Oral Dosing of the Novel Proteasome Inhibitor CEP-18770 Shows Marked Anti-Myeloma Effects in SCID-Hu Models of Multiple Myeloma.

Abstract 1840

Poster Board I-866

Introduction: Currently, there is no orally administered proteasome inhibitor (PI) which has been FDA approved for the treatment of any cancer. The first PI in clinical development, bortezomib, was approved in 2003 following two successful single-agent phase II trials in relapsed multiple myeloma (MM). In contrast to bortezomib which is administered by intravenous bolus, CEP-18770 is a PI that is active as an oral formulation. Furthermore, the efficacy of orally administered CEP-18770 in multiple MM models has not been reported. In this study, we determined the effects of orally administered CEP-18770 therapy at escalating doses either daily or twice weekly in severe combined immunodeficient (SCID) mice bearing human MM that has been serially passaged in SCID mice from bone marrow derived from a MM patient before (LAGκ-1A) and after resistance (LAGκ-1B) to bortezomib developed. Materials and Methods: Each naïve SCID mouse received a 20 — 40 mm³ MM tumor piece which was surgically implanted into the left hind limb superficial gluteal muscle. Seven days post-implantation mice were bled, human IgG levels were measured by ELISA and animals were randomized into treatment groups. CEP-18770 was administered via oral gavage either daily at 5 mg/kg or twice weekly at 10 mg/kg (M, W) throughout the study. Each week, mice were bled for hIgG levels (where applicable) and tumors were measured using standard calipers. Data graphed is the mean ± SEM with n = 15 mice/group. Results: Single-agent CEP-18770 administered orally significantly inhibited tumor growth in bortezomib-sensitive LAGκ-1A-bearing mice. A significant inhibition of both human paraprotein secretion and reduction of tumor volume was observed as soon as three weeks following initiation of treatment with CEP-18770 at 10 mg/kg twice weekly (hIgG: P = 0.0011 and tumor volume: P = 0.001). Furthermore, tumor volume growth to 700 mm³ was delayed by 94% (day 32.5 for control compared to day 63) among animals receiving this treatment regimen when compared to animals receiving no treatment. At day 35, daily administration of the PI at 5 mg/kg also resulted in significant tumor inhibition (hIgG: P < 0.0001 and tumor volume: P < 0.0001). Reductions of tumor growth by 75%, 95%, 97% and 98% on days 28, 35, 42 and 49 respectively, were observed when compared to the control group. The effect of single-agent CEP-18770 dosed orally in SCID mice bearing nonsecretory bortezomib-resistant LAGκ-1B tumors was also evaluated. Four weeks following initiation of treatment, 5 mg/kg administered daily or 10 mg/kg twice weekly, resulted in a significant reduction in tumor volume (P = 0.0327 and P = 0.0018 respectively). Tumor volume growth to 300 mm³ was delayed by 36% (day 31 for control compared to day 42 for CEP-18770-treated group) in animals receiving 5 mg/kg daily compared to animals receiving no treatment. Tumor volume at 220 mm³ was delayed by 50% (day 28 for control compared to day 42 for CEP-18770-treated mice) among animals receiving 10 mg/kg twice weekly when compared to the untreated control group. Reductions of tumor growth by 78%, 73%, 74% and 70% on days 35, 42, 49 and 56 respectively, were observed when compared to the control group. Moreover, body weights measured at treatment cessation were not significantly different between pre- and post-treatment levels for both treatment groups and MM tumor types. Conclusions: The results of these studies show a marked reduction of tumor size and delay of tumor growth, when compared to the control group, following oral administration of CEP-18770 in LAGκ-1A and LAGκ-1B-bearing mice. The potential availability of an oral PI will greatly enhance the convenience of administration of drugs in this class as bortezomib has only shown efficacy when given intravenously. Other PIs that are bioavailable and active orally in preclinical studies in the treatment of MM are now in early clinical development. The data presented in our study provide further support for clinical development of CEP-18770 as an oral formulation for the treatment of MM.