Abstract A107: Clinical trial combining proteasome (NPI-0052) and HDAC (vorinostat) inhibition in melanoma, pancreatic, and lung cancer
Authors: Millward Michael , Spear Matthew A. , Townsend Amanda , Sweeney Christopher , Sukumaran Shawgi , Longenecker Angie , Palladino Michael A. , Lloyd G. Kenneth , Neuteboom Saskia T.C , Price Timothy 
Published: June 2012

Abstract
Background: Combining proteasome inhibition with HDAC inhibition has recently been shown to provide synergistic anti-tumor activity in preclinical and clinical studies. A proposed mechanism centers around inhibition of both of the major protein disposal mechanisms of the cell, resulting in near complete lack of ability of the tumor to dispose of normal pro-apoptotic and growth inhibitory peptides. The bi-cyclic structure of NPI-0052 is not polypeptide based as are other proteasome inhibitors, leading to rapid, broad and prolonged inhibition of all 3 proteolytic sites, with unique proteasome inhibition, toxicology and efficacy profiles. Preclinical studies indicated marked synergy with a number of HDAC inhibitors in solid tumor and hematologic malignancy models.
Materials and Methods: Patients with melanoma, pancreatic carcinoma and NSCLC having failed standard therapies were given NPI-0052 intravenously on a weekly (Days 1, 8 and 15) schedule dose escalation, in combination with vorinostat 300 mg orally on the first 16 days of each 28 day cycle. A 3+3 design was used with the dose of NPI-0052 escalated from 0.15 mg/m2 to 0.7 mg/m2. In addition to standard safety laboratory studies, proteasome inhibition and pharmacokinetics are also assayed in blood on Day 1 and multiple subsequent time points.
Results: 20 patients have been enrolled into this study. There has not been an indication of increased toxicity with the combination, and the dose of NPI-0052 has been escalated to and is currently being administered at the full single agent dose without dose limiting toxicity. Pharmacokinetic data indicate a short half life of NPI-0052 (&lt;15 min) and large volumes of distribution (Vz =73.9 ± 44.7 L and Vss=80.7 ± 53.6 L), which do not seem to be dose dependent. The PK parameters of vorinostat were in agreement with published data (T1/2 of 1.69 ± 0.86 hours and Vz/F of 1040.1±458.3L). Co-administration of Vorinostat with NPI-0052 therefore does not appear to affect the kinetics of either drug. Proteasome inhibition assays demonstrate dose dependent inhibition of the chymotrypsin-like proteasome activity of up to 78%. The majority of the patients enrolled have had metastatic melanoma. Seven of 14 evaluable patients have demonstrated regressions in tumor measurements.
Conclusions: The combination of full dose NPI-0052 with vorinostat is tolerable and has not resulted in unexpected safety findings (of note the toxicity profile is dissimilar to that reported with other proteasome inhibitors, in not inducing neutropenia, thrombocytopenia or peripheral neuropathy). Pharmacokinetic and pharmacodynamic results were likewise consistent with what are expected from prior data with each drug. Enrollment continues to further characterize the combination at the recommended phase 2 dose.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A107.