125 - Phase I Trial with Expansion Cohort of DNA-PK Inhibitor Peposertib and Intensity Modulated Radiation Treatment (IMRT) in Cisplatin-Ineligible Patients with Stage 3-4 Local-Regionally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC)
Presenter(s)
M. A. Samuels1, J. Harris2, M. L. Gillison3, N. F. Saba4, C. F. Chuang5, J. N. Myers6, A. S. Garden7, J. J. Caudell8, S. Rudra9, R. A. Julian10, L. K. Mell11, J. Deeken12, R. Redman13, K. Attwood2, Q. T. Le14, and S. S. Yom15; 1Department of Radiation Oncology, Banner MD Anderson Cancer Center at Banner Gateway Medical Center, Gilbert, AZ, 2American College of Radiology, Philadelphia, PA, 3The University of Texas MD Anderson Cancer Center, Houston, TX, 4Emory University, Atlanta, GA, 5Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 6University of Texas MD Anderson Cancer Center, Houston, TX, 7Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 8H. Lee Moffitt Cancer Center and Research Institute, Department of Radiation Oncology, Tampa, FL, 9Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, 10University of Arizona Cancer Center, Tuscon, AZ, 11Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 12Inova Fairfax, Fairfax, VA, 13University of Louisville School of Medicine, Louisville, KY, United States, 14Stanford University, Stanford, CA, 15University of California, San Francisco, Department of Radiation Oncology, San Francisco, CA
Purpose/Objective(s):
Peposertib is a DNA protein kinase inhibitor that can limit repair of double-strand DNA breaks induced by radiation with the potential to radiosensitize head and neck squamous cell carcinoma (HNSCC). The goal of this phase I study was to determine the maximum tolerated/recommended phase II dose (MTD/RP2D) of peposertib when combined with IMRT for definitive treatment of locally advanced HNSCC, and to evaluate the safety profile of the combination, including acute radiation-induced toxicities.Materials/Methods:
NRG-HN008 was designed as a phase I dose-finding and safety trial. Eligible patients were age = 18 years with AJCC 8th edition stage III-IVB p16-negative HNSCC or unfavorable stage I-III p16-positive oropharyngeal carcinoma, with a contraindication to cisplatin (renal or hearing impairment, peripheral neuropathy, age =70 with moderate or severe comorbidity, or age < 70 with severe comorbidity). ECOG performance status 0-1 was required. IMRT was prescribed at 70 Gy in 35 fractions over 7 weeks. Peposertib was administered orally 60-90 minutes before each radiation treatment. A Bayesian Optimal Interval study design was used to evaluate 5 potential peposertib dose levels: 50 mg/day (dose level -1) and 100, 150, 200, and 250 mg/day (dose levels 1–4), followed by a dose-expansion cohort of 12 subjects, with up to 18 treated at the MTD. Dose-limiting toxicity (DLT) was defined as CTCAE grade = 3 within 28 days after IMRT most probably related to treatment with exclusions for common IMRT toxicities or inability to complete 80% of RT dose. Acute toxicity was defined as = 90 days after IMRT.Results:
21 subjects at 8 academic and community sites in the United States were enrolled and treated. Median age was 75 years, 81% were male, 81% had ECOG 1, and the median number of comorbidities was 5. 67% had a non-oropharyngeal or p16-negative oropharyngeal primary site. Three were treated at dose level 1, with DLT seen in 1 of 3 (grade 4 radiation dermatitis). Due to Safety Committee concern, the dose was de-escalated to dose level -1, where an additional 18 subjects were treated, with 2/18 experiencing a DLT (grade 5 oral hemorrhage and grade 3 aspiration). In this cohort, the rate of acute grade 3-5 toxicity was 78%, most not fulfilling DLT criteria. The most common grade 3-5 acute toxicities were oral mucositis (44%), lymphocytopenia (28%), dysphagia (22%), and radiation dermatitis (22%).Conclusion:
The MTD of peposertib with IMRT in cisplatin-ineligible patients with local-regionally advanced HNSCC was established at 50 mg/d. Using NRG HN004 results as a reference, peposertib at 50 mg demonstrated comparable incidence of grade =3 toxicity to other non-platinum radio-sensitizing agents concurrent with IMRT in the treatment of HNSCC.