Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma

Abstract

This phase 1 study sought to characterize the safety, tolerability, and pharmacokinetic behavior of VLX1570, a small molecule inhibitor of the deubiquitinases (DUBs) that remove sterically bulky ubiquitin chains from proteins during processing in the19S regulatory subunit of the proteasome, in patients with relapsed and refractory multiple myeloma (MM). Fourteen patients were treated with escalating doses of VLX1570 ranging from 0.05 to 1.2 mg/kg as a brief intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Due to its poor aqueous solubility, VLX1570 was formulated in polyethylene glycol, polyoxyethylated castor oil, and polysorbate 80 and administered as a brief intravenous (IV) infusion via a central venous catheter. Anti-myeloma effects were noted at doses at or above 0.6 mg/kg, however, two patients treated at the 1.2 mg/kg dose level experienced severe, abrupt, and progressive respiratory insufficiency, which was associated with diffuse pulmonary infiltrates on imaging studies, similar to those rarely noted with bortezomib and other inhibitors of the 20S proteasome, culminating in death. Although the contribution of VLX1570's formulation to the pulmonary toxicity could not be ruled out, the severity and precipitous nature of the toxicity and the steep relationship between dose and toxicity, the study was discontinued. Despite the severe pulmonary toxicity noted with VLX1570, efforts directed at identifying DUB inhibitors with greater therapeutic indices appear warranted based on the unique mechanism of action, robustness of preclinical antitumor activity, and activity of the DUB inhibitors in MM resistant to PIs targeting the 20S proteasome subunit.

Regulation of NFκB Signalling by Ubiquitination: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma?

“…VLX1570, a b-AP15 analogue with higher potency and higher selectivity for USP14, demonstrated anti-tumor activity, and enhanced survival in MM xenografts [ 162 ]. However, a recently reported Phase 1 study of VLX1570 in multiple myeloma patients showed that despite some preliminary anti-tumor effects, treatment resulted in severe toxicity in several patients, similar to previous observations after treatment with proteasome inhibitors [ 163 ]. USP14 has also been shown to regulate NFκB via the deubiquitination of IκBα [ 164 ].…”

Induction of ER Stress in Acute Lymphoblastic Leukemia Cells by the Deubiquitinase Inhibitor VLX1570

“…VLX1570 has passed GLP toxicity protocols and entered into clinical studies [45]. In vivo use requires the use of oil/detergents for formulation, leading to complications in the evaluation of toxicology due to species differences in the tolerance to such formulations [46].…”

“…In vivo use requires the use of oil/detergents for formulation, leading to complications in the evaluation of toxicology due to species differences in the tolerance to such formulations [46]. A Phase 1 study using VLX1570 in a PCT formulation (PEG/Chremophore/Tween; polyethylene glycol, polyoxyethylated castor oil and polysorbate 80) encountered pulmonary toxicity [45]. Pulmonary toxicity has, however, been observed also using bortezomib [47], and the PCT formulation enhances this type of toxicity for bortezomib [45].…”

“…A Phase 1 study using VLX1570 in a PCT formulation (PEG/Chremophore/Tween; polyethylene glycol, polyoxyethylated castor oil and polysorbate 80) encountered pulmonary toxicity [45]. Pulmonary toxicity has, however, been observed also using bortezomib [47], and the PCT formulation enhances this type of toxicity for bortezomib [45]. In order to examine toxicity and activity of VLX1570 to ALL cells, we used the zebrafish model.…”

USP14 Regulates DNA Damage Response and Is a Target for Radiosensitization in Non-Small Cell Lung Cancer

“…USP14 has a prominent role in NSCLC and several other cancers [17,18]. The pharmacological inhibitor of USP14, VLV1570, is already in clinical development for multiple myeloma, and it is effective in ovarian cancer [19,20]. Recently, we have identified a novel nuclear role of USP14 as a negative regulator of NHEJ and DDR-associated ubiquitination signaling in autophagy-deficient prostate cancer (PCa) cells [21,22].…”