A phase I pharmacokinetic (PK) study of vorinostat (V) in combination with irinotecan (I), 5-fluorouracil (5FU), and leucovorin (FOLFIRI) in advanced upper gastrointestinal cancers (AGC)

e15540 Background: Currently, advanced AGC has no clear standard regimen. The loss of transforming growth factor-β (TGFβ) response contributes to oncogenesis and has been described in gastric cancer. V, an inhibitor of histone deacetylase (HDAC) can restore TGFβ activity. We hypothesize that the addition of V to a standard chemotherapy regimen, FOLFIRI will result in improved therapeutic efficacy. Methods: AGC (esophagus, gastric, hepatocellular) patients (pts) with adequate organ function, performance status (ECOG 0–1), and 0–1 prior chemotherapy regimens are eligible for this phase 1 study to determine the MTD of V. Treatment consists of standard FOLFIRI (I 180mg/m 2 , leucovorin 400mg/m 2 , 5FU 400mg/m 2 followed by 46-hr infusion 5FU 2400 mg/m 2 q2w) with escalating doses of V given orally daily starting on day 2 (doses 200mg, 300mg, 400mg) in part 1 of the study. Per pre-specified design, initial intra- and inter-patient dose escalation was permitted, but then changed to a standard 3+3 design after observed toxicities. Tumor biopsy pre-Rx and at D13 are being done for TGFβ and survivin expression. PKs for I, SN-38 & SN-38G are being evaluated in part 1. Part 2 examines PK of V at the highest V dose tolerated. Results: 10 pts (7 M, 3 F), with a median age of 52 yr have been treated at 3 dose levels of V in part 1 (2 at 200mg, 5 at 300mg, 3 at 400mg). 2 pts have been given 400mg V in part 2. Major toxicities included neutropenia, leukopenia, fatigue, diarrhea, anemia, and hypoalbunemia. No DLT was noted at any dose level. Of the 8 pts evaluable for response, 2 pts experienced a partial response and 5 pts had stable disease. SN-38 exposure was similar prior to (316–395 ng-hr/mL) and in combination with escalating doses of V (426–469 ng-hr/mL), with a terminal half-life ranging from 7.5–14 hr. Conclusions: V continuously at 400mg/d with FOLFIRI was tolerable in AGC pts. Drug exposure of SN-38 is not affected by V coadministration. The expansion cohort will determine the recommended phase 2 dose. Correlative studies of survivin and TGFβ expression are ongoing. Part 3 will examine intermittent V dosing. This study is supported by an IISP research grant from Merck & Co., Inc. [Table: see text]