A phase I dose escalation safety and pharmacokinetic (PK) study of SSR244738 administered as a one-hour intravenous (IV) infusion twice-weekly during a 3-week cycle in patients (pts) with refractory solid tumors

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2539 Background: SSR244738 is a new cytotoxic agent (G2-cell cycle inhibitor). In this first in man study the original schedule of administration was an IV infusion once every 3 weeks (Q3W); and due to the high clearance variability, 1300 mg/m2 was considered the maximum administered dose (MAD). The study was amended to test the twice weekly schedule (D1-D4-D8-D11-D15, every 3 weeks). Methods: Standard escalation was used in cohorts of 3–6 pts. PK profiles (up to T48h or T96h) were obtained in each pt after the 1st and the 5th administration (D1 and D15) of Cycle 1. In the Q3W, there was a trend to lower clearance (CL) in CYP2C9 *3/*3 and *1/*3 genotype pts therefore genotype samples were analyzed at baseline to identify poor metabolizers (PM) and adjust-dosing accordingly. Results: 22 heavily pretreated patients received SSR244738 at doses of 200 (3 pts), 280 (4 pts), 400 (3 pts), 560 (3 pts), 780 (3 pt), 1000 (6 pts; one pt was a PM and received 500 mg/m2). 15 females, 7 males, median age: 60 years (29–82), ECOG: (0:12, 1:9, Unk:1). Main tumor types: ovary, lung, breast, colon and prostate. Nb cycles/pts: > 2 cycles/21 (95%), > 4 cycles/9 (41%), > 6 cycles/6 (27%), > 8 cycles/2 (9%). The most common reason for treatment discontinuation was disease progression. DLT was seen in 2 pts at 1000 mg/m2 dose level: one patient had febrile neutropenia associated with Grade 3 mucositis and the second patient had Grade 3 neutropenia, which caused a treatment delay. Both pts showed high SSR244738 plasma exposures on D15. SD was reported in 11 patients. No CRs or PRs were observed. SSR244738 exhibited an overall low plasma CL (mean [range]: 0.9 [0.3–2.1] L/h). CL slightly decreased with repeated administration. The distribution volume was low [Vss mean (CV%): 11.6 L (30%)] and the terminal half life was long [mean (CV%): 15.6 h (58%)]. No deviation from dose proportionality could be observed, despite the moderate-to-high inter-individual variability (CV<64%) in exposure. Conclusions: SSR244738 is well tolerated with PK profile similar to the Q3W schedule; by changing the schedule of administration we were able to reach the MAD dose (5000 mg/m2/cycle). [Table: see text]