Durvalumab and Aromatase Inhibitor before Surgery in Treating Postmenopausal Patients with Hormone-Receptor-Positive Breast Cancer
This phase II trial studies how well durvalumab and anastrozole (or other aromatase inhibitors) work when given before surgery in treating postmenopausal patients with hormone-receptor-positive breast cancer. Immunotherapy with monoclonal antibodies such as durvalumab may help the body’s immune system attack the cancer and may interfere with the ability of tumor cells to grow and spread. Aromatase inhibitors, such as anastrozole, are hormonal blockers that are used in standard of care treatment of hormone receptor-positive breast cancer. This study may help find out how well durvalumab and anastrozole work when given before surgery in treating postmenopausal patients with hormone-receptor-positive breast cancer.
- Able to provide a written informed consent and any locally-required authorization (e.g., Health Insurance Portability and Accountability Act [HIPAA] in the United States of America [USA]) prior to performing any protocol-related procedures, including screening evaluations.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Postmenopausal, defined as meeting at least 1 of the following criteria: * Age >= 60 * Prior bilateral oophorectomy * Age < 60 with a uterus AND amenorrhea for at least the past 12 months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) * Age < 60 without a uterus AND follicular stimulating hormone (FSH) and estradiol in the postmenopausal range per local normal range.
- Clinical T2-T4c, any N, M0 by American Joint Committee on Cancer (AJCC) 8th edition, with the goal being definitive surgery after completion of neoadjuvant therapy. * The tumor is palpable and its size can be measured bidimensionally by tape, ruler or caliper technique * The largest tumor diameter is > 2.0 cm.
- Pathologic confirmation of invasive breast cancer that is estrogen receptor (ER) positive with an Allred score of 6, 7 or 8. If an Allred score is not reported on the diagnostic pathology report, ER positivity in > 66% cells is eligible. If ER positivity is =< 66%, the staining intensity (weak, intermediate, strong) is needed to calculate the Allred score to determine eligibility.
- Invasive breast cancer is human epidermal growth factor receptor 2 (HER2) negative defined as 0 or 1+ by immunohistochemistry (IHC) or with an in situ hybridization (ISH) ratio (HER2 gene copy/chromosome 17) < 2.
- Documentation of mammogram and ultrasound [including ductal carcinoma in situ (DCIS) and invasive cancer] of the diseased breast performed within 60 days prior to enrollment. Mammogram for the unaffected contralateral breast is required within 12 months prior to enrollment.
- Hemoglobin >= 9.0 g/dL (obtained =< 14 days prior to enrollment).
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 per mm^3) (obtained =< 14 days prior to enrollment).
- Platelet count >= 100 x 10^9/L (>= 100,000 per mm^3) (obtained =< 14 days prior to enrollment)
- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained =< 14 days prior to enrollment). This will not apply to subjects with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (obtained =< 14 days prior to enrollment).
- Serum creatinine clearance > 40 mL/min by the Cockcroft-Gault formula (1976) or by 24-hour urine collection for determination of creatinine clearance (obtained =< 14 days prior to enrollment).
- Subjects must be willing to undergo a research biopsy at baseline and after one cycle of treatment and to provide tissue obtained at surgery for biomarker and correlative studies.
- Subjects must be 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.
- If taking herbal or natural remedies that may have immune modulatory effects, subjects must be willing to discontinue it prior to first dose of durvalumab.
- Body weight > 30 kg.
- Participation in another clinical study with an investigational product during the last 4 weeks.
- Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
- Inflammatory breast cancer defined as clinically significant erythema of the breast and/or documented dermal lymphatic invasion (not direct skin invasion by tumor or peau d'orange without erythema).
- An excisional biopsy of this breast cancer.
- Hormone replacement therapy of any type, megestrol acetate, or raloxifene within one week prior to registration.
- Surgical axillary staging procedure prior to study entry. Note: Fine needle aspiration (FNA) or core needle biopsy of axillary node is permitted.
- Treatment for this cancer including surgery, radiation therapy, chemotherapy, biotherapy, hormonal therapy or investigational agent prior to study entry.
- Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab.
- History of another primary malignancy except for malignancy treated with curative intent and with no known active disease >= 5 years or adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease or adequately treated carcinoma in situ without evidence of disease e.g., cervical cancer in situ.
- History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral ductal carcinoma in situ (DCIS) treated with radiotherapy or endocrine therapy or contralateral invasive breast cancer at any time.
- Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab, with the exceptions of intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection); systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid; or steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication).
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., 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 (e.g., 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 * Patients with celiac disease controlled by diet alone.
- History of primary immunodeficiency.
- History of allogeneic organ transplant.
- Known allergy or history of hypersensitivity to durvalumab, or any excipient.
- 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, active bleeding diatheses, or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
- Known active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice), 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 (hepatitis C virus [HCV]) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA). Note: This is applied only to patients with known infection. Screening tests for TB, hepatitis B and C, or HIV are not required.
- Receipt of live attenuated vaccination within 30 days prior to receiving durvalumab. Note: Patients, if enrolled, should not receive live vaccine while receiving durvalumab and up to 30 days after the last dose of durvalumab.
- Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.
- Subjects with uncontrolled seizures.
- Patients with multi-centric breast cancer (defined as more than one lesion is invasive breast cancer in the same breast separated by >= 2 cm of normal breast tissue.
- Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of investigational product.
Locations & Contacts
Contact: Hung T. Khong
Trial Objectives and Outline
I. To evaluate the efficacy of an aromatase inhibitor with durvalumab.
I. To evaluate safety and tolerability of the combination of an aromatase inhibitor and durvalumab.
II. To evaluate objective clinical response rate.
III. To evaluate pathologic complete response rate (pCR).
IV. To evaluate recurrence free survival.
I. To assess immune cell changes (phenotype and/or functionality) in tumor before, during and after treatment.
II. To assess cytokine patterns before, during and after treatment.
III. To evaluate biomarkers that may correlate with clinical outcome.
Patients receive anastrozole orally (PO) once daily (QD) on days 1-28 and durvalumab intravenously (IV) over 1 hour on day 1. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Within 28-35 days patients undergo surgery. Patients intolerant to anastrozole may receive letrozole or exemestane after the safety run-in stage, as per standard of care.
After completion of study treatment, patients are followed up every 6 months for 5 years.
Trial Phase & Type
Moffitt Cancer Center
Hung T. Khong
Secondary IDs NCI-2019-01753
Clinicaltrials.gov ID NCT03874325