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Clinical Trials Search at Vanderbilt-Ingram Cancer Center

Avelumab with Binimetinib, Sacituzumab Govitecan, or Liposomal Doxorubicin in Treating Patients with Stage IV or Unresectable, Recurrent Triple Negative Breast Cancer

This phase II trial studies how well the combination of avelumab with liposomal doxorubicin with or without binimetinib, or the combination of avelumab with sacituzumab govitecan works in treating patients with triple negative breast cancer that is stage IV or is not able to be removed by surgery (unresectable) and has come back (recurrent). Immunotherapy with checkpoint inhibitors like avelumab require activation of the patient's immune system. This trial includes a two week induction or lead-in of medications that can stimulate the immune system. It is our hope that this induction will improve the response to immunotherapy with avelumab. One treatment, sacituzumab govitecan, is a monoclonal antibody called sacituzumab linked to a chemotherapy drug called SN-38. Sacituzumab govitecan is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of tumor cells, known as TROP2 receptors, and delivers SN-38 to kill them. Another treatment, liposomal doxorubicin, is a form of the anticancer drug doxorubicin that is contained in very tiny, fat-like particles. It may have fewer side effects and work better than doxorubicin, and may enhance factors associated with immune response. The third medication is called binimetinib, which may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth, and may help activate the immune system. It is not yet known whether giving avelumab in combination with liposomal doxorubicin with or without binimetinib, or the combination of avelumab with sacituzumab govitecan will work better in treating patients with triple negative breast cancer.
Phase II
Chemotherapy - cytotoxic, Mol. targeted/Immunotherapy/Biologics
Avelumab, Binimetinib, Liposomal Doxorubicin, Sacituzumab govitecan
Abramson, Vandana
Vanderbilt University


18 Years
Inclusion Criteria:

Signed and dated written informed consent

Subjects >= 18 years of age

Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

Clinical stage IV invasive breast cancer or unresectable locoregional recurrence of invasive breast cancer meeting the following criteria: * Estrogen receptor (ER)/progesterone receptor (PR)-negative (= 10% cells) by immunohistochemistry (IHC) and HER2 negative (by IHC or fluorescence in situ hybridization [FISH]) * Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria and which can be followed by computed tomography (CT) or magnetic resonance imaging (MRI). A measurable lytic bone lesion(s) and/or skin lesion(s) are allowed. Skin lesions must also be followed by photography with measuring tools within the photograph at each tumor evaluation time point. Ultrasound may be used to follow breast lesions not visible by CT following discussion with Study Chair * Amenable to biopsy at the time of study entry * Known tumor/immune cell PD-L1 status by any assay

Cardiac ejection fraction at or above the institutional lower limit of normal, as assessed by either echocardiogram or multigated acquisition (MUGA) scan

Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (may have received growth factor)

Platelets >= 100 x 10^9/L

Hemoglobin >= 9 g/dL (may have been transfused)

Total serum bilirubin = 1.5 times upper limit of normal (ULN)

Aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT/serum glutamate pyruvate transaminase [SGPT]) = 2.5 x ULN (or = 5 x ULN if liver metastases are present)

Serum creatinine = 1.5 x ULN or estimated creatinine clearance >= 50 mL/min as calculated using the Cockcroft-Gault (CG) equation

Prothrombin time (PT)/international normalized ratio (INR) = 1.5 x ULN

Amylase = 1 x ULN, testing is only required in patients with a history of pancreatic disorders (Abnormality not of pancreatic origin is allowed)

Participants with treated and controlled hypo or hyperthyroidism are eligible

Male and female patients of childbearing potential must agree to use at least two methods of acceptable contraception from 15 days prior to first trial treatment administration until at least 30 days after study participants final dose of study drug(s) * NOTE: Females of childbearing potential are defined as those who are not surgically sterile or post-menopausal (i.e., patient has not had a bilateral tubal ligation, a bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 12 months without an alternative medical cause). Post-menopausal status in females under 55 years of age should be confirmed with a serum follicle-stimulating hormone (FSH) level within laboratory reference range for postmenopausal women

Patients unable to read/write in English are eligible to participate in the overall study but will not participate in the patient-reported outcome questionnaires throughout the trial

Re-enrollment of a subject that has discontinued the study as a pre-randomization screen failure (i.e., a consented patient who was not randomized and did not receive any study treatment) is permitted. If re-enrolled, the subject must be re-consented. Only the screening procedures performed outside of protocol-specified timing must be repeated; if biopsies and correlative blood samples were already obtained, and patient has not received any systemic anti-cancer therapy since they were obtained, they do not need to be repeated

Exclusion Criteria:

More than 2 prior lines of chemotherapy in the metastatic setting

More than one prior line of checkpoint inhibitor therapy in the metastatic setting

Prior treatment with sacituzumab govitecan

Concurrent anticancer therapy. Required washout from prior therapies are as follows: * Chemotherapy: >= 14 days: antibody-drug conjugants administered every 3 weeks require a 3-week washout * Major surgery: >= 14 days (provided wound healing is adequate) * Radiation: >= 7 days * Investigational/Biologic Therapy (halflife = 40 hours): >= 14 days * Investigational/Biologic Therapy (halflife > 40 hours): >= 28 days * Use of corticosteroids or immunosuppressive medication is exclusionary, except the following in the absence of active autoimmune disease: ** Subjects are permitted the use of corticosteroids with minimal systemic absorption (i.e., topical, ocular, intra-articular, intranasal, and inhaled); ** Systemic corticosteroids at physiologic doses = 10 mg/day of prednisone or equivalent are permitted; ** Adrenal replacement steroid doses including doses > 10 mg daily prednisone are permitted; ** A brief (less than 3 weeks) course of corticosteroids for prophylaxis (i.e., CT scan premedication against contrast dye allergy) or for treatment of non-autoimmune conditions (i.e., delayed-type hypersensitivity reaction caused by a contact allergen) is permitted

Previous malignant disease other than breast cancer within the last 5 years, with the exception of basal or squamous cell carcinoma of the skin, cervical carcinoma in situ, or low-risk cancers considered curatively treated (i.e. complete remission achieved at least 2 years prior to first dose of study drugs AND additional therapy not required while receiving study treatment)

All subjects with central nervous system metastases, and/or carcinomatous meningitis, except those meeting the following criteria: * Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment * No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable) * Subjects must be either off steroids or on a stable or decreasing dose of = 10 mg daily prednisone (or equivalent)

Receipt of any organ transplantation including allogeneic stem-cell transplantation

Significant acute or chronic infections including, among others: * Known history of testing positive for human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS) * A history of a positive test for hepatitis B virus (HBV) surface antigen (and/or core antibody) and/or confirmatory hepatitis C virus (HCV) ribonucleic acid (RNA) (if anti-HCV antibody tested positive); testing is not required for this protocol

Active autoimmune disease with reasonable possibility of clinically significant deterioration when receiving an immunostimulatory agent: * Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses = 10 mg or 10 mg equivalent prednisone per day * Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable

History of interstitial lung disease that is symptomatic or which may interfere with the detection or management of suspected drug-related pulmonary toxicity

Uncontrolled asthma (defined as having 3 or more of the following features of partially controlled asthma within 28 days prior to starting study treatment: Daytime symptoms more than twice per week, any limitation of activities, any nocturnal symptoms/awaking, need for reliever/rescue inhaler more than twice per week, or known lung function [peak expiratory flow (PEF) or forced expiratory volume in 1 second (FEV1)] without administration of a bronchodilator that is 80% predicted or personal best [if known])

Current symptomatic congestive heart failure (New York Heart Association > class II), unstable cardiac arrhythmia requiring therapy (e.g. medication or pacemaker), unstable angina (e.g. new, worsening or persistent chest discomfort), uncontrolled hypertension (systolic > 160 mmHg or diastolic > 100mmHg), or known cardiac ejection fraction below the lower limit of institutional normal. Or any of the following occurring within 6 months (180 days) prior to first dose of avelumab: Myocardial infarction, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack. (Use of antihypertensive medication to control blood pressure is allowed.)

Patients who have neuromuscular disorders associated with elevated creatine kinase (CK)

History of acute or chronic pancreatitis

History or current evidence of retinal vein occlusion (RVO), or current risk factors for RVO including uncontrolled glaucoma, ocular hypertension, history of hyperviscosity, or hypercoagulability syndromes (patients with a history of pulmonary embolism or deep vein thrombosis (DVT) are allowed on study if they are also on anticoagulation as noted below); history of retinal degenerative disease

Requirement of anticoagulant therapy with oral vitamin K antagonists such as Coumadin (warfarin). Low-dose anticoagulants for the maintenance of patency in a central venous access device or the prevention of deep vein thrombosis or pulmonary embolism is allowed. Therapeutic use of low molecular weight heparin or factor Xa inhibitors are allowed provided patients are safely able to interrupt it prior to biopsy procedures

Persisting toxicity related to prior therapy that has not reduced to grade 1 (National Cancer Institute Common Toxicity Criteria for Adverse Events [NCI CTCAE] version 5.0); however, alopecia and sensory neuropathy grade = 2 is acceptable

Known severe (grade >= 3 NCI-CTCAE version [v]5.0) hypersensitivity reactions to monoclonal antibodies, or history of anaphylaxis

Vaccination within 28 days of the first dose of study drugs and while on trial is prohibited, except for administration of inactivated vaccines (for example, inactivated influenza vaccine)

Pregnant or breastfeeding females

Known current alcohol or drug abuse

Prisoners or subjects who are involuntarily incarcerated

Known psychiatric condition, social circumstance, or other medical condition reasonably judged by the patients study physician to unacceptably increase the risk of study participation; or to prohibit the understanding or rendering of informed consent or anticipated compliance with scheduled visits, treatment schedule, laboratory tests and other study requirements

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trials, call 615-936-8422.