This phase I trial studies how well atezolizumab before and/or with standard of care chemoradiotherapy works in immune system activation in patients with stage IB2, II, IIIB, or IVA cervical cancer that has spread to the lymph nodes. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving atezolizumab before and/or with chemoradiotherapy may lower the chance of tumors growing or spreading.
PRIMARY OBJECTIVES: I. To determine whether differences in sequencing of atezolizumab and chemoradiation result in differential immune activation, as determined by clonal expansion of T cell receptor beta (TCRB) repertoires in peripheral blood on day 21. SECONDARY OBJECTIVES: I. To investigate the feasibility of administration of the anti PD-L1 antibody (atezolizumab) as an immune primer and concurrent with chemoradiation (CRT) therapy in patients with locally advanced cervical cancer. II. To determine the nature and degree of toxicity of the anti PD-L1 antibody (atezolizumab) administered as an immune primer and concurrent with chemoradiation (CRT) therapy in patients with locally advanced cervical cancer. III. To examine the changes in T cell receptor (TCR) clonality, diversity, and frequency in peripheral blood and tissue and correlate this with clinical outcomes, such as the exploratory response assessment on the post-treatment positron emission tomography (PET)-computed tomography (CT) scan and 2-year disease-free survival (DFS). IV. To assess the predictive value of baseline and on-treatment PD-L1 expression in the tissue in each treatment arm for clinical outcomes using post-treatment PET-CT scan and 2-year DFS as the outcome measures. EXPLORATORY OBJECTIVES: I. To explore baseline and on-treatment blood and tissue biomarkers that could predict response to the combination therapy, as correlated to the exploratory clinical endpoint of the week 12 (day 140) PET-CT scan and 2-year DFS. II. To explore the response assessment on the exploratory and optional post-treatment week 12 (day 140) PET-CT scan and the clinical 2-year disease free survival (DFS). OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on days -21, 0, and 21 in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care cisplatin chemotherapy IV over 90 minutes on days 0, 7, 14, 21, 28, and 35. Beginning on day 0, patients also receive standard of care radiation therapy once daily (Monday-Friday) for a total of 25 fractions with image guided brachytherapy beginning in week 4, 5, or at the end of radiation therapy. ARM B: Patients receive atezolizumab IV over 30-60 minutes on days 0, 21, and 42 in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care cisplatin chemotherapy, radiation therapy, and image guided brachytherapy as in Arm A. After completion of study treatment, patients are followed up at 1 and 3 months, and then every 3 months for 2 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
40
Given IV
Undergo standard of care image guided brachytherapy
Given IV
Undergo standard of care radiation therapy
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
UC San Diego Moores Cancer Center
La Jolla, California, United States
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States
UCHealth University of Colorado Hospital
Aurora, Colorado, United States
Augusta University Medical Center
Augusta, Georgia, United States
University of Iowa/Holden Comprehensive Cancer Center
Iowa City, Iowa, United States
Roswell Park Cancer Institute
Buffalo, New York, United States
Memorial Sloan Kettering Cancer Center
New York, New York, United States
Cleveland Clinic Foundation
Cleveland, Ohio, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
...and 6 more locations
Immune Response
The immune response is measured by total T cell receptor beta (TCRB) clonal expansion in peripheral blood at day 21 from baseline using Adaptive Biotechnologies' immunoSEQ platform from Day -21 to Day 21 for group 1 (i.e., Arm A), and from Day 0 to Day 21 for group 2 (i.e., Arm B). The higher number of total TCR clonal expansion indicates better immune response.
Time frame: Arm A: 42 days from the first dose of Atezolizumab Arm B: 21 days from the first dose of Atezolizumab
Percentage of Participants With Dose Limiting Toxicities
A DLT is defined as any drug related adverse effects that occur during treatment period until 30 days after the completion of CRT and meet the criteria as evaluated by NCI CTCAE v.5 unless clearly unrelated to study therapy (e.g., disease progression).
Time frame: Arm A: 111 days, i.e., from start of the priming dose of atezolizumab until 30 days after the completion of CRT Arm B: 90 days, i.e., from start of CRT until 30 days after the completion of CRT(Chemoradiation therapy).
Post-treatment 3-month PET/CT Metabolic Response
Percentage of participants with complete post-treatment 3-month PET/CT metabolic response. The post-treatment 3-month PET/CT metabolic response is evaluated based on the ratio of post-treatment week-12 PET-CT SUVmax to base-line PET-CT scan SUV max, and the response will be classified as complete metabolic response for the ratio \< 0.34, or classified as partial metabolic response for 0.34 \<= the ratio \< 0.76, or classified as stable metabolic response for 0.76 \<= the ratio \< 1.25, or classified as progressive metabolic disease for the ratio \>= 1.25.
Time frame: 3 months after completion of study treatment
Adverse Events (Grade 3 or Higher) During Treatment Period as Assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version (v)5
Number of participants with a maximum grade of 3 or higher during treatment period. Adverse events are graded and categorized using CTCAE v5.0.
Time frame: Arm A: 111 days, i.e., from start of the priming dose of atezolizumab until 30 days after the completion of CRT Arm B 90 days, i.e., from start of CRT until 30 days after the completion of CRT
T Cell Receptor (TCR) Simpson Clonality
TCR Simpson clonality in peripheral blood is measured at day 21 using Adaptive Biotechnologies' immunoSEQ platform. It quantitates the extent of mono- or oligoclonal dominance within a TCR repertoire by measuring the shape of the clone frequency distribution ranging from 0 to 1, where values approaching 1 indicate a nearly monoclonal population.
Time frame: Arm A: 42 days from the first dose of Atezolizumab Arm B: 21 days from the first dose of Atezolizumab
Pre-treatment PD-L1 Expression
Pre-treatment PD-L1 SP142 positive immune cells in tumor area in formalin-fixed paraffin-embedded (FFPE) biopsy primary tumor tissues
Time frame: Within 3 days after randomization but before start of study treatment
Disease-free Survival (DFS) at 2 Years
Percentage of participants who survive disease-free at 2 years, where DFS is defined as the duration of time from study entry to date of first documented recurrence or progression of disease or death, whichever occurs first. Progression is assessed by RECIST 1.1.Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: Up to 2 years
T Cell Receptor (TCR) Diversity
TCR diversity in peripheral blood is measured at day 21 by counting the number of unique rearrangements to a common number of T cells using Adaptive Biotechnologies' immunoSEQ platform. A higher TCR diversity indicates a richer TCR repertoire.
Time frame: Arm A: 42 days from the first dose of Atezolizumab Arm B: 21 days from the first dose of Atezolizumab
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