolic blood pressure (BP) > 150 mmHg or diastolic BP > 90 mmHg; (patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria)
  • Have a history of asymptomatic LVEF decline to < 40% during or after prior HER2-targeted therapy
  • Have cardiac disease (history of and/or active disease) that would preclude the use of the drugs included in the treatment regimens; this includes but is not confined to:
    • Active cardiac disease
      • Angina pectoris that requires the current use of anti-anginal medication
      • Ventricular arrhythmias except for benign premature ventricular contractions
      • Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication
      • Conduction abnormality requiring a pacemaker
      • Valvular disease with documented compromise in cardiac function or
      • Symptomatic pericarditis
    • History of cardiac disease
      • Prior myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular (LV) function
      • History of documented congestive heart failure (CHF) defined as symptomatic heart failure with an LVEF < 40%
      • Documented cardiomyopathy
  • Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory neuropathy) >= grade 2, per the Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0
  • History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  • Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or other recombinant antibodies
  • Known allergy or hypersensitivity to the components of the atezolizumab formulation or to any of the study drugs or excipients, (e.g., Cremophor EL)
  • Have a history or risk of autoimmune disease, including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis
    • Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible
    • Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible
    • Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:
      • Psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations
      • Rash must cover less than 10 percent of body surface area (BSA)
      • Disease is well controlled at baseline and only requiring low-potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)
      • No acute exacerbations of underlying conditions within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
  • Had treatment with systemic immunosuppressive medications (including but not limited to interferons, IL-2) within four weeks or five half-lives of the drug, whichever is longer, prior to randomization
  • Had treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis [anti-TNF] factor agents) within 14 days prior to randomization or anticipation of need for systemic immunosuppressive medications during the study (Note: Intranasal and inhaled corticosteroids or systemic corticosteroids at doses that do not exceed 10 mg/day of prednisone or an equivalent corticosteroid are allowed.)
  • Had a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within two weeks prior to randomization
  • Have active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B surface antigen (HBsAg) test at screening (Note: Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at screening, are eligible for the study if active HBV infection is ruled out on the basis of HBV deoxyribonucleic acid (DNA) viral load per local guidelines)
  • Have active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test at screening confirmed by a polymerase chain reaction (PCR) positive for HCV ribonucleic acid (RNA)
  • Have clinically active tuberculosis
  • Known to be human immunodeficiency virus (HIV) positive are eligible if they meet the following criteria within four weeks prior to randomization:
    • A stable regimen of highly active anti-retroviral therapy (HAART) and;
    • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections; and
    • A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR-based tests
  • Had a severe infection within four weeks prior to randomization, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
  • Had an allogeneic stem cell or solid organ transplant
  • Have symptomatic peripheral ischemia
  • Have a history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis or >= grade 1 pulmonary fibrosis, per the CTCAE v5.0, on screening chest CT scan
  • Received a live, attenuated vaccine within four weeks prior to randomization or anticipation that such vaccine will be required during the study
    • Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist) within 4 weeks prior to randomization, during treatment or within five months following the last dose of atezolizumab/placebo
  • Have any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease
     

Accepting new patients

 

Learn more at

clinicaltrials.gov

 

Principal Investigator(s)

Cynthia Lynch

Eugene Ahn

Sagun Shrestha