To determine the effect of neoadjuvant atezolizumab alone or in combination with other immune modulating agents on T-cell infiltration in advanced SCCHN. To determine the impact of neo-adjuvant immunotherapy on surgical outcomes.
PRIMARY OBJECTIVES: I. To determine the effect of neoadjuvant atezolizumab alone or in combination with tiragolumab, tocilizumab, or other immune modulating agent(s) on T-cell infiltration in advanced in advanced squamous cell carcinoma of the head and neck (SCCHN). (Translational). II. To determine the impact of neo-adjuvant immunotherapy on surgical outcomes. (Clinical). SECONDARY OBJECTIVES: I. To describe the changes in T-cell subtypes and other mediators of antitumor immune response induced by neoadjuvant atezolizumab alone or in combination with tiragolumab, tocilizumab, or other immune-modulating agent(s) in advanced SCCHN patients. (Translational). II. To describe the impact of neoadjuvant, surgical, and adjuvant therapy on peripheral immune responses. (Translational). III. To establish the safety/toxicity profile of each regimen in the perioperative settings for patients with advanced SCCHN. (Clinical). EXPLORATORY OBJECTIVES: I. To characterize changes in the gut microbiome associated with each therapeutic combination. II. To assess the correlation of disease status with C-Reactive Protein (CRP) and lactate dehydrogenase (LDH) levels. III. To assess the correlation of disease status with Interleukin 6 (IL-6) levels for participants in Arm C (atezolizumab + tocilizumab). IV. If leftover tissue and funding are available: To develop immune-competent tumor xenograft models. V. To determine whether neo-adjuvant immune therapy improves 2-year relapse-free survival (RFS) in patients with SCCHN OUTLINE: This is a phase II, multi-arm, open-label trial of perioperative atezolizumab alone or in combination with other immune-modulating agents in advanced SCCHN. Based on the results of these initial cohorts, the trial will be amended to explore other novel atezolizumab-based combinations (such as atezolizumab in combination with another immuno-oncology (IO) agent, chemotherapeutics, or a molecularly targeted agent that could potentiate the activity of atezolizumab). Each of these new cohorts will be tested and enrolled to in sequential, non-randomized fashion. Arm A: Patients receive 2 infusions of atezolizumab intravenously (IV) over 30-60 minutes for up to 15 days prior to definitive surgery and radiation. Arm A (Adjuvant): Patients received 2 infusions of atezolizumab intravenously (IV) over 30-60 minutes for up to 15 days prior to definitive surgery and radiation. In addition to neoadjuvant atezolizumab, the first 9 participants in Arm A (atezolizumab monotherapy) received adjuvant atezolizumab beginning 16 weeks after surgery and radiation, or chemoradiation therapy, every 3 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. Adjuvant atezolizumab will only be initiated if radiation-associated adverse events have resolved to grade 2 or better. Arm B: Patients receive atezolizumab IV over 30-60 minutes for up to 2 courses and tiragolumab administered by IV infusion on Cycle 1 Day 1 of neoadjuvant treatment prior to standard surgery. Arm C: Patients receive atezolizumab IV over 30-60 minutes for up to 2 courses and tocilizumab administered by IV infusion on Cycle 1 Day 1 of neoadjuvant treatment prior to standard surgery. Tocilizumab will be administered (prior to atezolizumab administration) as an intravenous infusion Atezolizumab will be administered 2 hours after the conclusion of the tocilizumab infusion. After completion of study treatment, patients are followed up at 30 days post surgery, 3 months, 6 months, 12 months, and at 24 months.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
55
Given intravenously (IV)
Given IV
Given IV
University of San Francisco, California
San Francisco, California, United States
RECRUITINGProportion of subjects with a >= 40% increase in the cluster of differentiation 3 (CD3) counts
Intratumoral CD3+ T-cells will be identified by immunohistochemistry in pre- and post-treatment tumor specimens. The analysis population for the primary outcome will be all patients who received at least 2 weeks of neoadjuvant therapy with pre- and post-treatment tumor specimens that are evaluable for CD3+ T-cells. The proportion of patients with a \>= 40% increase (from pre- to post-treatment) will be calculated. The exact 95% confidence intervals (CIs) using the Pearson-Clopper method and an exact binomial test will be used as an exploratory purpose. The change from pre-treatment to post-treatment CD3 count per mm\^3 as a continuous measure will also be summarized.
Time frame: Up to 2 years
R0 resection rate
Patients who undergo surgery will be evaluable for R0 resection rate. R0 resection rate will be described by point estimate and 95% CI using the Pearson-Clopper method.
Time frame: Up to 2 years
Changes in immune parameters using mass cytometry (CyTOF), histology and gene expression
The study will describe immune parameters at each time point by median and interquartile range (IQR) and compare the change between pre-treatment and surgical specimens by Wilcoxon singed rank test. Diversity of T-cell repertoires at each time point will be evaluated by clonality and compared by Wilcoxon singed ranked test. Moristas' distance will also be used to assess the change of T-cell repertoires.
Time frame: Up to 2 years
Changes in peripheral immune responses using CyTOF
The study will describe immune parameters at each time point by median and IQR and compare the change between pre-treatment and surgical specimens by Wilcoxon singed rank test.
Time frame: Up to 1 year post surgery
Number of participants with treatment-related adverse events
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Treatment-related adverse events will be classified according to Common Terminology Criteria for Adverse Events version 5. Evaluation of Safety Analyses will be performed for all patients having received at least one dose of treatment on study.
Time frame: Up to 30 days post-treatment