A phase Ib/II study of PXD101 alone and in combination with 5-fluorouracil in patients with advanced solid tumors

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Abstract
3501 Background: PXD101 is a hydroxamate HDAC inhibitor that has broad anti-neoplastic activity in vivo and in vitro. Preclinical data showing PXD101 down-regulation of thymidylate synthase (TS), an in vivo target of 5-fluorouracil (5-FU) provide a rationale for combination of PXD101 with 5-FU. Methods: This is a phase Ib/II trial of PXD101 plus 5-FU in patients with advanced solid tumors, with dose escalation to establish the maximum tolerated dose (MTD) and an expansion at the MTD in colorectal cancer (CRC) patients. Patients (pts) must be = 18 yrs, have measurable disease, and had disease progression after standard chemotherapy. PXD101 was administered as a 30-min IV infusion on Days 1–5 of a 3-wk cycle. 5-FU was administered from cycle 2 on, as a continuous 96-hr IV infusion starting on Day 2 of the same 3-wk cycle. The primary endpoints were safety, and effect of belinostat on TS expression in patients’ tumors. Dose-limiting toxicities (DLTs) were PXD101-related = Gr 3 non-hematologic or Gr 4 hematologic toxicities. Expression of TS mRNA was measured by RTQ-PCR. Results: Twenty pts have been treated for a median of 2 cycles (range 1–8). Cohorts of 3–6 pts were tested at 5 dose levels of PXD101/5-FU (mg/m2/d): 300/250, 600/250, 1,000/250, 1,000/500, and 1,000/1,000. Two pts did not complete cycle 2, and one pt at the 600/250 dose level received 1,000 mg/m2/d 5-FU. There were no DLTs in the first 4 dose cohorts; the 5th cohort is ongoing. In the first 4 dose cohorts (17 pts), the most frequent AEs were fatigue, nausea/vomiting, dysgeusia, dehydration, constipation, edema, anorexia and anemia. There were 2 Gr 4 AEs (pulmonary embolism, bacteremia); Gr 3 AEs in = 2 pts were fatigue and dehydration. All Gr 3/4 events were assessed as not related to PXD101. One pt with stage IV CRC treated at 600/1,000 mg/m2/d PXD101/5-FU had stable disease (SD) for 8 cycles, and one pt with stage IV esophageal cancer treated at the 1,000/250 mg/m2/d dose had SD for 4 cycles. Conclusions: PXD101 in combination with 5-FU has been well tolerated up to 1,000/500 mg/m2/d PXD101/5-FU. The study is ongoing and data from the MTD expansion part, including effect of PXD101 on tumor TS expression, will be presented. No significant financial relationships to disclose.

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