A Phase I Dose-Escalation and Expansion Study of Telaglenastat in Patients with Advanced or Metastatic Solid Tumors.

Purpose: Glutamine is a critical fuel for solid tumors. Interference with glutamine metabolism is deleterious to neoplasia in preclinical models. A phase I study of the oral, first-in-class, glutaminase (GLS) inhibitor telaglenastat was conducted in treatment-refractory solid tumor patients to define recommended phase II dose (RP2D) and evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.

A phase I single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma.

Purpose: Carfilzomib is a next-generation, selective, proteasome inhibitor with clinical activity in relapsed and/or refractory multiple myeloma. The objectives of this phase I study were to establish the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of escalating doses of carfilzomib in patients with relapsed or refractory hematologic malignancies.

Experimental Design: Carfilzomib (doses ranging from 1.

Pharmacokinetics, pharmacodynamics, metabolism, distribution, and excretion of carfilzomib in rats.

Carfilzomib [(2S)-N-[(S)-1-[(S)-4-methyl-1-[(R)-2-methyloxiran-2-yl]-1-oxopentan-2-ylcarbamoyl]-2-phenylethyl]-2-[(S)-2-(2-morpholinoacetamido)-4-phenylbutanamido]-4-methylpentanamide, also known as PR-171] is a selective, irreversible proteasome inhibitor that has shown encouraging results in clinical trials in multiple myeloma. In this study, the pharmacokinetics, pharmacodynamics, metabolism, distribution, and excretion of carfilzomib in Sprague-Dawley rats were characterized. After intravenous administration, the plasma concentration of carfilzomib declined rapidly in a biphasic manner.

A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies.

Purpose: Carfilzomib (formerly PR-171) is a novel proteasome inhibitor of the epoxyketone class that is selective and structurally distinct from bortezomib. Proteasome inhibition by carfilzomib is mechanistically irreversible. Consequently, proteasome inhibition is more sustained with carfilzomib than with bortezomib.

Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome.

Clinical studies with bortezomib have validated the proteasome as a therapeutic target for the treatment of multiple myeloma and non-Hodgkin's lymphoma. However, significant toxicities have restricted the intensity of bortezomib dosing. Here we describe the antitumor activity of PR-171, a novel epoxyketone-based irreversible proteasome inhibitor that is currently in clinical development.