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

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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...

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.

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