This phase I trial studies the side effects and best dose of berzosertib (M6620) when given together with cisplatin and radiation therapy in treating patients with head and neck squamous cell carcinoma that has spread from where it started to nearby tissue or lymph nodes (locally advanced). M6620 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving M6620 together with cisplatin and radiation therapy may work better in treating patients with locally advanced head and neck squamous cell carcinoma.
PRIMARY OBJECTIVES: I. Assess the safety and tolerability of M6620 (VX-970, berzosertib) when administered along with weekly cisplatin and radiation therapy (XRT) in patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC). II. Establish the recommended phase 2 dose (RP2D) of the combination. SECONDARY OBJECTIVES: I. Characterize the pharmacokinetic (PK) profile of M6620 (VX-970, berzosertib). II. Assess for potential drug-drug interaction between M6620 (VX-970, berzosertib) and aprepitant. III. To observe and record anti-tumor activity. IV. To assess the rate of complete metabolic response (CMR) at 12 weeks post completion of chemoradiation using 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) scans. V. To collect archival tumor material for retrospective analysis of association between tissue-based biomarkers and clinical outcome. OUTLINE: This is a dose-escalation study of berzosertib. Patients receive berzosertib intravenously (IV) over 60 minutes on day -7 and then weekly on day 2 and cisplatin IV over 30-60 minutes weekly on day 1. Patients also undergo radiation therapy once daily, 5 days a week. Treatment continues for up to 7 weeks in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo computed tomography (CT), PET/CT, or magnetic resonance imaging (MRI) throughout the study. After completion of study treatment, patients are followed up for 30 days, every 2 weeks for 3 months, and then every 3 months for 2 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
43
Given IV
Given IV
Undergo CT or PET/CT
Correlative studies
Undergo MRI
Undergo PET/CT
Undergo radiation therapy
City of Hope Comprehensive Cancer Center
Duarte, California, United States
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States
Smilow Cancer Center/Yale-New Haven Hospital
New Haven, Connecticut, United States
Yale University
New Haven, Connecticut, United States
Smilow Cancer Hospital Care Center-Trumbull
Trumbull, Connecticut, United States
Emory University Hospital Midtown
Atlanta, Georgia, United States
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, United States
University of Iowa/Holden Comprehensive Cancer Center
Iowa City, Iowa, United States
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, United States
University of Maryland/Greenebaum Cancer Center
Baltimore, Maryland, United States
...and 9 more locations
Number of Participants Experiencing Grade 3, 4, and 5 Adverse Events
According to the Cancer Therapy Evaluation Program National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v. 5). The highest grade experienced by the participant will be reported.
Time frame: Up to 6.5 years
Number of Participants Experiencing a Dose Limiting Toxicities
Dose limiting toxicities are protocol-specific adverse events considered at least possibly related to the study intervention. Graded according to NCI CTCAE v5.
Time frame: Up to 3 weeks after completion of radiation therapy
Establish the Recommended Phase 2 Dose (RP2D)
Defined as the highest doses of cisplatin and berzosertib safely combined with radiation.
Time frame: Up to 7 weeks
Pharmacokinetic Characteristics of Berzosertib
The maximum concentration ratio between Day -7 collections to Day 2 collections. Collection time points are baseline, 30 and 55 minutes after the start of M6620 infusion, 5, 15, 30 minutes, 1, 2, 4, 23 (Day 3), 48 (Day 4), and 72 hours (Day 5) after the end of M6620 infusion given on Day 2.
Time frame: Up to Day 5
Potential Drug-drug Interaction
The maximum concentration of M6620 in the blood when aprepitant is also given.
Time frame: Up to Day 5
Number of Participants Experiencing a Response
Evaluated by Response Evaluation Criteria in Solid Tumors 1.1. Response is defined as complete response (disappearance of all target and non-target lesions) or partial response (at least a 30% decrease in the sum of diameters of target lesions from baseline).
Time frame: Up to 6.5 years
Number of Participants Experiencing a Metabolic Response
Assessed by fluorodeoxyglucose-positron emission tomography (FDG PET) and measured by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Metabolic response are participants demonstrating a complete response (disappearance of all target and non-target lesions) or a partial response (at least a 30% decrease in the sum of diameters of target lesions from baseline).
Time frame: At week 12 after completing intervention
Expression of Tissue-based Biomarkers as Markers of Deoxyribonucleic Acid Damage and Predictors of Clinical Outcome
Kaplan-Meier curves for Progression Free Survival (PFS), defined as time to disease progression, and Overall Survival (OS), defined as time until death or off study, were used to evaluate if the gene expression profiles of ERCC1 and XRCC1, and TP53 correlated to these outcomes.
Time frame: Up to 6.5 years
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