A Study of HC-5404-FU to Establish the Maximum Tolerated Dose (MTD)

HC 5404-FU will be orally administered BID with food or within 30 minutes of completing a meal, starting at 25 mg, with doses escalating to 50, 100, 200, 400, 600 and 900 mg BID as safety allows. Up to 24 subjects will be enrolled to ensure 12 subjects complete the study at the estimated MTD of HC 5404-FU. Dosing will occur in 3-week cycles. Subjects are to spend Cycle 1/Day 1 (C1D1) in the clinic followed by an overnight stay for safety monitoring and PK sampling. Subjects will be hospitalized for administration of first 3 doses: C1D1 am and pm doses, and Cycle 1/Day 2 (C1D2) am dose; on Days 8, 15, and 21 the am dose will be taken in the clinic after the planned PK samples. All other doses are to be self administered at home. After the initial hospital stay at the start of study, subjects will be seen in outpatient clinic on Days 8, 15, and 21 of Cycle 1 for PK assessment and thereafter, the first day of each cycle for physical and laboratory assessments, adverse event (AE), and dosing compliance monitoring; the end of treatment visit will also be in person in outpatient clinic. Following completion of the treatment period of the study, subjects will be monitored for survival up for up to 24 months after the last post treatment follow-up visit. Dose escalation will follow the Bayesian Optimal Interval (BOIN) design. The decision to escalate to the next dose level will be based on safety assessments after all subjects of a cohort have reached the end of Cycle 1/Day 21 (DLT evaluation period). The safety monitoring committee (SMC) will be responsible for dose escalation decisions, including whether to modify the dose escalation based on the DLT observations and review of available PK data. The target toxicity rate of 30%, with limits of 0.236 to 0.359 for escalation/de escalation, will be employed to determine the MTD. With these predefined parameters, when the observed toxicity rate in a dose level is less than 0.236, the dose for the next cohort can escalate. If the observed toxicity rate is higher than 0.359, the dose will de escalate. Otherwise, the dose remains the same. Individual subjects may be considered for treatment at a higher dose than the dose to which they were initially assigned after subject has completed 2 cycles of treatment and 1 postbaseline CT scan and maintained at least a stable disease (SD) response. In order to escalate a dose level, the subject must have tolerated his/her current dose level without experiencing a DLT, and the dose level to which the subject is planned to be escalated must have completed a DLT evaluation period, not exceeded the MTD, and been declared safe. Each subject can go through 2 dose escalations and do not need to go through a DLT evaluation period for either escalation. Intrasubject dose escalation will be considered on a case-by-case basis, each case to be assessed and approved by the sponsor.