Abstract C33: A two‐arm phase 1 clinical trial with NPI‐0052, a novel proteasome inhibitor

Background: The bi‐cyclic structure of NPI‐0052 differentiates it from other proteasome inhibitors which are structurally polypeptide based, leading to its differential properties of rapid, broad and prolonged inhibition of all 3 proteolytic sites, and unique proteasome inhibition, toxicology and efficacy profiles. Preclinical studies indicated an increased therapeutic ratio with activity in hematologic and solid tumor malignancies leading to the initiation of Phase 1 clinical trials. These biologic differences also led to the question of whether twice weekly administration schedule, as is typical for other proteasome inhibitors, or more convenient once weekly schedule would be preferable. Materials and Methods: Patients with solid tumor, lymphoma, leukemia or myeloma diagnoses failing after standard therapies were given NPI‐0052 intravenously on a weekly or twice weekly arm in the dose escalation portion of this study. Subsequently 10 patient Recommended Phase 2 dose Cohorts of patients with lymphomas, CLL and myeloma are enrolled. Proteasome inhibition and pharmacokinetics are also assayed in whole blood, and/or peripheral blood mononuclear cells (PBMC) on Day 1 and multiple subsequent time points. Results: 44 patients have been enrolled into this study. Notable adverse events have been fatigue, parosmia/dysgeusia, transient peri‐infusion site pain, lymphopenia, headaches, dizziness / unsteady gait, closed‐eye visuals, cognitive changes. Peripheral neuropathy, neutropenia and thrombocytopenia do not appear to be induced. Pharmacokinetic data indicate a short T1/2 and large Vss. Proteasome inhibition assays demonstrated inhibition of chymotrypsin‐like activity of up to 88% Day 1 and 100% Day 15. Inhibition accumulates initially in whole blood presumably secondary to the inability of RBC to synthesize new proteasomes, whereas inhibition recovers over several days in PBMC further leading the question as to an optimal dosing regimen. Stable disease, regression or response, have been reported in mantle cell lymphoma, myeloma, Hodgkin9s lymphoma, cutaneous marginal zone lymphoma, follicular lymphoma, sarcoma, prostate carcinoma and melanoma. Conclusions: NPI‐0052 produces expected or greater levels of proteasome inhibition in patient blood samples, with a toxicity profile that is dissimilar to what is reported with other proteasome inhibitors. The profile of the proteasome inhibition, toxicity and efficacy profiles that have been revealed during this clinical trial and correlative studies reveals further basis and hypothesis as to what an optimal dosing regimen might be, which is being assessed in this study. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C33.