Expanded phase I study of vorinostat (VOR) in combination with capecitabine (CAP) in patients (pts) with advanced solid tumors

Abstract

11096 Background: VOR (suberoylanilide hydroxamic acid; SAHA) is a small molecule inhibitor of histone deacetylase (HDAC) that binds directly to the enzyme’s active site in the presence of a zinc ion. Aberrant HDAC activity has been implicated in a variety of cancers. The combination of 5-fluorouracil and VOR is synergistic in preclinical tumor models. Methods: This expanded phase I study evaluated safety, tolerability, and the recommended phase II dose (RPTD) of VOR and CAP in pts with advanced solid tumors. VOR was administered orally daily while CAP was administered orally bid on days 1–14 of a 21 d cycle. Results: Three dose levels were evaluated (VOR (mg/d) /CAP (mg/bid)): 300/750, 300/1000 and 400/1000. Twenty-eight pts have been treated: 7M/21F, median age 59 (range 36- 73), ECOG 0:1:2 = 12:15:1, prior therapy 1:2:3 or more = 7:8:13. Pts had colorectal cancer (n=9), nasopharyngeal (n=3) and various other tumors. A total of 137 cycles have been administered, with median = 4 (range 1–15). One dose limiting toxicity (DLT) (grade 3 diarrhea) occurred in 6 patients at dose level 1. No DLT were observed at dose level 2, and 2 DLTs (grade 3 fatigue and grade 3 nausea/vomiting) occurred at dose level 3. RPTD was determined to be VOR 300 mg/d and CAP 1000 mg/bid. This dose level was then expanded to include a total of 14 patients. The most frequent adverse events experienced of any grade were anemia (20 [71%] patients across 90 [66%] cycles), fatigue (16 [57%] patients across 87 [64%] cycles) and hyperglycemia (23 [82%] patients across 63 [46%] cycles). Grade 3 adverse events experienced by 3 or more patients were HFS (5 patients), fatigue and lymphopenia (4 patients each), diarrhea and vomiting (3 patients each). One pt died on study from ventricular fibrillation due to sotalol and hypocalcemia from pre-existing hypoparathyroidism. No other grade 4 or 5 adverse events occurred. One patient with breast cancer had a PR in cycle 2 followed by an unconfirmed CR in cycle 4, and three patients with various tumor types had a PR. In addition, disease stabilization was seen in 18 patients. Conclusions: VOR and CAP are well tolerated, and this combination is active in several tumor types. Further evaluations of VOR and CAP are warranted. No significant financial relationships to disclose.