This phase II trial studies how well nivolumab works, with or without BMS986205, in treating patients with stage II-IV squamous cell cancer of the head and neck. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. BMS986205 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving nivolumab with BMS986205 may work better than nivolumab alone in treating patients with squamous cell cancer of the head and neck.
PRIMARY OBJECTIVES: I. To assess the impact of IDO1 inhibitor BMS-986205 (BMS986205) and nivolumab versus nivolumab alone on tumor radiographic response both at the primary tumor site and in regional lymph nodes by investigator assessment at 5 weeks. SECONDARY OBJECTIVES: I. To investigate whether adding the IDO1 - inhibitor, BMS986205, to nivolumab therapy affects intratumoral and systemic anti-tumor immunity. II. To assess the impact of BMS986205 and nivolumab verses nivolumab alone on pathologic treatment effect bother at the primary and regional lymph nodes. III. To determine the effect of BMS986205 and nivolumab versus nivolumab alone on immune cell composition within the tumor microenvironment including the presence of effector T cells (Teff), regulatory T cells (Treg), and tumor-associated macrophages (TAM). IV. To further characterize the effect of BMS986205 when combined with nivolumab on kynurenine production and correlate these levels with effects on immune cell composition and polarization. V. To review the relationship of p16 status by immunohistochemistry with immune cell polarization, tumor radiographic response, and immune cell composition. VI. To review the relationship of PD-L1 status by immunohistochemistry with immune cell polarization, tumor radiographic response, and immune cell composition. VII. To assess the safety and tolerability of BMS986205 and nivolumab. VIII. Evaluate surgical wound healing post treatment. EXPLORATORY OBJECTIVES: I. To further characterize the effect of BMS986205 and nivolumab versus nivolumab alone through analysis of T cell repertoire. II. To assess the interactions between the immune and metabolic microenvironment through analysis of alterations in exosome composition in peripheral blood as it related to immune, cytokine and metabolic alterations before, during and after treatment. III. To identify risks for poor physical and mental health outcomes; examine bio-behavioral factors associated with cancer treatment outcomes; and evaluate the physical and psychosocial needs of cancer survivors through patient reported outcomes. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive IDO1 inhibitor BMS-986205 orally (PO) once daily (QD). Beginning week 2, patients also receive nivolumab intravenously (IV) over 30 minutes on day 1. Treatment repeats for up to 5 weeks in the absence of disease progression or unacceptable toxicity. Patients showing a treatment response receive IDO1 inhibitor BMS-986205 PO QD for 4 additional weeks and receive nivolumab IV over 30 minutes on day 1, then undergo surgery at week 10. Those without a treatment response after 5 weeks undergo surgery within 7 days. ARM II: Patients receive nivolumab IV over 30 minutes on day 1 in the absence of disease progression or unacceptable toxicity. Patients showing treatment response after 4 weeks receive nivolumab IV over 30 minutes on day 1, then undergo surgery at week 9. Those without a treatment response after 4 weeks undergo surgery within 7 days. After completion of study treatment, patients are followed up periodically for 12 months.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
45
Given IV
Given PO
Undergo Surgery
Ancillary studies
Ohio State University
Columbus, Ohio, United States
Sidney Kimmel Cancer Center at Thomas Jefferson University
Philadelphia, Pennsylvania, United States
Objective Response
Will be assessed by computed tomography (CT) or magnetic resonance imaging (MRI) scans. The proportions of the primary endpoint in the two treatment groups will be compared at 25% significance level using a two-sided test in proportions. Will re-analyze the primary endpoints using a combined patients collection. Historical controls of patients who received nivolumab alone for 4 weeks in previous window of opportunity trial (CA209-9A7) will be included in the control group. Patients' demographic as well as pre-treatment clinical measurements will be compared between the combined control group versus the treatment group to ensure the homogeneity of the two groups. A multi-variable logistic regression model will be used in the statistical analysis, if any difference in the demographic and clinical predictors between treatment groups is detected. Otherwise, the proportions of the primary endpoint in the two treatment groups will be compared at 5% significance level using a two-sided test.
Time frame: At 5 weeks
Objective pathologic response at time of surgery
If there is at least one significant difference between groups among the primary outcomes, the two randomization arms will be compared with respect to each secondary outcome using two-sample t-tests. P-values for comparisons of changes in secondary outcomes will be adjusted using the method of Benjamini and Hochberg to control the false discovery rate (FDR) among the secondary outcomes at 5%.
Time frame: At time of surgery
Change in immune cell polarization (Th1/Th2; M1/M2) in peripheral blood and tumor specimens
Will be analyzed and compared using multiplex cytokine analysis collected before and after exposure to nivolumab +/- IDO1 inhibitor BMS-986205 (BMS986205). If there is at least one significant difference between groups among the primary outcomes, the two randomization arms will be compared with respect to each secondary outcome using two-sample t-tests. P-values for comparisons of changes in secondary outcomes will be adjusted using the method of Benjamini and Hochberg to control the FDR among the secondary outcomes at 5%.
Time frame: Baseline up to 12 months
Change in inflammatory markers
These include soluble (s)CD40 ligand (L), EGF, eotaxin, FGF-2, Flt-3 ligand, fractalkine, granulocyte colony-stimulating factor (G-CSF), granulocyte colony-macrophage (GM)-CSF, GRO, IFN-alpha2, IL-1alpha, IL-1beta, IL-1ra, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-12 (p40), IL-13, IL-15, IL-17A, IP-10, MCP-1, MCP-3, MDC (CCL22), MIP-1alpha, MIP-1beta, PDGF-AA, PDGF-AB/BB, RANTES, TGF-alpha, TNF-alpha, VEGF. If there is at least one significant difference between groups among the primary outcomes, the two randomization arms will be compared with respect to each secondary outcome using two-sample t-tests. P-values for comparisons of changes in secondary outcomes will be adjusted using the method of Benjamini and Hochberg to control the FDR among the secondary outcomes at 5%
Time frame: Baseline up to 12 months
Change in prevalence of intratumoral immune cell populations (effector T cells [Teff], regulatory T cells [Treg], and tumor-associated macrophages [TAM] in patients treated with Nivolumab and BMS986205 as compared to patients treated with Nivolumab alone
Assessed by immunohistochemistry (IHC). If there is at least one significant difference between groups among the primary outcomes, the two randomization arms will be compared with respect to each secondary outcome using two-sample t-tests. P-values for comparisons of changes in secondary outcomes will be adjusted using the method of Benjamini and Hochberg to control the FDR among the secondary outcomes at 5%.
Time frame: Baseline up to 12 months
Localization of immune cells within the tumor
Will be analyzed using confocal microscopy.
Time frame: Up to 12 months
Multiplex colocalization of resident immune cells
Will utilize 5-6 markers per section.
Time frame: Up to 12 months
Kynurenine levels (blood and tumor)
Measured with commercial quantitative enzyme-linked immunosorbent assay (ELISA) kits. If there is at least one significant difference between groups among the primary outcomes, the two randomization arms will be compared with respect to each secondary outcome using two-sample t-tests. P-values for comparisons of changes in secondary outcomes will be adjusted using the method of Benjamini and Hochberg to control the FDR among the secondary outcomes at 5%.
Time frame: Up to 12 months
Intratumoral immune cell populations, immune polarization data, exosome composition, and exosome function in human papilloma virus (HPV) + and HPV- tumors
Baseline IHC staining for P16 will be performed as a surrogate for HPV status. If there is at least one significant difference between groups among the primary outcomes, the two randomization arms will be compared with respect to each secondary outcome using two-sample t-tests. P-values for comparisons of changes in secondary outcomes will be adjusted using the method of Benjamini and Hochberg to control the FDR among the secondary outcomes at 5%.
Time frame: Up to 12 months
Intratumoral immune cell populations, immune polarization data, exosome composition, and exosome function relative to PD-L1 expression levels
Assessed by IHC. If there is at least one significant difference between groups among the primary outcomes, the two randomization arms will be compared with respect to each secondary outcome using two-sample t-tests. P-values for comparisons of changes in secondary outcomes will be adjusted using the method of Benjamini and Hochberg to control the FDR among the secondary outcomes at 5%.
Time frame: Up to 12 months
Incidence of adverse events
Will be graded by Common Terminology Criteria for Adverse Events version 5.0. Safety outcomes will be summarized overall and by treatment arm.
Time frame: Up to 100 days
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