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Durvalumab and Combination Chemotherapy in Treating Patients with Stage I-III Triple Negative Breast Cancer

Trial Status: Active

This phase I / II trial studies the side effects and best dose of durvalumab when given together with paclitaxel albumin-stabilized nanoparticle formulation, doxorubicin hydrochloride, and cyclophosphamide and to see how well they work in treating patients with stage I-III breast cancer that does not have estrogen receptors, progesterone receptors, or large amounts of human epidermal growth factor receptor (HER)2 / neu protein. Monoclonal antibodies, such as durvalumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as paclitaxel albumin-stabilized nanoparticle formulation, doxorubicin hydrochloride, and cyclophosphamide, 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. Giving durvalumab together with paclitaxel albumin-stabilized nanoparticle formulation, doxorubicin hydrochloride, and cyclophosphamide may kill more tumor cells.

Inclusion Criteria

  • Newly diagnosed histologically confirmed stage I-III, estrogen receptor (ER), progesterone receptor (PR) and HER2 negative invasive breast cancer as defined by American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines for whom systemic chemotherapy would be indicated based on physician judgment following standard National Comprehensive Cancer Network (NCCN) practice guidelines (Theriault et al, 2013)
  • Patients with prior history of stage I-III breast cancer currently without evidence of metastatic disease are eligible if can tolerate further chemotherapy, patients with newly diagnosed synchronous bilateral breast cancers are also eligible if at least one tumor is triple negative (response will be assessed in both breasts if invasive cancer is present in both)
  • Willing and able to provide written informed consent for voluntary participation in the trial
  • Willing to undergo a baseline tumor core needle biopsy for correlative science studies; this study does not restrict eligibility based on PD-L1 expression because the relationship between PD-L1 expression and response is not fully understood and there are no standardized and validated clinical tests to assess PD-L1 expression
  • Female subjects must either be of non-reproductive potential (i.e., post-menopausal by history: >= 60 years old and no menses for >= 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative urine or serum pregnancy test upon study entry
  • Peripheral granulocyte count of > 1,500/mm^3
  • Platelet count > 100,000/mm^3
  • Hemoglobin > 9 g/dL
  • Total bilirubin < 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) each < 1.5 x ULN
  • Serum creatinine < 1.5 x ULN or serum creatinine clearance > 50mL/min
  • International normalized ratio INR/ prothrombin time (PT)/ partial thromboplastin time (PTT) each < 1.5 x ULN
  • Thyroid stimulating hormone (TSH) within normal limits

Exclusion Criteria

  • Patients who underwent partial excisional biopsy or lumpectomy, segmental mastectomy or modified radical mastectomy or sentinel node biopsy are not eligible because they cannot be assessed accurately for pathologic response
  • Patients for whom anthracycline, paclitaxel or antibody therapies are contraindicated: * Hypersensitivity reactions to any of the medications or to humanized monoclonal antibodies * History of congestive heart failure * Myocardial infarction within the past 12 months * Pre-existing peripheral neuropathy >= grade 2 * Prior anthracycline therapy with >= cumulative dose of 240 mg/m^2
  • Patients with active autoimmune disease or documented autoimmune disease within 2 years, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
  • Patients with hypothyroidism that is clinically stable and have normal TSH levels with hormone replacement, or patients with vitiligo or psoriasis not requiring treatment remain eligible for the study
  • Active or prior documented inflammatory bowel disease (Crohn’s disease, ulcerative colitis)
  • Patients with known active hepatitis B or C or human immunodeficiency virus (HIV) infection or with history of tuberculosis
  • Patients with a syndrome that requires administration of chronic systemic steroids or immunosuppressive agents; however, patients that require intermittent use of bronchodilators or local steroid injections are eligible
  • Attenuated vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial; examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu, hemagglutinin type 1 (H1) neuraminidase type 1 (N1) flu, rabies, bacillus Calmette-Guerin (BCG), and typhoid vaccine
  • Female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing effective methods of birth control for at least 6 months after completion of the last dose of MEDI4736 and AC chemotherapy
  • Any previous treatment with an anti-programmed cell death 1 (PD1) or PD-L1 inhibitor, including MEDI4736
  • Mean QT interval corrected for heart rate (corrected QT [QTc]) >= 470 ms calculated from 3 electrocardiograms (ECGs) using Bazett’s correction
  • Current or prior use of immunosuppressive medication within 28 days before the first dose of MEDI4736, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
  • History of primary immunodeficiency
  • History of allogeneic organ transplant
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
  • Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results


New Haven
Yale University
Status: ACTIVE
Contact: Lajos Pusztai
Phone: 203-737-8309


I. To assess the safety of MEDI4736 (durvalumab) combined with chemotherapy and determine if full dose of MEDI4736 can be administered in combination with weekly nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation) x 12 treatments followed by MEDI4736 in combination with dose-dense doxorubicin hydrochloride and cyclophosphamide (ddAC) x 4 treatments. (Phase I)

II. To estimate the pathologic complete response (pCR) rate, defined as no invasive cancer in the resected breast tissue and lymph nodes (ypT0/Tis, N0), after neoadjuvant (pre-operative) therapy with MEDI4736 in combination with weekly nab-paclitaxel x 12 treatments followed by MEDI4736 in combination with ddAC x 4 treatments for estrogen receptor (ER), progesterone receptor (PR) and HER2 negative (triple negative, TNBC), clinical stage I-III breast cancer. (Phase II)


I. To assess the toxicity of adding anti- programmed cell death-ligand (PD-L1) antibody, MEDI4736 to neoadjuvant chemotherapy with standard of care nab-paclitaxel and ddAC.


I. Correlation of baseline and post-treatment residual cancer immune parameters of the tumor with pCR.

OUTLINE: This is a phase I, dose-escalation study of durvalumab followed by a phase II study.

PHASE I: Patients receive paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) over 30 minutes once weekly and durvalumab IV over 60 minutes once every two weeks on day 1 for 12 cycles in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV once every two weeks on day 1. Patients also receive durvalumab IV once every two weeks over 60 minutes on day 2 for 4 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 2 and 6 weeks and at 90 days.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Yale University

Principal Investigator
Lajos Pusztai

  • Primary ID 1409014537
  • Secondary IDs NCI-2016-00070, ESR-14-10265
  • ID NCT02489448