BackgroundCC-220 is a cereblon E3 ligase modulatory compound currently in development for the treatment of Systemic Lupus Erythematosus as well as other autoimmune conditions and multiple myeloma. As a high affinity ligand for cereblon, CC-220 administration results in significant reductions in ikaros (IKZF1) and aiolos (IKZF3), transcription factors which are genetically linked to SLE risk, and are overexpressed in the peripheral blood of SLE patients compared to healthy controls.ObjectivesTo describe the pharmacokinetics (PK), pharmacodynamics (PD), and the PK-PD relationship of CC-220 in subjects with SLE.MethodsCC-220-SLE-001 is a randomized, double-blinded, placebo-controlled, phase 2a dose escalation study to investigate the safety, PK, PD, and efficacy of CC-220 in patients with SLE. Forty-two (42) adult SLE subjects fulfilling SLE ACR criteria, having a history of SLE for ≥6 months and a baseline Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥4 were randomized to placebo or 1 of 4 escalating doses of CC-220 (0.3 mg QOD, 0.3 mg QD, 0.6/0.3 mg alternating QD, or 0.6 mg QD).ResultsCC-220 concentration-time profiles demonstrated dose proportionality between cohorts, with moderate accumulation in the non-alternating dose cohort. CC-220 significantly reduced total CD20+ B cells by as much as 96%, immature B cells by as much as 91.2%, switched memory B cells by as much as 81.4%, BAFFR+ B cells by as much as 67.5%, and plasmacytoid dendritic cells (pDCs) by as much as 86.5% (Day 85 median percent change from baseline). Whereas reductions in B cells were observed, CD4+ as well as CD8+ T cells increased, and the rise in T cells paralleled the observed increase in plasma cells in those subjects who received the highest dose (0.6 mg). An exposure-response analysis demonstrated decreasing B cells, pDCs and neutrophils with increased exposure to CC-220.ConclusionsIt was determined that 0.3 mg QD to 0.6/0.3 mg alternating QD reduced concentrations of B cells and pDC's while avoiding neutropenia. These findings, in combination with the PK, safety, and exploratory efficacy data, support continued development of CC-220 in SLE.Disclosure of InterestA. Gaudy Shareholder of: Celgene, Employee of: Celgene, Y. Ye Shareholder of: Celgene, Employee of: Celgene, S. Korish Shareholder of: Celgene, Employee of: Celgene, D. Hough Shareholder of: Celgene, Employee of: Celgene, M. Weiswasser Shareholder of: Celgene, Employee of: Celgene, S. Choi Shareholder of: Celgene, Employee of: Celgene, R. Furie Consultant for: Celgene, V. Werth Grant/research support from: Celgene, Consultant for: Celgene, P. Schafer Shareholder of: Celgene, Employee of: Celgene
#4117 Background: Motesanib is a novel oral angiogenesis inhibitor designed to selectively target the tyrosine kinase activity of VEGF 1, 2 and 3; PDGF and Kit receptors. Here we report safety, preliminary efficacy and pharmacokinetics (PK) from an ongoing phase 1b dose-finding study of motesanib plus either paclitaxel (P) or docetaxel (D) in patients (pts) with advanced breast cancer.
 Methods: Eligible pts with ECOG 0 or 1 and ≤1 prior chemotherapy regimen for metastatic breast cancer received (until toxicity or disease progression) escalating doses of motesanib (50 or 125mg) QD orally continuously from day 3 of cycle 1 plus either P (Arm A) at 90mg/m2 on days 1, 8 and 15 of each 28-day cycle; or D (Arm B) at either 100mg/m2 on day 1 of every 21-day cycle or at 75mg/m2 with motesanib maximum tolerated dose (125mg QD). Objective response (OR) per RECIST was assessed every 8 (Arm A) or 6 wks (Arm B).
 Results: To date, 33 pts have received ≥1 dose of motesanib: Arm A, n=10; Arm B, n=23. Median age is 51 (range, 28-66) years. There were 5 DLTs (all grade 3) in 4 pts: abnormal liver function tests and deep vein thrombosis (Arm A, 125mg QD), fatigue (Arm A, 125mg QD), gallbladder enlargement (Arm B, 125mg QD+75mg/m2 D) and migraine (Arm B, 125mg QD). 28 pts (85%) had motesanib-related AEs; the most common were (worst grade): diarrhea, Arm A/B 60%/61% (grade 3, 0%/13%); fatigue, 30%/26% (grade 3, 10%/4%); hypertension, 20%/22% (grade 3, 10%/4%); and nausea, 10%/26% (no grade 3). Treatment-related AEs of interest in Arm A/B included epistaxis (10%/18%; all worst grade 1) and deep vein thrombosis (10%/0%; all worst grade 3). There were no grade 4 or 5 related AEs. Two deaths on study occurred (Arm B; 50 and 125mg QD n=1 each); both were not considered to be motesanib related. Motesanib PK parameters were generally within the range previously described for single-agent motesanib. PK profiles of P and D showed high interpatient variability, with AUC higher in some pts after motesanib coadministration. In pts with measurable disease at baseline (Arms A&B, n=7&18), best OR at time of last data cut-off was: confirmed PR in Arm A n=2 (29%), in Arm B n=5 (28%); SD in Arm A n=2 (29%), in Arm B n=9 (50%); durable SD ≥24 wks in Arm A n=0, in Arm B n=3 (17%). Median (range) duration of response currently is 169 (58-169) days in Arm A and 198 (96-337+) days in Arm B.
 Conclusions: Motesanib combined with P or D appears to be tolerable with evidence of antitumor activity in pts with advanced breast cancer. No marked effect on motesanib PK has been noted with coadministration of either P or D. Updated safety and efficacy data, including PFS, will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4117.
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