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. (Translational). II. To assess the correlation of disease status with C-Reactive Protein (CRP) and lactate dehydrogenase (LDH) levels. (Translational). III. To assess the correlation of disease status with Interleukin 6 (IL-6) levels for participants in Arm C (atezolizumab + tocilizumab). (Translational). IV. If leftover tissue and funding are available: To develop immune-competent tumor xenograft models. (Translational). V. To determine whether neo-adjuvant immune therapy improves 2-year relapse-free survival (RFS) in patients with SCCHN (Clinical). VI. To develop immune-competent tumor xenograft models (If leftover tissue and funding are available). (Translational). OUTLINE: This is a phase II multi-site, open-label prospective clinical trial of neoadjuvant atezolizumab alone and in combination with tiragolumab, tocilizumab, or additional immune-modulating agents in patients with SCCHN. Participants will be enrolled sequentially into each arm. Arm A: Patients receive 2 infusions of atezolizumab intravenously (IV) over 30-60 minutes between 15 - 42 days prior to definitive surgery and radiation, depending on response and per Investigator's discretion. For the first 9 participants in Arm A (atezolizumab monotherapy), atezolizumab will be administered following surgery and radiation or chemoradiation therapies. Arm A (Adjuvant): Patients received 2 infusions of atezolizumab intravenously (IV) over 30-60 minutes between 15 - 42 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. The last participant is anticipated to be enrolled no later than July 31, 2026
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
Proportion 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 12 months
R0 resection rate
Participants 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 12 months
Frequency of Tumor infiltrating immune cell (TIIC) populations
The frequency of not yet determined tumor infiltrating immune cell (TIIC) populations by Multiplexed ion beam imaging (MIBI) and Immunohistochemistry (IHC) will be reported. These could possibly include Cluster of differentiation 8 (CD8), Granzyme B (GZMB), Cluster of differentiation 68 (CD68), and Cluster of differentiation 163 (CD163) populations.
Time frame: Up to 12 months
T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) expression in tumor-infiltrating immune cells (TIICs) (Arm B)
The proportion of participants with TIGIT expression in the TIICs by IHC for Arm B will be reported.
Time frame: Up to 12 months
Proportion of participants with programmed death-ligand 1 (PD-L1) expression in TIICs
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
The proportion of participants with PD-L1 expression in the TIICs by IHC will be reported.
Time frame: Up to 12 months
Change in T-cell repertoires and clonality
Change in T-cell repertoires and clonality by next-generation sequencing (NGS) will be reported. Moristas' distance will be used to assess the change of T-cell repertoires.
Time frame: Up to 12 months
Frequency of peripheral immune responses using Cytometry by time of flight (CyTOF) (Pre-treatment)
The study will describe immune parameters by enumerating circulating immune cell populations (phenotypes and frequencies) using CyTOF.
Time frame: Up to 30 days
Frequency of peripheral immune responses using CyTOF (Day of Surgery)
The study will describe immune parameters by enumerating circulating immune cell populations (phenotypes and frequencies) using CyTOF.
Time frame: Day of surgery (1 day)
Frequency of peripheral immune responses using CyTOF (First post-operative visit)
The study will describe immune parameters by enumerating circulating immune cell populations (phenotypes and frequencies) using CyTOF.
Time frame: First post-operative visit (1 day)
Frequency of peripheral immune responses using CyTOF (3 months)
The study will describe immune parameters by enumerating circulating immune cell populations (phenotypes and frequencies) using CyTOF.
Time frame: 3 months
Frequency of peripheral immune responses using CyTOF (6 months)
The study will describe immune parameters by enumerating circulating immune cell populations (phenotypes and frequencies) using CyTOF.
Time frame: 6 months
Frequency of peripheral immune responses using CyTOF (12 months)
The study will describe immune parameters by enumerating circulating immune cell populations (phenotypes and frequencies) using CyTOF.
Time frame: 12 months
Number of participants with treatment-related adverse events
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