This phase II trial compares the effect of adding ipatasertib to pembrolizumab (standard immunotherapy) vs. pembrolizumab alone in treating patients with squamous cell cancer of the head and neck that has come back (recurrent) or that has spread from where it first started (primary site) to other places in the body (metastatic). Ipatasertib is in a class of medications called protein kinase B (AKT) inhibitors. It may stop the growth of tumor cells and may kill them. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving ipatasertib in combination with pembrolizumab may be more effective than pembrolizumab alone in improving some outcomes in patients with recurrent/metastatic squamous cell cancer of the head and neck.
PRIMARY OBJECTIVE: I. To compare progression-free survival (PFS) in first line relapsed/metastatic (R/M) head and neck squamous cell cancer (HNSCC) patients treated with the combination ipatasertib and pembrolizumab versus pembrolizumab monotherapy treatment. SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability of the combination ipatasertib and pembrolizumab in first line R/M HNSCC patients. II. To describe overall response rate (ORR) and duration of response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in first line R/M HNSCC treated patients with the combination ipatasertib and pembrolizumab and pembrolizumab monotherapy treatment. III. To assess changes in the tumor microenvironment by immunophenotyping with the combination ipatasertib and pembrolizumab and pembrolizumab monotherapy treatment. IV. To assess changes in Akt, ERK, and MEK signaling with the combination ipatasertib and pembrolizumab and pembrolizumab monotherapy treatment. V. To determine changes in immune-cell population in peripheral blood with the combination ipatasertib and pembrolizumab and pembrolizumab monotherapy treatment. EXPLORATORY OBJECTIVE: I. To investigate the relationship between the combination ipatasertib and pembrolizumab treatment and biomarkers which may predict response, such as tumor PD-L1 expression and alterations in the PI3K/AKT pathway. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and ipatasertib orally (PO) once daily (QD) on days 1-14 of each cycle. Cycles repeat every 21 days for a period of 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy on study, undergo collection of blood samples on study and during follow up, and undergo computed tomography (CT) scans throughout the trial. ARM II: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for a period of 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy on study, undergo collection of blood samples on study and during follow up, and undergo CT scans throughout the trial. After completion of study treatment, patients are followed every 3 months until disease progression, the next line of therapy is started, or death, whichever occurs first.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
52
Undergo biopsy
Undergo collection of blood samples
Undergo CT
Given PO
Given IV
City of Hope Comprehensive Cancer Center
Duarte, California, United States
City of Hope at Irvine Lennar
Irvine, California, United States
City of Hope Antelope Valley
Lancaster, California, United States
Keck Medicine of USC Koreatown
Los Angeles, California, United States
Los Angeles General Medical Center
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
USC Norris Oncology/Hematology-Newport Beach
Newport Beach, California, United States
Stanford Cancer Institute Palo Alto
Palo Alto, California, United States
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States
MedStar Georgetown University Hospital
Washington D.C., District of Columbia, United States
...and 10 more locations
Progression free survival (PFS)
The 1-sided log rank test for equality of risk for PFS-event will be performed (Dang et al., 2020). If the p-value is less than or equal to 0.15, it will be concluded that the ipatasertib plus pembrolizumab has sufficient efficacy for further evaluation.
Time frame: From date of randomization until disease progression, death, or date of last contact, whichever occurs first, assessed up to 1 year after the last patient is enrolled
Incidence of adverse events
Tables will be created to summarize the numbers of patients who experienced toxicities (graded according to the Common Terminology Criteria for Adverse Events version 5.0), by arm, toxicity system, type, grade, and attribution.
Time frame: Up to 1 year after the last patient is enrolled
Overall response rate
Will be assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for both cohorts in the study. The primary analysis will be based on a modified intention-to-treat analysis which will include all eligible, randomized patients who receive any amount of treatment according to the patient's randomization. The two arms will be compared in terms of the overall response rate (probability of complete response \[CR\] or partial response \[PR\] by RECIST version 1.1) using a one-sided, 0.10-level Mantel-Haenszel. Two-sided 80% confidence intervals will be constructed for the probability of response in each arm. In addition, a logistic regression (exact, if required based on the numbers) will be used to estimate the odds ratio comparing the 2 arms adjusting for the stratification variables.
Time frame: Up to 1 year after the last patient is enrolled
Duration of response
Will be assessed according to RECIST 1.1 for both cohorts in the study. Will be calculated as the date of the scan that first demonstrated a PR or CR until the patient demonstrates a PFS-event.
Time frame: From the date of the scan that first documented a PR or CR until the patient demonstrates a PFS event, assessed up to 1 year after the last patient is enrolled
Changes in the tumor microenvironment by immunophenotyping
Will be assessed by comparing immunophenotype of paired biopsy specimens for individual patients, with archival/pre-treatment biopsy and the C2D7 biopsy. Categorical data methods, including exact conditional methods, will be used to compare the proportions of these various response categories across randomized treatment assignment.
Time frame: Baseline up to 1 year after the last patient is enrolled
Changes in Akt, ERK, and MEK signaling
Categorical data methods, including exact conditional methods, will be used to compare the proportions of these various response categories across randomized treatment assignment.
Time frame: Baseline up to 1 year after the last patient is enrolled
Changes in immune-cell population in peripheral blood
Will be assessed by comparing blood specimens for individual patients over time: baseline, defined as the blood sample obtained closest to but not exceeding the date of the first dose of protocol therapy; on day 7 of cycle 2; on day 1 of every odd cycle; and at progression while the patient is receiving combination therapy. The statistical null hypothesis is defined as no change in percent of each cell type across time points and between regimens. These will be assessed quantitatively using a non-parametric analysis of variance with time point and randomized regimen as predictor variables.
Time frame: Baseline up to 1 year after the last patient is enrolled
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