PI-007

M. E. Thomas,1 Y. Ye,1 D. Weiss,1 A. Gaudy,1 N. Chen,1 Z. Yang,1 L. Liu,1 P. H. Schafer,1 D. Mandarino,2 M. Palmisano,1 E. O'Mara1; 1Celgene Corporation, Summit, NJ, 2Covance Clinical Research Unit Inc., Madison, WI

BACKGROUND: This study evaluated the safety, tolerability, PK, and PD of multiple doses of CC‑220.
METHODS: Healthy subjects, ages 18-55, were enrolled into cohorts of up to 9 each (randomized 6 active: ≤ 3 placebo). Planned dose regimens were 0.3 mg QD x 14 and 28 days; 1 mg QD x 28 days; 1 mg QD (7 days on, 7 days off, 7 days on); 0.3 mg once every 3 days (Q3D) x 14 days (5 doses); and 1 mg once every 7 days (Q7D) x 28 days (4 doses). Blood samples were collected for clinical laboratory, PK and PD analyses.
RESULTS: Of the 52 enrolled, 29 subjects (55.8%) reported a total of 106 treatment emergent AEs (TEAEs). There were no SAEs. For CC-220 QD dose regimens, TEAEs were more frequent than compared to placebo. No such trend was observed with Q3D or Q7D dosing. For the 1 mg QD x 28 days cohort, drug related decreases in mean WBC parameters were observed at ~Day 21 with 4 subjects noted to have asymptomatic, reversible Grade 3 neutropenia. All other dose regimens were well tolerated. Systemic CC‑220 exposure was dose proportional from 0.3 to 1 mg. Median Tmax occurred ~3 hours postdose, mean t1/2 ranged from 9 to 22 hours, and steady state was reached by ~Day 7 after QD dosing with an accumulation ratio of ~2 (no noticeable accumulation with Q3D or Q7D dosing). Immunomodulatory effects of CC‑220 included reduced peripheral blood absolute CD19+ and CD3+ cells, decreased aiolos expression in CD19+ and CD3+ cells, inhibition of ex vivo endotoxin induced proinflammatory cytokine production, and increased anti-CD3 induced T cell cytokine production ex vivo.
CONCLUSION: CC‑220 was well tolerated at all dose regimens except for 1 mg QD x 28 days, where asymptomatic Grade 3 neutropenia was observed. CC‑220 multiple-dose PK demonstrated rapid absorption and dose proportionality. Multiple doses of 0.3 and 1 mg CC‑220 were pharmacologically active.