Clinical trial of NPI-0052 in advanced malignancies including lymphoma and leukemia (advanced malignancies arm)

Abstract

3582 Background: The novel structure (non-peptide based) of NPI-0052 (NPI) appears to lead to unique proteasome inhibition (PI), toxicology and signal transduction profiles. Preclinical research suggests improvements in therapeutic ratio and activity in hematologic and solid tumor models, leading to clinical trials in patients with myeloma, lymphomas, leukemias, and solid tumors. Methods: Patients with solid tumor, lymphoma or leukemia diagnoses without standard treatment options were treated with IV NPI on Days 1, 8 and 15 of 28-day cycles in a 3+3 design dose escalation to a Recommended Phase 2 Dose (RP2D). Enrollment then began in 10 patient lymphoma and CLL RP2D cohorts. PI (D1 and D15) and PK (D1 and D15) were assayed. Results: 30 patients were treated at doses ranging from 0.1 mg/m2 to 0.9 mg/m2. 0.7 mg/m2 was selected as the RP2D secondary to DLT of transient “hallucinations” (visual imprints when eyes closed) and dizziness/unsteady gait at 0.9 mg/m2. At the RP2D fatigue, parosmia/dysgeusia, transient peri-infusion site pain and lymphopenia were commonly ascribed to NPI. At the RP2D PK data showed: half-life = 31 ± 28 min; AUCtotal = 270 ± 219 ng/mL*min; Cmax = 33.4 ± 34.2 ng/mL; clearance = 7.17 ± 0.40 L/min; volume of distribution (Vz) = 223.3 ± 229.7 L. PI was assayed in blood, indicating a dose:response relationship with mean inhibition of chymotrypsin-like activity up to of 88% Day 1 and 100% Day 15, and inhibition of caspase-like and trypsin-like activity of up to 51% and 72%. PI remained between doses in whole blood (RBC), but recovered between doses in PBMC. Stable disease was induced in 31% of patients, including one each with mantle cell, Hodgkin's lymphoma, follicular lymphoma, sarcoma, prostate carcinoma, and two with melanoma. Conclusions: NPI-0052 produces dose-dependent pharmacologic effects through the predicted efficacious range to an MTD, while producing a toxicity profile that is tolerable and dissimilar to bortezomib in spite of reaching higher PI levels. These data indicate potential for a greater range of uses than other proteasome inhibitors and lead to additional studies being initiated in hematologic malignancies and solid tumors alone and in combination. [Table: see text]