Avelumab With Binimetinib, Utomilumab, or Anti-OX40 Antibody PF-04518600 in Treating Triple Negative Breast Cancer

This phase II trial studies how well avelumab in combination with binimetinib, utomilumab, or anti-OX40 antibody PF-04518600 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 patients 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. Patients on this trial will receive two weeks of treatment with one of three treatments to stimulate the bodies immune system, including the monoclonal antibodies, utomilumab, and the anti-OX40 antibody PF-04518600 which may help the body's immune system attack the cancer, and could interfere with the ability of tumor cells to grow and spread. 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 binimetinib, utomilumab, or anti-OX40 antibody PF-04518600 will work better in treating patients with triple negative breast cancer

OUTLINE: Patients are randomized to 1 of 3 arms.

Arm I: Patients receive binimetinib orally (PO) twice daily (BID) for a lead-in period of 15 days in the absence of disease progression or unacceptable toxicity. Patients then receive binimetinib orally (PO) twice daily (BID) on days 1-28 and avelumab intravenously (IV) over 60 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity

Arm II: Patients receive anti-OX40 antibody PF-04518600 IV over 60 minutes for a for lead-in period of 15 days in the absence of disease progression or unacceptable toxicity. Patients then receive anti-OX40 antibody PF-04518600 IV over 60 minutes and avelumab IV over 60 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Arm III: Patients receive utomilumab IV over 60 minutes for a lead-in period of 15 days in the absence of disease progression or unacceptable toxicity. Patients then receive utomilumab IV over 60 minutes every 4 weeks and avelumab IV over 60 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients have a follow-up at 30 days after treatment ends and then every 6 months for a minimum of one year following start of study therapy or until the study is stopped.

PRIMARY OBJECTIVES:

I. Anti-tumor effect of avelumab in combination with different targeted agents explored in the sub-protocols of the trial.

SECONDARY OBJECTIVES:

I. Additional anti-tumor effects. II. Safety and tolerability of avelumab in combination with different targeted agents explored in the sub-protocols of the trial.

III. Patient reported outcomes (PRO) between baseline and cycle 3 day 1 across arms.

IV. Longitudinal trends in PRO outcomes across treatment arms. V. Differences in PRO outcomes for patients who respond compared to those who do not respond.

CORRELATIVE OBJECTIVES:

I. To determine the therapeutic predictive role of the following on clinical outcome:

I a. Programmed cell death-ligand 1 (PD-L1) expression and immune 'hot-spots'. I b. Tumor infiltrating lymphocyte (TIL)s, and cluster of differentiation 8 (CD8) and cluster of differentiation 4 (CD4) positivity in TIL.

I c. Human leukocyte antigen (HLA)-A (Major Histocompatibility complex class 1 (MHC-I)) and Human Leukocyte Antigen - DR isotype (HLA-DR) (Major Histocompatibility complex class 2 (MHC-II)), FoxP3, OX40 and OX40L, Phosphatase and tensin homolog (PTEN), and myelocytomatosis oncogene (MYC) expression.

I d. Number/levels of expressed predicted class I and class II neoantigens, central memory T-cells and T-cells.

I e. Expression of effector/regulatory immune gene, innate Programmed cell death protein 1 (PD-1) resistance signature (IPRES), and B cell, T cell, and/or macrophage signatures.

I f. Basal or claudin-low molecular subtypes. I g. T cell receptor (TCR) clonality in the tumor and peripheral blood. I h. Genomic mutational burden. I i. PD-L1 positivity in circulating tumor cells (CTCs). I j. Soluble B7-H1 (sB7-H1) levels.

II. To determine if circulating tumor deoxyribonucleic acid (DNA) (ctDNA) results will discriminate pseudo-progression from true progression.

III. To determine if certain genomic alterations detected in tumor tissue or ctDNA are potentially associated with resistance to the tested drug combinations.

• Stage III Breast Cancer
• Stage IIIA Breast Cancer
• Stage IIIB Breast Cancer
• Stage IIIC Breast Cancer
• Stage IV Breast Cancer
• Invasive Breast Carcinoma
• Recurrent Breast Carcinoma
• Triple-Negative Breast Carcinoma

• Biological: Anti-OX40 Antibody PF-04518600
  Given IV
  Other Name: PF-04518600
• Drug: Avelumab
  Given IV
  Other Names:

  • Bavencio
  • MSB-0010718C
  • MSB0010718C
• Drug: Binimetinib
  Given PO
  Other Names:

  • ARRY-162
  • ARRY-438162
  • MEK162
• Biological: Utomilumab
  Given IV
  Other Names:

  • PF 05082566
  • PF 5082566
  • PF-05082566
  • PF-2566

• Experimental: Arm I (binimetinib, avelumab)
  Patients will receive a 15-day lead-in of binimetinib, followed by binimetinib PO BID and avelumab IV over 60 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Avelumab
  • Drug: Binimetinib
• Experimental: Arm II (anti-OX40 antibody PF-04518600, avelumab)
  Patients will receive a 15-day lead-in of anti-OX40 antibody PF-04518600, followed by anti-OX40 antibody PF-04518600 IV over 60 minutes and avelumab IV over 60 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Biological: Anti-OX40 Antibody PF-04518600
  • Drug: Avelumab
• Experimental: Arm III (utomilumab, avelumab)
  Patients will receive a 15-day lead-in of utomilumab, followed by utomilumab IV over 60 minutes every 4 weeks and avelumab IV over 60 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Avelumab
  • Biological: Utomilumab

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 mammary carcinoma or unresectable locoregional recurrence of invasive mammary carcinoma that is:

  • Estrogen receptor (ER)/progesterone receptor (PR)-negative (=< 5% cells) by immunohistochemistry (IHC) and human epidermal growth factor receptor 2 (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 measureable 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
  • Amenable to biopsy at the time of study entry
  • Known tumor/immune cell PD-L1 status by any assay
• Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
• 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
• Thyroid stimulating hormone (TSH) within institutional normal limits
• Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 x ULN
• Amylase =< 1 x ULN
• Lipase =< 1 x ULN

• 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 participant's final dose of study drug(s). See sub-protocols for additional arm specific details

  • 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-treatment screen failure (i.e. a consented patient who did not receive avelumab) 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, they do not need to be repeated

Exclusion Criteria:

• More than 3 lines of chemotherapy in the metastatic setting
• More than 1 prior line of checkpoint inhibitor therapy in the metastatic setting

• Concurrent anticancer therapy. Required washout from prior therapies are as follows:

  • Chemotherapy: >= 14 days
  • Major surgery: >=14 days (provided wound healing is adequate)
  • Radiation: >= 7 days
  • Investigational/biologic therapy (half-life =< 40 hours): >= 14 days
  • Investigational/biologic therapy (half-life > 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 (e.g. 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 (e.g. CT scan premedication against contrast dye allergy) or for treatment of nonautoimmune conditions (e.g. 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 brain metastases, 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 with type 1 diabetes mellitus, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
  • 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 that are 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; 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 is 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 v5.0) 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 patient's 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

• Translational Breast Cancer Research Consortium
• Hoosier Cancer Research Network
• Array BioPharma
• Pfizer
• Breast Cancer Research Foundation
• Johns Hopkins University