Nivolumab and Capecitabine in Treating Patients with Triple Negative Breast Cancer with Residual Cancer Burden
This phase II trial studies how well nivolumab and capecitabine work in treating patients with triple negative breast cancer with residual cancer burden and to assess whether a test in a patient’s blood can be used to predict who may benefit from further treatment with immunotherapy following standard primary chemotherapy for triple negative breast cancer. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as capecitabine, 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. It is not yet known whether nivolumab or capecitabine work better in treating patients with triple negative breast cancer.
Inclusion Criteria
- Biopsy proven TNBC: * Estrogen receptor (ER)- and progesterone receptor (PR)- defined as =< 5% cells stain positive * HER2 negativity defined as: ** Immunohistochemistry (IHC) 0, 1+ without in situ hybridization (ISH) HER2/neu chromosome 17 ratio OR ** IHC 2+ and ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 2.0 and if reported average HER2 copy number < 6 signals/cells
- Residual disease of 1.0 cm at least of the primary tumor and/or node positive disease (at least ypN1) and/or residual cancer burden (RBC) classification II or III. Tissue availability needs to be confirmed and should be received by the lead institution by day 1 of study treatment. (Note: As long as tissue sample is confirmed shipped, the subject will be eligible)
- Patients must have completed neoadjuvant chemotherapy; patients must NOT have received capecitabine as part of their neoadjuvant therapy regimen. Acceptable preoperative regimens include an anthracycline or a taxane, or both. Participants who received preoperative therapy as part of a clinical trial may enroll. Participants may not have received adjuvant chemotherapy after surgery prior to randomization. Carboplatin-containing neoadjuvant chemotherapy is also allowed. Patients who cannot complete all planned neoadjuvant treatment cycles for any reason are considered high risk and therefore are eligible for the study if they have residual disease
- Recovery of all toxicities from previous therapies to at least grade 1, except alopecia and =< grade 2 neuropathy which are allowed
- Must have completed definitive resection of primary tumor and have no evidence of unresected or metastatic disease at the time of study entry. The most recent surgery for breast cancer must have been completed at least 14 days prior to day 1 of study treatment, but no more than 84 days prior. * Negative margins for both invasive and ductal carcinoma in situ (DCIS) are desirable, however patients with positive margins may enroll if the treatment team believes no further surgery is possible and patient has received radiotherapy; patients with margins positive for lobular carcinoma in situ (LCIS) are eligible * Either mastectomy or breast conserving surgery (including lumpectomy or partial mastectomy) is acceptable * Sentinel node biopsy post neoadjuvant chemotherapy (i.e. at the time of definitive surgery) is allowed; axillary dissection is encouraged in patients with lymph node involvement, but is not mandatory * Whole breast radiotherapy is required for participants who underwent breast-conserving therapy, including lumpectomy or partial mastectomy. Participants must have completed radiotherapy at least 14 days prior (but no more than 84 days prior) to day 1 of study treatment * Post-mastectomy radiotherapy is required for all participants with a primary tumor >= 5 cm or involvement of >= 4 lymph nodes. For participants with primary tumors < 5 cm or with < 4 involved lymph nodes, provision of post-mastectomy radiotherapy is at the discretion of the treating physician
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
- Patients must not be planning to receive concomitantly other biologic therapy, hormonal therapy, other chemotherapy, surgery or other anti-cancer therapy except radiation therapy while receiving treatment on this protocol
- A serum thyroid-stimulating hormone (TSH) prior to registration to obtain a baseline value (obtained within 28 days prior to registration)
- Absolute neutrophil count (ANC) >= 1,500 microliter (mcL) (obtained within 28 days prior to registration)
- Platelets >= 100,000/mcL (obtained within 28 days prior to registration)
- Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration)
- Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (except Gilbert’s syndrome, who must have a total bilirubin < 3.0 mg/dL) (obtained within 28 days prior to registration)
- Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase SGPT (alanine aminotransferase [ALT]) =< 2.5 x IULN (obtained within 28 days prior to registration)
- Alkaline phosphatase =< 2.5 x IULN (obtained within 28 days prior to registration)
- Serum creatinine =< IULN OR (obtained within 28 days prior to registration)
- Measured or calculated creatinine clearance >= 60 mL/min (obtained within 28 days prior to registration)
- Normal thyroid function or stable on hormone supplementation (obtained within 28 days prior to registration) (Patients that meet the definition of asymptomatic subclinical hypothyroidism will be eligible to participate)
- Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test within 28 days prior to registration and within 24 hours (h) prior to the start of nivolumab. In addition, women of childbearing potential must agree to have a pregnancy test every 4 weeks while on nivolumab
- Signed informed consent form (ICF)
Exclusion Criteria
- Stage IV disease
- Receipt of adjuvant chemotherapy
- Diagnosis of other invasive cancer except for adequately treated cervix cancer or skin cancer, or more than 5 years since other diagnosis of invasive cancer without current evidence of disease
- Previous exposure to capecitabine, fluorouracil or immunotherapy with anti-PD1, anti-PDL1, anti-CTLA4 or similar drugs
- Active autoimmune disease that has required systemic treatment in the past 2 years; replacement therapy is not considered a form of systemic therapy. Autoimmune diseases include but are not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjogren’s syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis or glomerulonephritis
- Tuberculosis (TB), active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg]), active hepatitis C (defined as positive test for hepatitis C viral load by polymerase chain reaction [PCR]) or other active infection. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients with positive hepatitis C antibody and negative quantitative hepatitis C by PCR are eligible. Patients who have completed curative therapy for hepatitis C virus (HCV) are eligible. Patients with known human immunodeficiency virus (HIV) infection are eligible if they meet each of the following 3 criteria: CD4 counts >= 350 mm^3; serum HIV viral load of < 25,000 IU/ml and treated on a stable antiretroviral regimen
- History of (non-infectious) pneumonitis that required steroids or evidence of active pneumonia
- Uncontrolled disease
- Chronic use of systemic steroids
- Live vaccine within 30 days prior to registration
- Incapacity to provide consent or to follow clinical trial procedures
- Pregnancy, lactation, or planning to be pregnant
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03487666.
PRIMARY OBJECTIVE:
I. To assess the immunologic effects of capecitabine, nivolumab or the combo, post neoadjuvant and post-surgery, in the adjuvant setting, in patients with high risk triple negative breast cancer (TNBC) as defined by presence of residual disease (breast and or lymph nodes [LNs]) at surgery, in terms of the change of peripheral immunoscore (PIS).
SECONDARY OBJECTIVES:
I. To determine the incidence of toxicity graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.0 until 30 days after last dose of treatment on trial.
II. To determine association between changes in PIS from baseline to week 6 and week 12 and clinical outcome variables (distant recurrence free survival [DRFS] and overall survival [OS] at 3-years).
III. Circulating-tumor deoxyribonucleic acid (DNA) (ct-DNA).
EXPLORATORY OBJECTIVES:
I. To describe the immune contexture in residual tumors of patients with high risk TNBC after receiving neoadjuvant chemotherapy.
II. Tissue banking for future studies (next generation sequencing [NGS] of initial biopsy and surgical specimen), plasma, peripheral blood mononuclear cells (PBMCs).
III. To explore the impact of nivolumab on patient-reported outcomes (PROs) of health-related quality of life (HRQoL), as measured by the European Organization for Research and Treatment of Cancer (EORTC) EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) disease related multi-item symptom and functional scales.
OUTLINE: Patients are randomized to 1 of 3 arms.
ARM A: Patients receive nivolumab intravenously (IV) on 60 minutes on day 1. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive capecitabine orally (PO) twice daily (BID) on days 1-14. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.
ARM C: Patients receive nivolumab IV on 60 minutes on day 1 and capecitabine PO BID on days 1-14. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMedStar Georgetown University Hospital
Principal InvestigatorCandace Bavette Mainor
- Primary ID2017-1535
- Secondary IDsNCI-2018-01915
- ClinicalTrials.gov IDNCT03487666