Nivolumab and Standard Chemotherapy before Surgery in Treating Patients with Inflammatory Breast Cancer
This phase II trial studies how well nivolumab and standard chemotherapy work before surgery in treating patients with inflammatory breast cancer. Immunotherapy with a monoclonal antibody such as nivolumab works by attaching to and blocking a molecule called PD-1. PD-1 is a protein that is present on different types of cells in the immune system and controls parts of the immune system by shutting it down. Antibodies that block PD-1 can potentially prevent PD-1 from shutting down the immune system, thus allowing immune cells to recognize and destroy tumor cells. Drugs used in standard chemotherapy 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. The purpose of this study is to determine whether the addition of nivolumab to standard chemotherapy improves response rate in patients with inflammatory breast cancer.
- Histological diagnosis of invasive adenocarcinoma of the breast made by core needle biopsy and a clinical diagnosis of IBC based on presence of inflammatory changes in the involved breast, including diffuse erythema and edema (peau d'orange), with or without an underlying palpable mass involving the majority of the skin of the breast (T4d according to American Joint Committee on Cancer [AJCC] breast cancer staging, 8th edition [ed.]). Pathological evidence of dermal lymphatic invasion should be noted but is not required for diagnosis of IBC.
- In case of bilateral cancer, the investigator should decide prospectively which side will be evaluated for the primary endpoint.
- Local testing on the diagnostic core for estrogen receptor (ER), progesterone receptor (PR), and HER2 must be performed: * HR-positive: defined as estrogen receptor (ER) and/or progesterone receptor (PR) >= 1% per American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) guidelines * HER2-positive: immunohistochemistry (IHC) 3+ or 2+ with HER2/CEP17 ratio > 2.0 or average HER2 copy number > 6.0 signals/cell) per ASCO-CAP guidelines * TNBC: defined as ER/PR < 1% and HER2-negative per ASCO-CAP guidelines.
- Individuals of all races and ethnic groups are eligible.
- Eastern Cooperative Group (ECOG) performance status of 0 or 1.
- Left ventricular ejection fraction (LVEF) assessment performed by echocardiogram or multigated acquisition scan (MUGA) scan based on institutional preferences. Results must be above the normal limit of the institution and/or >= 50%.
- All patients with disease that is deemed by the treating investigator as safely accessible to biopsy are required to undergo research biopsies as outlined in this protocol.
- Ability to understand and willingness to sign a written informed consent document or if appropriate, have an acceptable surrogate capable of giving consent on the subject’s behalf.
- Absolute neutrophil count (ANC) >= 1,500/mcL (within 28 days prior to the first study treatment [cycle 1, day 1]).
- Platelets >= 100,000/mcL (without transfusion within 1 week prior to cycle 1, day 1).
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (without transfusion or erythropoietin [EPO] dependency within 1 week prior to cycle 1, day 1).
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (within 28 days prior to the first study treatment [cycle 1, day 1]). * Creatinine clearance should be calculated per institutional standard.
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 28 days prior to the first study treatment [cycle 1, day 1]).
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 X ULN (within 28 days prior to the first study treatment [cycle 1, day 1]).
- Albumin >= 2.5 mg/dL (within 28 days prior to the first study treatment [cycle 1, day 1]).
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 28 days prior to the first study treatment [cycle 1, day 1]).
- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 28 days prior to the first study treatment [cycle 1, day 1]).
- For women of childbearing potential (pre-menopausal women and women less than 12 months after the onset of menopause): must have a pregnancy test every 4 weeks and must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of nivolumab.
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization) during study treatment and for a total of 5 months post-treatment completion. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm.
- Definitive clinical or radiologic evidence of distant metastases.
- Has a known additional malignancy that progressed within the last five years.
- Cardiac disease (history of and/or active disease) that would preclude the use of the drugs included in the treatment regimens.
- Patients known to be human immunodeficiency virus (HIV) positive.
- Neuropathy >= grade 2, per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0.
- History of allogeneic stem cell or solid organ transplantation.
- Has active clinically significant autoimmune disease where in the opinion of the investigator would preclude the use of immunotherapy.
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), or evidence of active pneumonitis.
- Patients with clinically active tuberculosis.
- Pregnancy or lactation at the time of enrollment.
- 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.
- Treatment with systemic immunosuppressive medications (including but not limited to interferons, IL-2) within 28 days or 5 half-lives of the drug, whichever is longer, prior to study entry.
- Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis [anti-tumor necrosis factor (TNF)] factor agents) within 2 weeks prior to randomization or anticipation of need for systemic immunosuppressive medications during the study.
- Inadequate LVEF at baseline, < 50% by either transthoracic echocardiography (TTE) or MUGA.
- History of symptomatic congestive heart failure (CHF): Grade >= 3 per NCI CTCAE version 5.0 or class >= II per New York Health Association.
- History of a decrease in LVEF to < 40% or symptomatic CHF.
- Myocardial infarction or unstable angina within 6 months of start of study treatment.
- Current dyspnea at rest due to complications of malignancy, or other disease requiring continuous oxygen therapy.
- Corrected QT interval (QTc) > 450 msec on screening electrocardiography (EKG).
- Clinically significant history of liver disease, including cirrhosis, autoimmune hepatic disorders, HIV infection, or active hepatitis B or hepatitis C.
- Active infection requiring treatment with antiviral therapy or presence of positive test results for hepatitis B (e.g. hepatitis B surface antigen and/or total hepatitis B core antibody) or hepatitis C virus (HCV) antibody. Hepatitis B virus (HBV) and HCV assessments are required at screening.
- Patients who test positive for hepatitis B core antibody are eligible if polymerase chain reaction (PCR) is negative for HBV deoxyribonucleic acid (DNA).
- Patients who are positive for HCV serology are only eligible if testing for HCV ribonucleic acid (RNA) is negative.
- Subject is pregnant or nursing.
- Known documented or suspected hypersensitivity to the components of the study drugs(s).
Locations & Contacts
Trial Objectives and Outline
I. To determine whether the addition of nivolumab to chemotherapy improves pathologic complete response (pCR) in the breast and post-therapy lymph nodes evaluated histologically in patients with inflammatory breast cancer (IBC).
I. To evaluate the safety and tolerability of the combination of nivolumab with neoadjuvant chemotherapy in IBC.
II. To evaluate the invasive recurrence-free interval (IRFI) (time frame: up to 24 months after study entry).
I. To evaluate baseline expression of PD-L1 and baseline percentage of tumor infiltrating lymphocytes (TILs) and expression of PDL1 and percentage of TILs, M1 and M2 macrophages and composition of immune response following treatment with nivolumab and chemotherapy as a predictor for pCR and IRFI.
II. To assess the frequency of mutational and neoantigen load and to explore mutational and neoantigen load as predictive markers of response.
III. To assess changes in expression levels of biomarkers or biomarker panels before, during, and after treatment.
OUTLINE: Patients are assigned to 1 of 2 cohorts.
COHORT I (TRIPLE-NEGATIVE BREAST CANCER [TNBC] OR HORMONE RECEPTOR [HR]-POSITIVE/HER2-NEGATIVE): Patients receive nivolumab intravenously (IV) over 30 minutes on day 1 and paclitaxel IV on days 1, 8, and 15. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive doxorubicin IV on day 1 and cyclophosphamide IV on day 1. Treatment repeats every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Four weeks later, patients undergo mastectomy and axillary lymph node dissection.
COHORT II (HR-POSITIVE/HR-NEGATIVE AND HER2-POSITIVE): Patients receive nivolumab IV over 30 minutes on day 1, docetaxel IV on day 1 or paclitaxel IV on days 1, 8 and 15, trastuzumab IV on day 1, and pertuzumab IV on day 1. Treatment repeat every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive doxorubicin IV on day 1 and cyclophosphamide IV on day 1. Treatment repeats every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Four weeks later, patients undergo mastectomy and axillary lymph node dissection.
After completion of study treatment, patients are followed up every 3 months for up to 24 months.
Trial Phase & Type
Laura and Isaac Perlmutter Cancer Center at NYU Langone
Maryann J. Kwa
Secondary IDs NCI-2019-03074
Clinicaltrials.gov ID NCT03742986