Phase I trial of the ATR inhibitor BAY 1895344 combined with stereotactic body radiation therapy and pembrolizumab for recurrent head and neck squamous cell carcinoma.
Authors: Mowery Yvonne Marie , Niedzwiecki Donna , Choe Jennifer Hsing , Kirsch David G. , Brizel David M. 
Published: June 2022

TPS6108 Background: Despite aggressive multimodal treatment that typically includes radiation therapy (RT), recurrence rates approach 50% for patients with non-HPV-related locally advanced HNSCC. Treatment options for unresectable recurrent or metastatic HNSCC are limited, though PD-1 inhibitors improve survival for a subset of patients. Radiation resistance contributes to locoregional recurrence—a major driver for HNSCC morbidity and mortality. In preclinical studies, we observed significant HNSCC radiosensitization by targeting ataxia telangiectasia and Rad 3-related (ATR) kinase with small molecule inhibitor BAY 1895344. ATR inhibition with RT has also been shown preclinically to increase antigen presentation and anti-tumor T cell activity. Similarly, preclinical data suggest synergy between BAY 1895344 and anti-PD-1 therapy. We hypothesize that treating recurrent HNSCC with concurrent anti-PD-1 therapy, ATR inhibition and RT will improve tumor control through radiosensitization and stimulating a host anti-tumor immune response. An ongoing clinical trial (NCT04095273) is assessing concurrent BAY 1895344 and pembrolizumab, but BAY 1895344 with concurrent RT has not been evaluated in patients. To determine the safety and optimal dosing of concurrent RT and BAY 1895344, we opened a multi-institutional, CTEP-sponsored phase I trial (NCT04576091) evaluating reirradiation with stereotactic body radiation therapy (SBRT) combined with BAY 1895344 and pembrolizumab for patients with recurrent HNSCC. Methods: Eligible patients for this single-arm trial are adults with recurrent, unresectable HNSCC who received prior head and neck RT and cisplatin. Exclusion criteria include gross skin or mandible involvement, disease encasing >180° of the carotid artery, and prior RT < 6 months before enrollment. Patients with oligometastatic disease (<5 metastases) are eligible. The initial dose escalation phase utilizes a Bayesian Optimal Interval design to determine the MTD for concurrent SBRT and BAY 1895344. In cycle 1, patients receive 200 mg pembrolizumab, followed by 2 weeks of BAY1895344 (30 mg PO Q12h, 3 days on/4 days off). In cycle 2, patients receive pembrolizumab followed by SBRT with concurrent BAY1895344. SBRT dose levels are 21 Gy or 24 Gy delivered in 3 fractions every 2-3 days. Three doses of BAY 1895344 (dose levels: 10 mg, 20 mg, or 30 mg) are given Q12h with each RT fraction. Up to 8 patients will be treated at the starting dose level (24 Gy; 10 mg BAY 1895344). The target DLT rate is 0.33 and the dose elimination rate is 0.75. DLT is defined as any grade >4 AE within 90 days of RT completion. An 18-patient expansion cohort will be enrolled at the MTD. Pre-treatment tissue and serial blood samples will be collected for correlative studies. This trial opened to accrual in November 2021, with no patients enrolled as of February 2022. Clinical trial information: NCT04576091.