Phase I study of proteasome inhibitor bortezomib (B) concurrent with re-irradiation therapy (re-RT) for recurrent squamous cell carcinoma of the head and neck (SCCHN).

Abstract

2603 Background: B demonstrated antitumor and radiosensitizing activity in preclinical solid tumor models. Methods: A phase I trial was designed to assess escalating doses of B 0.6, 0.9 or 1.2 mg/m2 IV twice weekly concurrent with re-RT 2Gy/5 days/wk to 60-70 Gy. Evaluations included standard measures for adverse events (CTC v3.0), tumor response (RECIST), progression-free survival (PFS) and overall survival (OS). Baroreceptor reflex testing was initiated in a subset of patients to assess the potential cause of observed orthostatic hypotension. Results: 25 patients with recurrent SCCHN were treated: 19 men, 6 women, median age 57 yrs, ECOG performance status∼1, prior surgery and chemotherapies∼1 and > 6 mos since prior RT. All were evaluable for toxicity and 19 for response. B 0.6 or 0.9 mg/m2 + re-RT given 2x/wk for 6-7 wks without breaks was associated with dose-limiting orthostatic hypotension and/or hyponatremia. Amended schedules with a mid-course 2-wk break from B and re-RT, or B alone, were better tolerated. B 0.9 mg/m2 2x/wk with a 2-wk mid- course break was established as the MTD and schedule, based on a dose-limiting neuropathy. Pre-existing and treatment-associated baroreceptor reflex dysfunction was seen in several subjects. Radiation mucositis was less than expected at doses and schedules studied. 5/5 pts given B 0.6 mg/m2 2x/wk without break had early progressive disease, while 5 PRs and 1 SD were seen in 10 subjects treated at the same dose with a 2 wk break. At 0.9 mg/m2, 3 SD and 3 PD were seen. The median PFS and OS of ∼2 + 4 mos in subjects treated without break was inferior to that of ∼4 + 11 months seen in patients treated with breaks. Conclusions: Decreased response in patients treated with B+re-RT without break or at higher doses suggests that proteasome inhibition may confer radioprotection in SCCHN. Peripheral or baroreceptor reflex neuropathy is dose-limiting in some heavily pretreated HNSCC patients. Supported by NIH Intramural Project ZIADC-000016 and a CRADA with Millennium Pharmaceuticals. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium