Abstract
3574 Background: NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of all three catalytic activities of the 20S proteasome. Preclinical data suggest NPI-0052 may demonstrate an improved therapeutic ratio, with activity as a single agent or in combination in hematologic (myeloma, lymphoma, leukemia) and solid tumor models. Clinical trials are being conducted in patients with myeloma, lymphomas, leukemias and solid tumors. Methods: In this first-in-human study cohorts of 3 or more patients with solid tumor or lymphoma were treated with NPI-0052 administered weekly, for 3 weeks in 4-week cycles using a 3+3 design dose escalation. The dose of NPI-0052 was escalated in 50–100% increments dependent on observed adverse events (AE). In addition to regular safety monitoring, proteasome inhibition (PI) (baseline, D1–2, D8, D15–17, D22 and D29) and PK (D1 and D15) were assayed in blood. A Recommended Phase 2 Dose (RP2D) cohort of up to 20 patients will be enrolled at the RP2D. Results: 23 patients have been treated over a 20-fold dose range (0.0125 mg/m2 to 0.25 mg/m2) for up to 11 cycles without reaching an MTD. The AE profile has been unremarkable at the highest dose level assessed. Sixteen patients (73%) had no > Grade 1 drug-related AE. Preliminary PK data indicate an T1/2 of approximately 3–4 minutes, with clearance at 8–21 mL/min and Vz of 44–99L. PI has been assayed in blood, indicating a dose:response relationship with inhibition of up to 64% observed. No responses have been confirmed, however, 6 patients have had stable disease for at least 2 cycles, including one with melanoma (4 months), one with colorectal carcinoma (3 months), one with hepatocellular carcinoma (6 months), two with adenoid cystic carcinoma (4 months each), and one with cervical carcinoma (11 months). This patient (cervical carcinoma) underwent four intra-patient dose escalations, with increased PI observed at the higher dose assessed. Conclusions: NPI-0052 produces dose-dependent pharmacologic effects at doses below the MTD. Combination studies are being initiated in solid tumor diagnoses with other cytotoxic / targeted agents. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Nereus Nereus Nereus
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