Optimization of the phase 2 dose of KOS-1584 (a novel, synthetic epothilone) via weekly administration

A286 Background: KOS-1584 is a potent synthetic epothilone with an attractive pharmacologic profile (water soluble, excellent tumor penetration and low CNS exposure). This dose-escalation trial explored 2 weekly schedules of administration: Days 1, 8 & 15 every 4 weeks and Days 1 & 8 every 3 weeks . Methods: Define the MTD, toxicity, PD, PK, and activity of KOS-1584 when administered to pts with advanced malignancies on each of 2 schedules (both 1-hour and 3-hour times of administration were assessed). PD: assessed by serial sampling of PBMCs for soluble and polymerized microtubules by immunoblot. Results: 4-week schedule: 46 pts enrolled in 10 cohorts at doses between 0.8 - 25 mg/m2 (29 F; medians age 57, ECOG 0 and 3 prior regimens). For this schedule: Cycle 1 DLT was observed at 20 (for both the 1-hour and 3-hr time of administration cohorts) and 25 mg/m2 (over 1-hr). All episodes of DLT except 1 involved diarrhea with increasing severity after successive infusions despite maximal supportive care; 1 pt had typhlitis upon biopsy. At the recommended dose of 16 mg/m2 (n=8), toxicity was manageable, consisting of diarrhea, vomiting (both 50%), nausea, fatigue, constipation, weakness and peripheral sensory neuropathy (all 38%) and headache (25%). At this dose, only 1 patient experienced any-cycle drug-related Grade 3 toxicity (Cycle 2 diarrhea of limited duration with peripheral sensory neuropathy). Peripheral sensory neuropathy was observed but remained Grade 1-2 in all other patients. 3-week schedule: 13 pts were enrolled in 4 cohorts at doses between 16 - 30 mg/m2 (5 F; medians age 65, ECOG 1 and 2 prior regimens). One Grade 3 ↑AST was seen at 16 mg/m2 (this patient had progression of liver metastases however the ↑AST declined quickly following cessation of dosing). No subsequent DLT was seen at either 20 or 25 mg/m2 (assessment of the 30 mg/m2 cohort is on-going). PK (n=42 on 4-week schedule; 1-hr infusion): systemic exposure assessed by Cmax and AUC increased in dose dependent manner over 16-fold dose range. Data was well fitted to a 2-compartment model with weighting 1/Ypredicted giving the smallest objective function. For all patients: alpha half-life =7.9 ± 8.2 mins; elimination half-life = 24 ± 7 hours. At 16.0 mg/m 2 (n=8) AUC = 3529 ± 3364 ng/mL*h, Cmax = 514 ± 165 ng/mL and CL = 14.0 ± 8.4 L/h. The 3 hour infusion at comparable doses gave similar results for AUC with lower Cmax. Antitumor activity: NSCLC (2 pts: confirmed PR, 10 cycles; MR, 4 cycles), ovarian cancer (1pt: 40% ↓CA125; 6 cycles), pancreatic cancer (1 pt: 39% ↓CA19-9; 4 cycles), and SD (6 pts: HN prostate, 6 cycles; pancreatic, 6 cycles; breast, 5 cycles; colon, 4 cycles in 2 pts); these pts had all received doses > 7.5 mg/m2. Increased polymerized microtubules were observed with maximal effect at end of infusion and sustained polymerization through 24 hours. Conclusions: KOS-1584 shows antitumor activity in a variety of tumor types. The recommended phase 2 dose on the 4-week schedule (16 mg/m2 with antidiarrheal supportive care; dose intensity of 12 mg/m2/week) is well tolerated. Accrual continues on the 3-week schedule; current dose intensity at 16.7 mg/m2/week predicts that this schedule may provide the maximal dose intensity.