1018 - Dose-Escalated Hypofractionated Adaptive Radiotherapy (DEHART) and 60 Gy in 15 Fractions for Advanced Head and Neck Cancers: An Interim Analysis of a Phase I Trial

M. J. Awan¹, S. Tarima², J. Zenga³, E. S. Paulson¹, M. E. Shukla¹, H. A. Himburg¹, A. Shreenivas², S. Firat², B. Massey², B. Campbell², M. Stadler², J. Bruening⁴, S. Stevens⁵, C. J. Schultz², and S. Wong⁶; ¹Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, ²Medical College of Wisconsin, Milwaukee, WI, ³Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, ⁴Medical College of Wisconsin, Milwaukee, WI, United States, ⁵Froedtert Hospitals, Milwaukee, WI, ⁶Department of Medical Oncology, Medical College of Wisconsin, Milwaukee, WI

Purpose/Objective(s): To determine the maximum-tolerated dose of Dose-Escalated Hypofractionated Adaptive Radiotherapy (DEHART) with atezolizumab in patients with head and neck squamous cell carcinomas (HNSCCs) in a Phase I trial. Materials/

Methods: Eligible patients were 18 years or older with de novo metastatic HNSCC or patients with localized AJCC 8th edition T3-T4 N0-N3, T0-T4 N1-N3 HNSCC meeting one of the following criteria: 1) not a candidate for concurrent bolus cisplatin, 2) refusal of concurrent cisplatin-based chemoradiation, 3) had unresected oral cavity cancer or 4) had recurrent disease after definitive surgery. DEHART is a novel 15-fraction radiation regimen in which dose is volume adapted weekly to MR-documented regression of gross tumor. Pre-specified dose levels to gross tumor were 50 Gy, 55 and 60 Gy (Dose Levels 1, 2, and 3, respectively) with elective nodal radiation to 40 Gy in 15 fractions. A Time-to-Event Continual Reassessment Methodology (TiTE-CRM) was used for to select the dose level for each newly enrolled patient. All patients were treated on a 1.5T MR Linear Accelerator. For the first five patients, atezolizumab (1680 mg) was delivered on the first day of radiation and q4w for up to 1 year after DEHART. The protocol was subsequently amended to remove concurrent atezolizumab due to observed toxicity, and remaining patients only received adjuvant atezolizumab only.
Results: Enrollment to this phase I study is complete. 18 patients have enrolled with details in Table 1. Five patients enrolled to Dose Level 1 prior to the amendment. HSV-1 reactivation was noted in three of these patients two weeks after initiating treatment, two of whom experienced dose-limiting toxicity (ICU admission and discontinuation of radiation). The study was amended to remove concurrent atezolizumab and the TITE-CRM was restarted. Subsequently, three additional patients were enrolled to Dose Level 1, three patients were enrolled to Dose Level 2 and seven patients were enrolled to Dose Level 3. No further HSV-1 reactivation or dose-limiting toxicities have occurred. Four of the 18 patients have died, two of disease. Three patients required salvage surgery and are alive without recurrence. The one-year follow-up periods for Dose Levels 1 and 2 are complete. Of seven patients treated at 60 Gy, no locoregional recurrences and no Grade 4+ toxicities have been observed at a median follow-up of 5.8 months (range: 0.2-9.8 months), though two have died (one of distant disease).
Conclusion: 60 Gy in 15 fractions with elective nodal treatment using weekly MR-adaptation is safe with an early signal of efficacy. In our population, administration of concurrent atezolizumab with hypofractionated radiation resulted in HSV-1 re-activation and excess toxicity. Table. Patient Characteristics

Median Age (Range)	74 (52-89)
Primary Site
HPV+ Oropharynx	4
Oral Cavity	13
Larynx	1
Indication(s) for Enrollment
Recurrent Disease after Surgery	4
T3-T4 Disease	12
N+ Disease	9
M1 Disease	1