Phase I Study of Continuous Mkc-1 (Cmkc-1) in Patients (pts) with Advanced or Metastatic Solid Malignancies Using A Modified Time-To-Event Continual Reassessment Method (Tite-Crm) for Dose Assignment.

e13001 Background: MKC-1 is an oral cell-cycle inhibitor amenable to a variety of dosing schedules. Previous clinical trials used intermittent dosing schedules with modest activity for doses of 225 mg/d averaged over 28 days. Preclinical data suggested continuous drug would be more efficacious. The primary objectives were the maximum tolerated dose (MTD) and response rate (RR) of cMKC-1. Secondary objectives included characterizing the dose-limiting toxicities (DLTs) and pharmacokinetics (PK). Methods: Pts with solid malignancies were eligible, if they had measurable disease, ECOG PS ≤1, and adequate organ function. Exclusions included brain metastases and inability to receive oral drug. MKC-1 was dosed twice-daily, continuously for 28 days. Other medications were eliminated if there were possible drug interactions. Doses were assigned using a TITE- CRM algorithm after the first 3 pts. Disease response was assessed every 8 weeks. Results: Between 5/08-9/09, 24 pts enrolled (15 M/9 F, median 58 yo). Pts 1-3 received 120 mg/d of MKC-1; Pts 4-24 were dosed per the TITE-CRM algorithm: 150 mg [1 pt], 180 [2], 200 [1], 230 [1], 260 [5], 290 [6], 320 [5]. The median weeks on drug was 8 (range 4-28). The only DLT occurred at 320 mg (grade 3 fatigue). Stable disease occurred at 150 mg/d (28 weeks; RCC) and 320 mg/d (16 weeks; breast, parotid). Escalation halted at 320 mg/d. Day 28 PKs indicated absorption and active metabolites. Conclusions: cMKC-1 was well-tolerated; RR was 0/24, clinical benefit occurred in 3/24 pts. Dose escalation stopped at 320 mg/d; this cumulative dose/cycle exceeds that reached with intermittent dosing. A TITE-CRM allowed for rapid dose escalation; late toxicities with continuous drug can be accounted for via a modified algorithm. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration EntreMed EntreMed