3516 Background: NPI-0052 is a second-generation proteasome inhibitor that has a novel structure with preclinical studies suggesting unique proteasome inhibition (PI), signal transduction, efficacy and toxicology profiles, and activities in a broad range of models including bortezomib (BZ) resistant models.
METHODS
Patients were treated with NPI-0052 IV weekly x 3 in 4-week cycles in a 3+3 design dose escalation to a Recommended Phase 2 Dose (RP2D). PI was assayed in whole blood (PWB) and in PBMCs. Up to 10 patients each (lymphoma and solid tumors) are treated at the RP2D.
RESULTS
39 patients have been treated between 0.0125 mg/m2 to 0.8 mg/m2 for up to 12 cycles. The RP2D was 0.8 mg/m2 and has been well tolerated in this study, with the most notable drug-related adverse events being N/V, fatigue, diarrhea, dizziness, headache, decreases in hemoglobin, and insomnia. Thrombocytopenia or neuropathy did not appear to be induced by NPI-0052. Escalation was halted at 0.8 mg/m2, as DLT of transient "hallucinations" (visual imprints when eyes closed) and dizziness/unsteady gait were reported in another study at 0.9 mg/m2. PK data indicate T1/2 ∼4-10 minutes, with clearance at 3-15 L/min and Vz of 35-85L. PI (chymotrypsin-like activity) in PWB and PBMC were dose dependent (mean D1 and D15 PI in PWB at 0.8 mg/m2 was 75 and 100%) (efficacious doses of BZ have been reported to result in a range of ∼40-70% PI). PI in PBMC returned to ∼baseline within one week of each dose, while inhibition remained in PWB. Stable disease was observed in patients with cervical carcinoma (11 months; maximum response was 24%; PI increased with dose escalation), colorectal, hepatocellular, adenoid cystic, melanoma, granulosis cell and ovarian.
CONCLUSIONS
NPI-0052 produces dose-dependent pharmacologic effects, with equal to greater PI seen than reported with therapeutic doses of BZ. At the RP2D toxicity is mild-to-moderate, without the toxicity profile associated with BZ. Together with preclinical data this suggests NPI-0052 may have utility in treating patients who are not candidates for BZ as well as in indications and combinations that have not supported BZ use. Additional trials have been initiated including combinations with other targeted agents. [Table: see text].