Abstract
5592 Background: We & others have previously shown that bortezomib inhibits activation of NFκB & other survival effectors & has cytotoxic, radiosensitizing, & anti-tumor activity in preclinical HNSCC models. A previous NCI phase 1 study evaluating dose escalation of bortezomib with rRT established a maximum tolerable dose (MTD) of 0.6 mg/m2 twice weekly IV with daily rRT for 6.6 weeks (60–70 Gy) based on dose limiting toxicity (DLT) of grade 3 hyponatremia & hypotension in 2 pts. The current study was designed to further explore the MTD & best tolerated schedule of bortezomib with rRT by introducing a treatment break. Methods: Pts with recurrent or metastatic HNSCC in whom rRT was feasible, who were ≥ 6 months since prior RT, had PS ≤2, AST/ALT <2.5x normal, bilirubin <1.5x normal, adequate hematopoetic & renal function were enrolled. Bortezomib was administered twice weekly as an IV bolus at the 0.6 mg/m2 dose level with rRT 1.8 Gy/day to 60–72 Gy. A 2-week break in both drug & rRT was given halfway through planned rRT. Results: 5 of 6 pts enrolled are currently evaluable for toxicity (CTC v 2.0) & response. Median ECOG PS was 1 (0–1). DLT was seen in 1 pt (hyponatremia & orthostatic hypotension), who died unexpectedly less than a week after treatment completion. Other grade 3 toxicities (non-DLT) included mucositis, vomiting, hyperglycemia & pain. Four pts completed treatment at the 0.6 mg/m2 dose without DLT & are alive 3–9 months after treatment; one pt remains on treatment. Conclusions: The combination of bortezomib & rRT is feasible with this novel schedule employing a treatment interruption. Bortezomib MTD with rRT is ≤0.6 mg/m2. A future study will explore continuous rRT with 2-week midcourse bortezomib treatment break. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millenium Millenium
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