First-in-Human Phase 1 Dose Escalation Study of NPI-0052, a Novel Proteasome Inhibitor, in Patients with Lymphoma and Solid Tumor

Background: NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of all three catalytic activities (C-L, T-L, CT-L) of the 20S proteasome. Preclinical data demonstrated activity in hematologic malignancies (myeloma, lymphoma, leukemia) and solid tumors. This Phase 1 study in patients with refractory lymphomas or solid tumors was the first-in-human study of NPI-0052.

Materials and Methods: Patients were treated with NPI-0052 administered as a weekly IV injection for 3 weeks in 4-week cycles in a 3+3 design dose escalation study. The dose of NPI-0052 was escalated in 50–100% increments dependent on observed adverse events. Proteasome inhibition was assayed in whole blood and in peripheral blood mononuclear cells (PBMCs). All patients underwent plasma PK sampling. Once a Recommended Phase 2 Dose (RP2D) is identified, two groups of up to 10 patients each (lymphoma and solid tumors) will be treated at that dose.

Results: 35 patients (including 5 patients with lymphoma) have been treated between 0.0125 mg/m² to 0.55 mg/m² for up to 12 cycles without reaching an MTD. Drug related adverse events at the highest dose level assessable (n=4) include Grade 1: diarrhea (n- 2), fatigue, muscle stiffness, hypotension and hypomagnesemia. At doses tested to date, thrombocytopenia or neuropathy have been unremarkable. SAE reported as potentially related included MRSA sepsis and post-infectious glomerulonephritis/renal failure recovering after antibiotic treatment in one patient treated at 0.1 mg/m² and Grade 4 neutropenia recovering after 3 days in one patient treated at 0.112 mg/m². Preliminary PK data indicate an elimination half life of approximately 3–13 minutes, with clearance at 11.7 ± 7.4 mL/min and Vz of 44–99L. Proteasome inhibition in whole blood demonstrate dose dependency for CT-L inhibition (at 0.55 mg/m²), mean D1 and D15 inhibition in whole blood equaled 65 and 90%, respectively. Using PBMCs (cells that can regenerate proteasomes), similar CT-L inhibition was also observed on D1 and D15. Inhibition returned to baseline within one week of each dose in PBMC, whereas significant inhibition remained throughout the cycle in whole blood. No responses have been confirmed; stable disease (>3 months) was observed in patients with cervical carcinoma (11 months; time to progression on the prior treatment regimen was 3 months), colorectal, hepatocellular (6 months), adenoid cystic (4 and 5 months), melanoma (4 months), granulosis cell and ovarian (3+ months). The patient with cervical carcinoma, underwent four dose escalations (from 0.025 to 0.168 mg/m²) with increased proteasome inhibition observed at each higher dose assessed (from 24% to 64%). Preliminary PK data indicate an elimination half life of approximately 3–13 minutes, with clearance at 11.7 ± 7.4 mL/min and Vz of 44–99L.

Conclusions: NPI-0052 produces dose-dependent pharmacologic effects through the range of proteasome inhibition produced by therapeutic doses of the approved proteasome inhibitor bortezomib without resulting in the toxicity profile seen with bortezomib treatment. These data have supported additional studies being initiated in hematologic malignancies and solid tumors, including combination studies with other targeted agents.