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Durvalumab and Tremelimumab in Treating Patients with Metastatic HER2 Negative Breast Cancer

Trial Status: Active

The main purpose of this study is to determine the anti-tumor activity of durvalumab in combination with tremelimumab in patients with metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Both durvalumab and tremelimumab are antibodies (proteins used by the immune system to fight infections and cancers). Durvalumab attaches to a protein in tumors called PD-L1. It may prevent cancer growth by helping certain blood cells of the immune system get rid of the tumor. Tremelimumab stimulates (wakes up) the immune system to attack the tumor by inhibiting a protein molecule called cytotoxic T lymphocyte associated 4 (CTLA-4) on immune cells. Combining the actions of these drugs may result in better treatment options for patients with breast cancer.

Inclusion Criteria

  • Patients must have a histologically documented (either primary or metastatic site) diagnosis of breast cancer that is HER2 non-overexpressing by immunohistochemistry, namely 0 or 1; if they have an equivocal immunohistochemistry, 2, the tumor must be non-gene amplified by fluorescence in situ hybridization (FISH) performed upon the primary tumor or metastatic lesion (ratio < 2 and HER2 copy number < 4); estrogen receptor (ER) positivity is defined as 1% or greater; progesterone receptor (PR) positivity will be defined as a result of greater than 10%; documentation of ER and PR status should be available at registration; the expansion cohort will only include HER2-negative, ER and PR-negative patients
  • Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
  • Patients must have been treated with at least one prior chemotherapy regimen in the metastatic setting or within 12 months of their last adjuvant systemic treatment and must be felt to be chemotherapy refractory; patients with ER positive disease must have demonstrated to be clinically endocrine-insensitive by progressing through at least one line of endocrine therapy, including approved combinations and considered candidate for more aggressive therapies (e.g. chemotherapy) per principal investigator (PI) or treating physician
  • Completion of prior chemotherapy systemic anticancer therapy at least 2 weeks prior to study entry
  • Radiation therapy must be completed at least 2 weeks prior to study entry; radiated lesions may not serve as measurable disease unless they have been radiated >= 12 months prior to enrollment
  • Patients may have parenchymal brain metastases if stable (no evidence of progression) for at least 1 month after local therapy (radiation or surgery); leptomeningeal disease is excluded; must have completed any prescribed steroid taper prior to registration
  • Patients may have had a prior diagnosis of cancer if it has been > 3 years since their last treatment (with the exception of squamous cell carcinoma or basal cell carcinoma of the skin or cervical intraepithelial neoplasia)
  • Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
  • Patients must weigh greater than 30 kg
  • Within 14 days of first dose of study drug administration: Hemoglobin >= 9.0g/dl
  • Within 14 days of first dose of study drug administration: Absolute neutrophil count >= 1,500/mcL (1.5 x 10^9/L)
  • Within 14 days of first dose of study drug administration: Platelets >= 100,000/mcl
  • Within 14 days of first dose of study drug administration: Total bilirubin =< 1.5 times the institutional upper limit of normal (ULN) (or =< 3 times ULN in case of liver metastasis)
  • Within 14 days of first dose of study drug administration: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SPGT]) =< 2.5 X institutional ULN (or =< 5 times ULN in case of liver metastasis)
  • Within 14 days of first dose of study drug administration: Serum creatinine: creatinine clearance (CL) > 40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance
  • Female subjects must either be of non-reproductive potential or must have a negative serum pregnancy test within 7 days prior to registration on study; evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients; women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause; the following age-specific requirements apply: * Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy) * Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
  • Female and male patients of reproductive potential must agree to use effective birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy or 180 days after the last dose of durvalumab monotherapy, whichever is the longer time period; should a female patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • Willingness to provide a fresh biopsy prior to study enrollment and after 2 cycles of treatment as clinically appropriate per PI discretion
  • Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study; written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization will be obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
  • Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up

Exclusion Criteria

  • Patients with documented HER2-positive metastatic disease based on most recent biopsy
  • Patients with definite liver metastasis > 1 cm or signs of visceral crisis or impending visceral crisis at the clinical discretion of the treating physician
  • Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria * Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the treating physician and/or PI * Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the treating physician and/or PI
  • Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study
  • Current or prior use of immunosuppressive therapy within 14 days before the first dose of durvalumab or tremelimumab, 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
  • Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 2 electrocardiograms (ECGs) using Bazett’s correction; two electrocardiogram (EKGs) 5 minutes (+/- 2 min) apart is mandatory
  • Receipt of live attenuated vaccination within 30 days prior to registration; NOTE: patients should also not receive such vaccination within 30 days of receiving durvalumab or tremelimumab
  • Patients who are taking any herbal (alternative) medicines are NOT eligible for participation; patients must be off any such medications by the time of registration for at least 2 weeks; NOTE: Vitamin supplements are acceptable
  • Patients may not have received any other investigational agents within 2 weeks or 5 half life’s prior to registration, whichever is shorter
  • Prior treatment with immune therapy (including but not limited to cluster of differentiation [CD]137, OX40, programmed cell death [PD]-1, PD-L1 or cytotoxic T-lymphocyte antigen 4 [CTLA4] inhibitors)
  • Prior severe infusion reaction to a monoclonal antibody
  • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: * Patients with vitiligo or alopecia * Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic therapy * Patients without active disease in the last 5 years may be included but only after consultation with the study physician and/or PI * Patients with celiac disease controlled by diet alone
  • Known active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and positive tuberculosis (TB) test (purified protein derivative [PPD], Quantiferon), hepatitis B (known positive hepatitis B virus [HBV] surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies) * Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible * Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
  • History of allogeneic organ transplant
  • History of hypersensitivity to durvalumab or tremelimumab or any excipient
  • Major medical conditions that might affect study participation (uncontrolled pulmonary, renal, or hepatic dysfunction, uncontrolled infection) are not eligible; other significant comorbid condition which the investigator feels might compromise effective and safe participation in the study
  • Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible: * Symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia * Interstitial lung disease, serious gastrointestinal conditions associated with diarrhea * Uncontrolled pulmonary, renal, or hepatic dysfunction * Ongoing or active infection requiring systemic treatment * Psychiatric illness/social situations that would limit compliance with study requirements, substantially increase risk of incurring adverse events (AEs) or compromise the ability of the patient to give written informed consent * Any other illness or condition that the treating investigator feels would interfere with study
  • Female patients who are pregnant or nursing are not eligible
  • Patients who are involved in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site); previous enrollment or randomization in the present study


Northwestern University
Contact: Massimo Cristofanilli
Phone: 312-503-5488
Lake Forest
Northwestern Medicine Lake Forest Hospital
Status: ACTIVE
Contact: Valerie Marie Nelson
Phone: 847-535-7285


I. To evaluate overall response rate (ORR) in patients with metastatic HER2 negative breast cancer treated with durvalumab in combination with tremelimumab.

II. To evaluate overall response rate (ORR) in patients with metastatic triple negative breast cancer (TNBC) treated with durvalumab in combination with tremelimumab.


I. To evaluate progression free survival (PFS) and overall survival (OS) in patients with metastatic HER2 negative breast cancer treated with durvalumab in combination with tremelimumab.

II. To evaluate safety and tolerability.

III. To evaluate clinical benefit rate in this population.


I. To evaluate if serum and tissue-based biomarkers including: circulating tumor deoxyribonucleic acid (DNA), immunohistochemical expression of PD-L1; tumor infiltrating lymphocytes (TILs); peripheral T cell subpopulations; changes in tissue and peripheral T cell receptor genotype; mutational and neoantigen burden; and immune-related candidate gene expression signatures predict response to durvalumab in combination with tremelimumab.

II. To determine the response rate (RR) and duration of response (DoR) of next line

therapy after progression on durvalumab/tremelimumab study regimen, for those patients who are able to submit detailed follow up data about subsequent treatment and response.


INDUCTION PHASE: Patients receive durvalumab intravenously (IV) over 1 hour and tremelimumab IV over 1 hour on day 1. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE PHASE: Four weeks after the last combination dose, patients continue to receive durvalumab every 2 weeks for up to 18 additional doses in the absence of disease progression or unacceptable toxicity. Patients who achieve clinical benefit (complete response [CR], partial response [PR], or stable disease [SD]) until the end of the 48 week period will then enter follow-up. During follow-up patients who develop progressive disease (PD) may be re-treated with durvalumab at the dose previously administered IV for an additional 52 weeks using the same guidelines as with the initial 52 week period if they meet treatment in the setting of PD criteria. Only one 52 week re-treatment period will be allowed.

After completion of study treatment, patients are followed up at 3, 6, 9, and 12 months, and then every 6 months for 3 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Northwestern University

Principal Investigator
Massimo Cristofanilli

  • Primary ID NU 15B01
  • Secondary IDs NCI-2015-01445, ESR-14-10694, D4190C00030, STU00200984
  • ID NCT02536794